Ketamine and Esketamine in Clinical Trials: FDA‐Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations

Abstract

Ketamine has a long and very eventful pharmacological history. Its enantiomer, esketamine ((S)‐ketamine), was approved by the US Food and Drug Administration (FDA) and EMA for patients with treatment‐resistant depression (TRD) in 2019. The number of approved indications for ketamine and esketamine continues to increase, as well as the number of clinical trials. This analysis provides a quantitative overview of the use of ketamine and its enantiomers in clinical trials during 2014–2024. A total of 363 trials were manually assessed from clinicaltrial.gov with the search term “Ketamine.” The highest number of trials were found for the FDA‐approved indications: anesthesia (~22%) and pain management (~28%) for ketamine and TRD for esketamine (~29%). Clinical trials on TRD for both ketamine and esketamine also comprised a large proportion of these trials, and interestingly, have reached phase III and phase IV status. Combinatorial treatment of psychiatric disorders and non‐psychiatric conditions with pharmacological and non‐pharmacological combinations (electroconvulsive therapy, psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation) is prevalent. Sub‐anesthetic doses of ketamine may represent novel therapeutic avenues in neuropsychiatric conditions, that is, major depression, schizophrenia, and bipolar disorder, where glutamate excitotoxicity and oxidative stress are likely to be involved. The study suggests that the number of ketamine studies will continue to grow and possible ketamine variants can be approved for treatment of additional indications.

The history of ketamine traces back to 1956 when phencyclidine (PCP, CI‐395) trademarked as Sernyl was first synthesized. PCP was used as a preoperative anesthetic; however, a high rate of side effects instigated the search for similar compounds with less pronounced post‐surgical complications ¹ , ² , ³ , ⁴ , ⁵ (Figure 1 ). The original form of ketamine (CI‐581) was synthesized as a short half‐life derivative of PCP in 1962, and in 1966 ketamine's first human trials demonstrated its efficacy as an analgesic and anesthetic agent that produced a post‐surgical delirium with a much shorter duration ⁶ , ⁷ , ⁸ (Figure 1 ). Along with its approval for anesthetic use by the US Food and Drug Administration (FDA) in 1970, ketamine became popular for recreational use. ⁹ , ¹⁰ , ¹¹ Since then, researchers explored its pharmacokinetics and mechanism of anesthetic and analgesic action for therapeutic purposes. ¹² , ¹³ , ¹⁴ One of the most significant discoveries was ketamine's NMDAR antagonism promoting pain relief and sedation ¹⁵ , ¹⁶ and ketamine was added to the WHOs essential medicines list in 1985 (Figure 1 ). The interest in using ketamine in psychiatry first emerged in the late 1950s and reached a peak in the late 1900s–2000s. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² The 2000s were also significant in the ketamine timeline due to the first application in sub‐anesthetic doses in patients with major depression ²¹ and treatment‐resistant depression (TRD). ²³

Figure 1.

Ketamine and esketamine timeline. Beginning with the synthesis of a new arylcyclohexylamine CI‐395 (Sernyl™) in 1956, now known as phencyclidine (PCP), the timeline indicates each milestone in ketamine research and its implementation to clinical practice as analgesic and anesthetic, up to 2019, the year of intranasal esketamine spray device (Spravato™) was approved by FDA and EMA. Since 2019, clinical trials of another enantiomer, arketamine began. MDD, major depressive disorder; R‐ket, arketamine; S‐ket, esketamine; TRD, treatment‐resistant depression.

Ketamine is a hydrosoluble aryl‐cyclo‐alkylamine racemic mixture that has two enantiomers: esketamine ((S)‐ketamine) and arketamine ((R)‐ketamine) isomer. The (S)‐ketamine was shown to be twice as potent as the racemic mixture and has a fourfold higher affinity for the NMDAR than arketamine. ²⁴ Ketamine is mostly metabolized to norketamine that interacts with glutamate‐dependent ((NMDA and non‐NMDA) receptors) as well as being proposed to act on several glutamate‐independent sites, such as opioid, monoaminergic, cholinergic, nicotinic, and muscarinic receptors. ²⁵ The NMDA receptor antagonism is responsible for amnesic and psychosensory effects, and analgesia. The NMDA receptors are also involved in neuronal tissue physiology and synaptic plasticity; however, in certain circumstances, glutamate gets the status of an “excitotoxin” and causes acute or chronic neurotoxic effects. ²⁶ Being an NMDA receptor antagonist, ketamine has neuroprotective properties by reducing neuronal apoptosis or brain injury induced by hypoxia or brain trauma in animal models. ²⁷ Apart from NMDA antagonism, ketamine might directly inhibit NO‐synthase that could underlie its analgesic and anesthetic effects. ²⁸ Interactions between NMDAR and glutamate‐independent (opioid) sites have been suggested to explain the antihyperalgesic properties of ketamine. ²⁹

In high doses, ketamine produces anesthesia and is suitable for diagnostic and surgical procedures that do not require the application of muscle relaxants. Low‐dose ketamine as a supplement to other anesthetic drugs (general anesthetics, benzodiazepines, and propofol) can prolong their action and reduce the dose of opioids required in postoperative period. ³⁰ , ³¹ The main advantage of ketamine application in anesthesia is its ability to maintain heart rate and cardiac output, increase blood pressure, provide bronchodilation, and preserve pharyngeal and laryngeal reflexes without respiratory depression. ³² In sub‐anesthetic doses, ketamine is used along with opioids to treat cancer pain, particularly breakthrough pain, ³³ chronic pain, including chronic neuropathic pain, phantom and ischemic limb pain, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia, and chronic regional pain syndromes, ³⁴ , ³⁵ and acute perioperative pain. ³⁶

