INTRODUCTION

Ketamine, a dissociative anaesthetic, is extensively used in trauma and emergency medicine for its rapid analgesic and sedative effects [1]. Since its introduction in 1970, it has been employed in both civilian and military trauma care as an anaesthetic with dissociative and analgesic properties, valued for its rapid onset, hemodynamic stability, and minimal respiratory depression, while preserving airway reflexes [2].

Ketamine's role in trauma care has expanded, particularly in battlefield medicine, where traditional analgesics such as intramuscular morphine presented risks of delayed onset, respiratory depression, and overdose, which are amplified as risks in resource-limited settings. In response, tactical combat casualty care adopted the triple-option analgesia approach, designating ketamine as the preferred analgesic for severely injured patients, especially those in haemorrhagic shock or respiratory distress [3].

Despite its advantages, ketamine’s long-term psychological impact remains debated, particularly regarding posttraumatic stress disorder (PTSD). The neurobiological effects of ketamine on PTSD are multifaceted, involving modulation of N-methyl-D-aspartate (NMDA) receptors, neuroinflammatory pathways, and synaptic plasticity. Some research suggests that peritraumatic ketamine administration may lower PTSD risk by disrupting maladaptive fear memories, attenuating maladaptive fear responses, and enhancing emotional regulation—particularly in patients without traumatic brain injury (TBI). In contrast, other studies indicate that immediate post-trauma ketamine use may strengthen distressing memory consolidation, heighten hyperarousal, and exacerbate PTSD symptoms in certain individuals [4]. Moreover, evidence suggests that ketamine’s psychological effects vary considerably between individuals, influenced by factors such as timing, dosage, and underlying neurobiological mechanisms.

Acknowledging the conflicting evidence, a systematic review is essential to determine whether ketamine’s effects on PTSD are predominantly neuroprotective or maladaptive, thereby guiding evidence-based clinical practice. This review synthesizes clinical and preclinical research to assess ketamine’s role in PTSD risk, memory processing, neuroinflammation, and psychiatric outcomes. Its aim is to clarify whether ketamine mitigates or aggravates PTSD and to inform clinical guidelines for its safe use in trauma settings. Understanding ketamine’s long-term psychological effects will be critical in optimizing its application for both acute trauma management and long-term mental health outcomes.

METHODS

This review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure transparency and reproducibility in study selection and data synthesis. A structured search strategy was applied across PubMed, Embase, and Scopus to identify studies examining the role of ketamine in PTSD prevention and risk modulation. The following search terms were used to identify relevant studies on ketamine’s impact on PTSD symptomatology: "Ketamine and PTSD," "ketamine and post-traumatic stress disorder and memory consolidation," "ketamine and trauma and hyperarousal," "ketamine and dissociation and psychological outcomes." Studies were included if they met the following criteria:

(1) Population: Trauma-exposed individuals receiving ketamine in emergency, perioperative, or experimental settings.

(2) Intervention: Studies examining the effects of ketamine on PTSD symptoms, memory processing, dissociation, or neuroinflammation.

(3) Comparison: Studies comparing ketamine to opioids (e.g., morphine, fentanyl) or placebo controls.

(4) Outcomes: PTSD symptom severity, hyperarousal, fear extinction, dissociation, and neurobiological changes.

(5) Study design: Randomized controlled trials (RCTs), observational studies, and preclinical animal models.

Studies were excluded if they did not evaluate PTSD outcomes or neurobiological effects of ketamine, were case reports or reviews lacking primary data, or dealt with ketamine abuse or recreational use unrelated to trauma care.

Fifty studies were initially identified across PubMed, Embase, and Scopus. Of which, 12 studies excluded due to duplication. Thirty-eight studies were assessed for relevance (titles and abstracts were screened). Of which, 22 studies underwent detailed evaluation (full-text reviews). Finally, 10 studies were incorporated into the final synthesis. The included studies addressed the following: (1) the impact of ketamine on PTSD symptom severity; (2) comparisons between ketamine and alternative interventions such as opioids (morphine, fentanyl) or placebo; (3) the timing of ketamine administration and its role in memory consolidation, dissociation, and neuroinflammation; and (4) RCTs and observational studies assessing long-term psychiatric outcomes.

REVIEW OF LITERATURE

According to a Delphi study, trauma is defined as “significant injury or injuries that have potential to be life-threatening or life-changing sustained from either high energy mechanisms or low energy mechanisms in those rendered vulnerable by extremes of age” [5].