Drug repurposing, that is, exploring novel uses for known drugs, has gained increasing popularity. ³⁷ Modifying the existing formulation to change a dose and/or an administration route is a possible avenue. The intranasal route of administration is interesting for the delivery of drugs in a broad range of therapeutic areas including pain management and CNS disorders. ³⁸ Intranasally administered drugs are rapidly absorbed due to the rich vasculature of nasal cavity and avoidance of the first‐pass effect can lead to a higher bioavailability, promoting a fast onset of action. ³⁹ , ⁴⁰

Since its approval by the FDA in 1970, the pharmacological properties of ketamine and its enantiomers were of great interest. Anesthetic effect of both enantiomers was examined in healthy volunteers suggesting that esketamine was more potent compared with arketamine. ⁴¹ Vollenweider et al. studied psychotic reactions after esketamine and arketamine infusions in healthy volunteers, including depersonalization and hallucinations. Metabolic changes in the brain after esketamine appeared to be similar to an acute psychotic episode in schizophrenia, whereas arketamine produced no psychotic symptoms but relaxation. The authors suggested arketamine may cause minimal or no acute side effects compared with the (S)‐enantiomer of ketamine. ⁴² The results of a multicenter trial of esketamine in nasal spray form showed a robust antidepressant effect in patients with TRD ⁴³ and major depressive disorder with imminent risk for suicide. ⁴⁴ The growing need for new antidepressant compounds resulted in a number of clinical studies on esketamine while the arketamine remained at the level of nonclinical studies. However, preclinical findings showed it is likely that the (R)‐enantiomer of ketamine contributes to the long‐lasting antidepressant effects of racemic ketamine rather than the esketamine. ⁴⁵ , ⁴⁶ , ⁴⁷ The first clinical study of arketamine in TRD patients was conducted in 2020. ⁴⁸ , ⁴⁹ Previous clinical studies of arketamine were aimed at studying its analgesic properties ⁵⁰ , ⁵¹ , ⁵² and metabolic features comparing those to (S)‐enantiomer or the racemic ketamine. ⁴² , ⁵³ Although only two of five phase III trials showed positive results for esketamine, on March 5, 2019, esketamine nasal spray (Spravato®) got approval by the FDA for TRD in conjunction with an oral antidepressant. ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ In December, 2019, the European Medicines Agency (EMA) approved Spravato® in combination with selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) for patients with TRD.

Recent reviews on ketamine in clinical trials have described its use mostly in chronic pain management ⁵⁹ and in psychiatric disorders. ⁶⁰ , ⁶¹ , ⁶² A systematic review and meta‐analysis by Orhurhu et al. offers an overview of seven randomized controlled trials consisting of 211 patients receiving intravenous (IV) ketamine infusions for pain relief in chronic conditions. ⁵⁹ It was concluded that IV ketamine provides short‐term and most likely dose‐related analgesic effect in patients with refractory chronic pain. However, protocol dose‐finding studies are further needed for optimal dosage in neuropathic and other types of chronic pain.

A more recent systematic review covers subcutaneous and intravenous ketamine use in patients with refractory anxiety with and without depression. ⁶² These authors highlighted the transient nature of anxiolytic and antidepressant effects produced by ketamine, hence illustrating the need for more detailed pharmacological studies. In 2023, several studies focused on ketamine and esketamine use in MDD ⁶⁰ and TRD. ⁶¹ Nikolin et al. suggested that the antidepressant effect expressed in response and remission rates produced by racemic ketamine was higher than that of esketamine in major depression patients. Research in the area of comparing effectiveness of ketamine and esketamine is however scarce, so more studies are needed to clarify this important topic. Systematic review by Brendle et al. ⁶² aimed at characterizing registered trials of ketamine and esketamine for TRD regarding study design and general data rather than effectiveness to one of them. The findings showed the growing number of large‐scale and late‐phase centralized trials of esketamine over ketamine. As can be seen, most of the recent studies focus on particular aspects of ketamine and esketamine use in clinical practice. To the best of our knowledge, there is no current extensive analysis of the effectiveness of ketamine and esketamine in clinical trials.

In this study, we provide a comprehensive analysis of clinical trials focused on ketamine, esketamine and (R)arketamine starting from 2014 to 2024. We aimed to investigate the general trends of ketamine and its enantiomers' use in clinical research, the diversity of conditions, novel applications with different dosage and administration routes, and therapies indications that seem to be gaining attention.

MATERIALS AND METHODS

All trials included in this article were retrieved from one of the largest web‐based resources of clinical trials at the NIH clinicaltrials.gov. This data source has been used for several of our previous large analyses. ⁶³ , ⁶⁴ , ⁶⁵ Information about NCT number, title, status, phase, conditions, interventions, sex, age, enrollment, design, study type, study start year, and the primary completion date was collected for each analyzed clinical trial. We used the term “Ketamine” in the “Intervention/treatment” field. The studies were analyzed from the year 2014–2024. There were no criteria for inclusion/exclusion regarding the gender and age of participants or trial status. Overall, the dataset consisted of 363 clinical trials. Data filtering was carried out manually trial by trial. Some trials had incorrectly/ambiguously assigned phases, thus requiring correction. If a study had a double phase (e.g., phase I|phase II), we took an earlier one since it is not clear whether a trial has successfully transitioned to the next phase. If the phase was categorized as “Early phase I” we classified it as phase I. To check the FDA‐approved indications for ketamine and esketamine, we used https://www.fda.gov/drugs and Approved Drug Products with Therapeutic Equivalence Evaluations (https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm). To check EMA‐approved indications for ketamine and esketamine, we used https://www.ema.europa.eu/en.

RESULTS

Dataset overview

Overall, we identified 363 clinical trials. Out of these 363 trials, 314 were interventional, 48 were observational, and one clinical trial had expanded access. Results were available in 59 clinical trials. At first, the studies were divided according to the phase (Figure 2 a ). Most of the clinical trials were in phase IV (107, 29.5%). At the same time, 11% of the total sample of studies was found in phase II, and the number of trials in phase III was 13.5%. For observational trials and a trial with expanded access study status was not stated (49; 13.5%). The study status of 82 interventional studies (22.6%) was marked as not applicable.

Figure 2.

Phases of the trials (a), study status (b), sex (c) and age groups (d). This figure provides a graphical representation of the phases, study status, sex, and age distribution of all trials (from 2014 to 2024). Out of 363 trials, 314 were interventional, 48 were observational, and one clinical trial had expanded access (providing access to a medical product that has not been approved by the FDA). In our analysis, a pre‐approval access program (PAAP) to provide access to esketamine nasal spray was available for eligible participants with severe TRD (NCT03829579). Results were available in 59 clinical trials. Almost a third of trials were phase IV (107, ~30%), and about 10% of studies had phase I status (36). More than 40% of clinical trials were completed (158).

We then analyzed the study status for all the 363 trials (Figure 2 b ). Almost half of those trials were completed (158; ~44%), 29 (8%) were terminated early, 108 (29.6%) were ongoing: 35 (10%) were active but not yet recruiting, and 73 (20.2%) had recruitment status. One trial (NCT03829579) of expanded access type provided access to esketamine nasal spray to an eligible participant with TRD who underwent all other treatment options including alternative ones and who cannot participate in a clinical trial to gain access to it.

Figure 2 c,d presents the sex and age distribution. 26 (7%) of the clinical trials studied ketamine as an anesthetic and multimodal analgesic in female patients undergoing hysterectomy, cesarian section, postpartum pain, abortions, minor gynecologic surgeries, oocyte retrieval, surgical treatment of breast cancer (mastectomy, lumpectomy, tumorectomy) and associated postoperative pain, unilateral total knee arthroplasty, and plastic surgeries (including rhytidoplasty). Four studies included male participants with Duchenne muscular dystrophy receiving sedation for a muscle biopsy, bronchospasm requiring mechanical ventilation, predisposition to substance use disorders, and patients undergoing herniorrhaphy surgery. A large majority of all the 363 trials studied adult populations (355), and only 37 clinical trials enrolled children as participants.

Ketamine, esketamine, and arketamine use in clinical trials

According to the FDA, ketamine is approved only as a general anesthetic either on its own or in combination with other medications by intravenous or intramuscular administration (Figures 3 and 4 ). The EMA approves ketamine use in acute pain treatment when co‐administered with opioid analgesic Sufentanil in an intranasal form. Its robust analgesic effect in sub‐anesthetic doses and little impact on the respiratory system compared with opioids were determined empirically, and thus, initiated its use as multimodal analgesic in the perioperative period and intensive care unit (Figure 5 ). esketamine is an FDA‐ and an EMA‐approved intranasal form for adults with TRD and MDD with suicidal thoughts in combination with SSRIs or SNRIs (Figures 3 and 4 ). According to the EMA assessment report, esketamine is approved for induction and maintenance of anesthesia via intravenous or intramuscular administration in several European Union (EU) countries. However, off‐label indications comprise acute and chronic pain, including cancer breakthrough pain, postoperative complications (postoperative pain, cognitive impairment), other psychiatric disorders (post‐traumatic stress disorder (PTSD), anxiety, bipolar disorder of both types, obsessive‐compulsive disorder (OCD), suicidal ideation), epilepsy, migraine for both ketamine and esketamine and depressive disorders for ketamine. One trial observed the safety and tolerability of arketamine in patients with TRD (NCT06232291).

Figure 3.

Conditions and indications for ketamine use (blue), esketamine use (green), and sublingual racemic ketamine wafer (Wafermine™) use (red) in clinical trials. FDA‐approved conditions for ketamine and esketamine are marked as yellow asterisk. EMA‐approved indications include anesthesia and analgesia for ketamine, induction/maintenance for anesthesia, and TRD for esketamine. The highest number of trials with ketamine was in patients with postoperative pain (73), chronic pain (46), and sedation during surgical interventions (50). esketamine was predominantly used for treating depression (17 trials); however, conditions for esketamine use also included postoperative pain management (11) and analgesia (9). Sublingual racemic ketamine wafer (Wafermine™) was implemented in patients who experience postoperative pain. “Anesthesia” and “analgesia” were related to intraoperative period. Pain management in the emergency department and prehospital care was considered “acute pain.” Postoperative pain complications were subsequently marked as “postoperative pain.” Use of ketamine as an anti‐inflammatory agent included its inhibitory effect on the synthesis of interleukin 6 (IL‐6) and tumor necrosis factor‐alpha (TNFα) for preventing perioperative inflammatory complications and in COVID‐19 infection. Postoperative neurological impairment included delirium and cognitive dysfunction. We considered separating “depression” from other “psychiatric disorders” groups that comprised bipolar disorder, PTSD, OCD, suicidal ideation, anxiety, etc. to highlight the use of ketamine and its forms in terms of FDA‐approved indications. Other postoperative complications consisted of postoperative nausea and vomiting (PONV), sore throat, and acute kidney injury. Among the trials of the “pharmacology” group, there were those evaluating the pharmacokinetics of ketamine/esketamine and possible mechanisms of its adverse effects (see “Pharmacological studies of ketamine and (S)‐ketamine” in the text). Trials that studied personality traits and predisposition to drug abuse (including ketamine abuse) were marked as “psychology.”

Figure 4.

Administration routes of ketamine (blue), esketamine (green), and sublingual racemic ketamine wafer (Wafermine™) (red) in clinical trials. FDA‐approved administration routes for ketamine and esketamine are marked as yellow asterisk. Ketamine is approved by EMA for intranasal administration in patients with acute pain co‐administered with opioid analgesic Sufentanil; esketamine is approved by EMA in intravenous and intramuscular administration forms for anesthetic purposes, inhalational powder for MDD and bipolar depression treatment, gel for intratympanic injection in acute inner ear tinnitus. The leading administration route for both ketamine and esketamine was intravenous: 228 (~72%) and 36 (~68%), respectively. Although esketamine is FDA‐approved only for intranasal route, it was also administered in intravenous (36) and epidural (1) routes. In 11 trials, ketamine was administered per os. In a few trials, ketamine was used in topical forms, that is, gels, creams, and mouthwash (7), transmucosal injections (1), spinal injections (1), epidural injections (1), interfascial injections as a part of erector spinae plane block (1), intrabursal injections in subacromial space (1), subcutaneous injections (5) and mesotherapy (1) in intra‐epidermal and superficial intradermal injections. Racemic ketamine wafer (Wafermine™) was administered in sublingual form. “In vitro” mark referred to a patient‐derived model of induced pluripotent stem cells (iPSCs) obtained from ketamine‐responsive and nonresponsive patients with TRD. A total of 35 trials did not contain information on ketamine administration route.

Figure 5.

Doses of ketamine (a) and esketamine (b) used in clinical trials. Sub‐anesthetic doses for ketamine were the following: below 0.5 mg/kg IV, below 1 mg/kg IM and IN, below 0.15 mg/kg SQ, below 0.5 mg/kg PO. Sub‐anesthetic doses for esketamine were below 0.5 mg/kg IV. Doses above these numbers were marked as anesthetic. In 9 out of 11 trials with intranasal esketamine its dosing was according to esketamine nasal spray (Spravato™) instructions; in other trials, the dosed were 6 mg and 0.2 mg/kg in patients with postoperative pain and perioperative sleep disturbances respectively. Sublingual racemic ketamine (Wafermine™) was given in a sublingual wafer of 35 or 70 mg (IM, intramuscular; IN, intranasal; IV, intravenous; PO, oral; SQ, subcutaneous).

Ketamine use in perioperative period

Ketamine is widely used in perioperative period for anesthetic and antihyperalgesic purposes. The pathophysiology of the latter is closely associated with pro‐inflammatory agents and the various pathways they activate. A phase III study (NCT03513822) was focused on kynurenine pathway that is considered to cause hyperalgesia. Kynurenine synthesis is enhanced when pro‐inflammatory cytokines are present: these compounds activate tryptophan metabolism into kynurenine. The metabolites of kynurenine pathway, particularly quinolinic acid, are thought to promote hyperalgesia in animal models which may reflect the mechanisms of opioid‐induced hyperalgesia (secondary hyperalgesia) in postoperative period in patient‐controlled analgesia (PCA). ⁶⁶ , ⁶⁷ The use of ketamine in perioperative pain management is often suggested to be feasible. Previous studies have shown that ketamine inhibited the synthesis of interleukin 6 (IL‐6) in vitro ⁶⁸ , ⁶⁹ and in vivo in surgical patients. ⁷⁰ , ⁷¹ KITS trial (NCT00504725) and a parallel phase IV study (NCT00978757) took these anti‐inflammatory effects as a basis and administered ketamine to the patients undergoing lobectomy and hepatic resection.

Ketamine has beneficial effects in neurosurgical and cardiological patients due to its neuroprotective properties. ⁷² , ⁷³ Ketamine ability to antagonize glutamate‐mediated excitotoxicity and inflammation may offer protection from cellular mechanisms of neuronal death during cardiopulmonary resuscitation (CPR) in cardiac arrest (NCT04360070, NCT04009759) and stroke (NCT03223220) with minimal influence on hemodynamic status in therapeutic doses. In patients with traumatic brain injury, ketamine combined with midazolam was not associated with increased intracranial pressure or decreased cerebral perfusion pressure. Early studies have also shown the reduced production of pro‐inflammatory cytokines and immune response after ketamine administration in patients undergoing cardiac surgery with extracorporeal circulation (ECC). ⁷⁴ , ⁷⁵

Certain trials aimed at investigating the effects of ketamine in ICUs, that is, duration of mechanical ventilation, total opioid consumption, hemodynamic changes in mechanically ventilated acute respiratory distress syndrome (ARDS) patients, and elimination of sleep disturbances in the perioperative period. Ketamine alone or in combination with other sedatives has appeared as an option for procedural sedation: it successfully attenuates propofol‐induced hypotension, so it may be advantageous for traumatic injuries, hypovolemia or sepsis. ⁷⁶ Moreover, ketamine is suitable for intubation due to its pharmacokinetic properties: quick onset (< 60 seconds), short duration (~10 minutes), and minimal impact on the cardiovascular system. Thus, in several trials, ketamine was a drug of choice for rapid sequence intubation (RSI) (NCT03545503, NCT00440102, NCT06179485, NCT04291521).

Anti‐inflammatory effects of ketamine and their role in depression

Advances in psychoneuroimmunology research led to the growing number of reports on the relationship between inflammation and depressive disorders. Activated inflammatory mediators induce depressive symptoms through a direct effect on the brain tissue, modulation of the serotonergic system, and initiation of neurodegenerative processes. High inflammation levels increase the risk of developing MDD and bipolar disorder and vice versa. ⁷⁷ , ⁷⁸ , ⁷⁹ Evidence suggests the presence of active immune response and increased neutrophils and monocytes as well as increased levels of inflammatory biomarkers (cytokines and C‐reactive protein (CRP)) in a significant proportion of depressed patients. ⁸⁰ , ⁸¹ Effective antidepressant medications have been shown to restore this neuroimmune association. ⁸²

The above‐mentioned tryptophan (TRP)–kynurenine (KYN) pathway has been suggested to be one of the links between inflammation and depression: pro‐inflammatory cytokines activate TRP transformation into KYN instead of serotonin. ⁸³ Its metabolite kynurenic acid (KYNA) contributes to neurotoxicity and can further exacerbate inflammation.

TRD is defined as a failure to respond to at least two antidepressants from different pharmacological classes after adequate treatment duration. ⁸⁴ , ⁸⁵ Inflammatory biomarkers like tumor necrosis factor (TNF)‐α R1 and CRP are related to resistance. TNF‐α R1 levels were significantly higher in patients with TRD compared with those without resistance ⁸⁶ ; patients resistant to conventional antidepressant therapy had increased CRP level. ⁸⁷ Thus, patients with increased levels of inflammatory markers tend to be less responsive to antidepressant medications. A recent systematic review concluded that treatment‐resistant patients with higher inflammation have better response to medication with anti‐inflammatory properties including ketamine. ⁸⁸

Esketamine and arketamine in treatment‐resistant depression

Esketamine, the (S)‐enantiomer of ketamine, was approved by the FDA and EMA for TRD in 2019 and is supposed to enhance the effects of serotonin selective or SNRIs. ⁸⁹ Patients with TRD received esketamine nasal spray as an “intervention” in eight trials of 56 that used ketamine and its enantiomers in different forms in patients with depression. TRANSFORM‐3, a phase III double‐blind trial (NCT02422186) studied 138 patients older adults with TRD who received flexible doses of esketamine (28, 56 or 84 mg). In SUSTAIN‐2 (NCT02497287) and SUSTAIN‐3 (NCT02782104) trials participants self‐administered esketamine nasal spray and combined it with an oral antidepressant: Duloxetine, Escitalopram, Sertraline, or Venlafaxine with extended release. In a retrospective case series (NCT04856124), 10 patients were treated with intravenous racemic ketamine and those with clinical improvement were then prescribed intranasal esketamine for maintenance therapy. Other trials suggested a combination of esketamine with nonselective monoamine oxidase inhibitors (MAOIs) (NCT05530668), computer‐based self‐help program as add‐on therapy to esketamine (NCT04843462), or a monotherapy of intranasal esketamine (NCT04599855).

Arketamine, the (R)‐enantiomer of ketamine, is gaining interest in preclinical studies: results show that arketamine may have greater potency and longer‐lasting antidepressant‐like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDA receptors. ⁴⁴ , ⁴⁵ , ⁴⁶ Moreover, adverse effects, that is, psychotomimetic, dissociative effects, and abuse liability, of arketamine were less pronounced in nonclinical studies which can be extrapolated to humans and compared with those of ketamine and esketamine. Among 363 clinical trials that we have analyzed, only one trial focused on the use of arketamine in patients with TRD (NCT06232291).

Ketamine in chronic pain management

Ketamine is increasingly used in chronic pain due to its ability to regulate the “wind‐up” effect, a phenomenon involved in the central hypersensitization that is inevitably present in neuropathic pain of prolonged duration. Being a drug of choice for opioid‐induced hyperalgesia, ketamine is thought to adjunct or even replace opioid treatment in systemic diseases, for example, sickle cell disease (SCD). ⁹⁰ , ⁹¹ It often results in acute vaso‐occlusive crisis (VOC) characterized by an obstruction of blood vessels resulting in ischemic injury and acute pain. A large pool of patients with SCD report continued pain despite treatment with opioids. New drugs are being tested to prevent and treat acute pain associated with SCD and ketamine is of special interest in clinical trials as well (NCT03502421, NCT04330183, NCT00595530).

Another rare condition of possible ketamine application is Gulf War Illness (GWI). Due to exposure to insecticides (e.g., organophosphates, DEET, permethrin), pills with the anti‐nerve gas agent pyridostigmine bromide (PB), and low‐level chemical nerve agents Gulf War veterans suffer from chronic pain, cognitive impairment, debilitating fatigue, gastrointestinal complications, and other persistent symptoms. Animal models have shown that used neurotoxicants (insecticides, nerve agents) could induce neuroinflammation which is marked by enhanced inflammatory cytokines, and activated microglia and astrocytes. ⁹² Secondary effects of neuroinflammation and glia activation could be excessive glutamate‐mediated neuronal activation. Although recent studies on animal GWI models show promising results on reduced anxiety‐like behavior, anhedonia, and rapid onset antidepressant effect, ⁹³ , ⁹⁴ its sub‐anesthetic dose could be an anti‐inflammatory agent and protect microglia and astrocytes from being activated by inflammatory agents (NCT04712071).

Sub‐anesthetic ketamine administration has been suggested to be useful in the treatment of other pain disorders such as complex regional pain syndrome (CRPS), fibromyalgia, and chronic daily headaches (chronic migraine and tension‐type headache). The latter is characterized by the presence of a headache for 15 days or more per month for at least 3 months. ⁹⁵ Several articles report the of sub‐anesthetic ketamine in patients with refractory chronic headache disorders—the majority of participants were discharged with 2‐ to 7‐point improvement in headache pain. ⁹⁶ , ⁹⁷ , ⁹⁸ The KetHead multicenter, placebo‐controlled, randomized controlled trial examined high‐dose (1 mg/kg) intravenous ketamine administration in patients with chronic daily headaches (NCT05306899). Another trial was targeted a refractory chronic migraine but ketamine was chosen in sub‐anesthetic dose (NCT03896256).

Pharmacological studies of ketamine and esketamine

Among the 15 trials of “pharmacological studies” group in Figure 3 , there were those evaluating the pharmacokinetics of ketamine and possible mechanisms of its adverse effects. Specifically, bladder dysfunction, dissociative state, neuropsychiatric effects, oscillations in EEG after ketamine injection, safety and tolerability, medication interactions, QT distance during anesthesia, impact on intracranial pressure, psychological sequelae were explored to improve therapeutic strategies and minimize unwanted effects.

Research using animal models has provided insights into the neural mechanisms underlying psychiatric disorders, but how precisely these findings can be extrapolated to humans remains difficult to assess. The development of induced pluripotent stem cell (iPSCs) technology offers a new approach to address the genetic complexity issue in psychiatric disorder research. This method has already been used to study bipolar disorder and schizophrenia, ⁹⁹ , ¹⁰⁰ Rett syndrome, ¹⁰¹ SSRI‐resistant major depressive disorder. ¹⁰² One clinical trial (NCT05887310) used an induced pluripotent stem cell (iPSC) model with cells obtained from ketamine‐responsive and nonresponsive TRD patients to unravel its antidepressant mechanisms of action.

Combination treatment

Along with pharmacological studies, 22 clinical trials investigated combinations of ketamine with non‐pharmacological treatment (Figure 6 ). Particularly, electroconvulsive therapy, different psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation were used as ketamine adjuvants in treatment‐resistant and major depression, suicidal ideation, anxiety, PTSD, chronic neuropathic, and postoperative pain.

Figure 6.

Pharmacological and non‐pharmacological combinations of ketamine (a) and esketamine (b). Sublingual racemic ketamine wafer (Wafermine™) was given in combination with oxycodone (opioid analgesic) in patients with postoperative pain complications. And 21 clinical trials investigated combinations of ketamine with non‐pharmacological treatment, including electroconvulsive therapy (9), psychotherapeutic techniques (10), that is, cognitive behavioral therapy, music therapy, acutherapy, existential psychotherapy, ketamine‐assisted psychotherapy, interpersonal psychotherapy, guided imagery psychotherapy, virtual reality (1), and transcranial magnetic stimulation (1). These ketamine adjuvants were used in patients with treatment‐resistant and major depression, suicidal ideation, anxiety, PTSD, chronic neuropathic and postoperative pain. Esketamine was used in the combinatorial treatment of treatment‐resistant and major depression with virtual reality (1) and psychotherapy: pretreatment and post‐treatment follow‐up sessions (1) and computer‐based self‐help program that combined cognitive behavioral therapy, psychoeducation, and mood tracking (1).

Electroconvulsive therapy (ECT) has long been applied in TRD due to rapid antidepressant effects after a few sessions. Using ketamine as the primary anesthetic during ECT is thought to be more effective due to faster depression remission compared with propofol—traditional anesthetic agent used in general anesthesia (GA) for ECT. However, previous studies showed controversial results regarding ketamine use in ECT; some studies have shown it to have synergistic antidepressant effects and improve cognitive outcomes, ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ while others claim no significant effect. ¹⁰⁶ , ¹⁰⁷ The results of the above‐mentioned prospective randomized double‐blinded control trial (NCT01935115) suggest that ketamine‐based anesthesia provides a better response and remission after fewer ECT sessions compared with propofol‐based anesthesia. ¹⁰⁸ Another trial (NCT01567852) compared ketamine and methohexital anesthesia for ECT since they were the focus of previous studies. ¹⁰⁹ , ¹¹⁰ Re‐orientation time, that is, state of confusion after GA scored based on questions about name, age, year, and day of the week and location that should be the same as baseline, was longer in ketamine group compared with methohexital group (24.5 minutes vs. 19.5 minutes, respectively). Recovery time and incidence of adverse events was almost equal; however, patients who received ketamine experienced dysphoria more frequently than those in methohexital group.

DISCUSSION

This analysis provides quantitative data on the use of ketamine, esketamine, and arketamine in clinical trials in children, adults, and older adults, covering 363 studies from the year 2014 to 2024. Overall, we see that the highest number of trials covers FDA and EMA‐approved indications for ketamine (anesthesia and analgesia) and esketamine (depression). However, trials on off‐label indications for both substances also comprised a large proportion, and interestingly, reached phase III and phase IV status (Figure 2 and 3 ). Great attention is given to combinatorial treatment for different conditions that suppose not only pharmacological combinations, but also non‐pharmacological methods, that is, electroconvulsive therapy, psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation (Figure 6 ).

Out of the 49 clinical trials with phase III status (13.5%) and 107 clinical trials that have reached phase IV status (29.5%), there were those using ketamine and esketamine for depressive disorders (Figure 2 a ). Particularly, four phase III trials (1.1%) and nine phase IV (2.5%) trials described the use of ketamine in patients with TRD (4) and major depression (9), including cases with suicidal ideation (3), in spite of the fact that these indications are not FDA and EMA‐approved conditions for the use of ketamine. Esketamine was used in three phase III and two phase IV trials which referred to TRD as its FDA and EMA‐approved indication, but also in phase IV studies on prenatal and postpartum depression (2). Sublingual racemic ketamine (Wafermine™) clinical trial is currently in phase II and aims at managing acute postoperative pain following bunionectomy surgery (NCT02541396). According to iX Biopharma Ltd, further trials of Wafermine™ will be focused on its safety and efficacy in patients with CRPS.

The highest number of trials with racemic ketamine was in patients with postoperative pain, chronic pain, and sedation during surgical interventions (Figure 3 ). Adding up all indications referring to pain management (analgesia, postoperative pain, acute pain, chronic pain), the total number will comprise more than a third of all indications for ketamine. The use of ketamine for anesthetic purposes (anesthesia, sedation) also forms a large proportion of its overall indications. It is important to mention that sub‐anesthetic doses of ketamine and esketamine were used not only as a multimodal analgesic, but also as an adjuvant to other anesthetics. Moreover, we also see a number of indications that are not FDA‐approved but still reaching a quite considerable portion of the trials, such as inflammation, postoperative neurological and other complications, depression, and other psychiatric disorders.

The leading administration route for both ketamine and esketamine was intravenous: 228 (~72%) and 36 (~68%), respectively (Figure 4 ). Intranasal administration route is FDA and EMA‐approved for esketamine; however, this form of (S)‐ketamine was presented in a lesser number of studies compared with intravenous esketamine (16 or 30% vs. 36 or ~68%). Besides, there is a number of ongoing trials where ketamine was used in intranasal, oral, sublingual, intramuscular, topical (gels, creams, and mouthwash), subcutaneous, transmucosal, spinal, epidural, interfascial, intrabursal injections, and by mesotherapy. Apart from the intravenous and intranasal administration route, esketamine was tested during epidural anesthesia. Racemic ketamine wafer (Wafermine™) was administered in sublingual form. As can be seen from Figure 5 , esketamine is commonly used in anesthetic dosees while ketamine is given most often in sub‐anesthetic doses in intravenous, intramuscular, intranasal, subcutaneous, and oral forms.

Arketamine, the (R)‐enantiomer of ketamine, is gaining interest as a possibly more potent antidepressant compared with esketamine and racemic ketamine. The results of preclinical studies demonstrate that arketamine has a longer‐lasting antidepressant‐like effect in rodents. ¹¹¹ , ¹¹² , ¹¹³ The first open‐label study of arketamine in TRD patients was conducted by Leal et al. ⁴⁸ After a single intravenous infusion of arketamine (0.5 mg/kg) patients demonstrated rapid and sustained antidepressant effects with low psychotomimetic and dissociative symptoms. Due to certain limitations following open‐label design, authors conducted a double‐blind, placebo‐controlled clinical trial with a sample size of 10 participants. ⁴⁹ Findings did not suggest the efficacy of arketamine as compared with placebo in TRD patients due to a carryover effect meanwhile demonstrating its safety. Among 363 trials included in our analysis, there was one trial observing the safety and tolerability of arketamine in patients with drug‐resistant depression (NCT06232291). Further clinical trials with larger experimental and control groups are needed.

Intravenous administration of sub‐anesthetic doses of ketamine in patients with TRD showed better performance compared with benzodiazepines: the frequency of cardiac, gastrointestinal, sleep complications, ear complaints, and sexual dysfunction was on average twofold less in ketamine (NCT02556606). In the KARMA‐dep study (NCT03256162), ketamine group demonstrated significant improvement in the Hamilton Rating Scale for The Depression‐24 Item Version (HRSD‐24) showed a score of 28.4 before treatment vs. a mean score of 11.2 after four once‐weekly infusions of ketamine at 0.05 mg/kg; for midazolam, the initial and final HRSD‐24 scores were 27.4 and 16.6, respectively. This was consistent with remission criteria of ≥ 60% decrease in HRSD from baseline. One trial (NCT01887990) compared the effectiveness of ketamine alone and in combination with opioids in patients with suicidal ideation: the Beck Scale for Suicidal Ideation showed almost triple ketamine superiority over opioids (7.3 vs. 18.0 mean scores); however, the Montgomery‐Åsberg Depression Rating Scale (MADRS) results were the opposite (43.9 vs. 22.5 mean scores for ketamine and ketamine + opioids, respectively). Ketamine groups also showed no suicidal attempts which can be considered desirable therapeutic effect in subjects with suicidal ideation. However, in KEEP‐WELL study it caused dissociative symptoms in patients who successfully underwent electroconvulsive therapy and were referred to ketamine infusions to prevent depression relapse (NCT02414932).

Among the 62 clinical trials with posted results, three studies (SUSTAIN‐2, SUSTAIN‐3, TRANSFORM‐3) evaluated the safety and efficacy of self‐administered esketamine nasal spray in combination with an oral antidepressant (Duloxetine, Escitalopram, Sertraline, or Venlafaxine with extended release). Common treatment‐emergent adverse events (≥ 20%) were headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis. ⁵⁶ , ¹¹⁴ , ¹¹⁵ In SUSTAIN studies (NCT02497287, NCT02782104) mean MADRS total score decreased during the induction phase and this reduction persisted during optimization/maintenance phases. ¹¹⁴ And 35.6% and 46.1% of participants were in remission (MADRS total score ≤ 12) at the induction phase and optimization/maintenance phases, respectively. Cognitive tests did not show clinically significant differences between the age groups. ¹¹⁵ In TRANSFORM‐3 (NCT02422186), a higher percentage of patients in esketamine group achieved both clinical response (23.6%) and remission (15.3%) compared with control group (12.3% and 6.2%, respectively). ⁵⁶

Anti‐inflammatory properties of ketamine may underlie its antidepressant and analgesic effects. Recent advances in psychoneuroimmunology shed light on an inflammatory hypothesis that is gaining evidence supplementing monoamine and other theories: neuroinflammation induced by reactive oxygen species (ROS), pro‐inflammatory cytokines, and other active substances is suggested to promote depression. ¹¹⁶ , ¹¹⁷ , ¹¹⁸ Kynurenine pathway is thought to be a link between inflammation and depression: pro‐inflammatory cytokines activate tryptophan transformation into kynurenine instead of serotonin. ⁸³ In reactive astrocytes and microglia, transcription of kynurenine pathway enzymes, especially IDO1, is enhanced by pro‐inflammatory substances (IL‐1β, LPS, and TNF‐α) in an NF‐κB‐dependent manner. ¹¹⁹ Ketamine promotes inhibition of NF‐κB resulting in upregulation of excitatory amino acid transporter 2 (EAAT2) and producing a potent anti‐inflammatory effect. ¹²⁰ Thus, down‐regulating pro‐inflammatory kynurenine metabolites and upregulating glutamate reuptake via EAAT2, ketamine exhibits a dual protective mechanism against neuroexcitotoxicity. It is also noteworthy that the upregulation of EAAT2 not only facilitates the reuptake of glutamate from synaptic clefts but also indirectly strengthens the anti‐oxidative capacity within the synapse. This is enabled by the system of xc‐ transporter responsible for the exchange of intracellular glutamate for extracellular cysteine in astrocytes. ¹²¹ Ketamine thereby restores neurotransmitter equilibrium and produces an anti‐oxidative effect. Some studies revealed esketamine may produce an anti‐oxidative effect as well via Nuclear factor erythroid 2‐related factor 2 (Nrf2): Nrf2 enhances xc⁻ a system by upregulating superoxide dismutase (SOD) and glutathione peroxidase (GPX); the latter regulates cysteine availability for GSH synthesis. ¹²² , ¹²³ , ¹²⁴

As can be seen, sub‐anesthetic doses of ketamine may have a therapeutic potential in neurological conditions where glutamate excitotoxicity and oxidative stress have been involved. Particularly, the relationship between KYN‐induced glutamate damage and chronic neuropathic pain has been explored in animal models. ¹²⁵ , ¹²⁶ We have found that in a few clinical trials ketamine was chosen for chronic neuropathic pain management (NCT03513822) and neuroprotective purpose during cardiac surgery (NCT02782429) due to its anti‐inflammatory profile. Besides, neuroinflammation underlying such psychiatric disorders as MDD, schizophrenia, and bipolar disorder is also thought to be linked to glutamatergic dysfunction and oxidative stress. ⁷⁷ , ⁷⁸ , ⁷⁹ , ¹²⁷ Furthermore, the potential applications of ketamine may include the above‐mentioned conditions and substance use disorders, where neurochemical imbalances and oxidative stress are also prevalent. The ability of ketamine to restore neurotransmitter equilibrium and promote cellular resilience might offer new avenues for managing addiction and reducing relapse rates. ¹²⁸ , ¹²⁹ , ¹³⁰ , ¹³¹

In conclusion, ketamine and its enantiomers are receiving great attention for new indications beyond the initial ones. Novel indications include TRD and MDD complicated by suicidal ideation that are targets for not only FDA‐approved esketamine, but also arketamine, proven its effectiveness in animal models and currently being used in clinical studies. Apart from depression, acute and chronic pain management and anesthesia are the three groups (indications represented in Figure 3 ) with a rapidly growing number of trials. Moreover, new form of racemic ketamine with a promising sublingual administration route has completed phase II and is in the advanced planning stage. Besides, a special role is assigned to combinatorial treatment of psychiatric disorders and non‐psychiatric conditions with both pharmacological and non‐pharmacological combinations (electroconvulsive therapy, psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation). Ongoing pharmacological studies of ketamine and its enantiomers may reveal previously unknown molecular and cellular mechanisms of action and provide a basis for broadening ketamine's application in neurological and neuropsychiatric conditions. We suggest that it is likely that the number of ketamine studies will continue to grow and perhaps address not only psychiatry and anesthesiology indications but also unique indications reflecting the molecular mechanism of action of ketamine.

CONFLICT OF INTEREST

The authors declared no competing interests in this work.

FUNDING

No funding was received for this work.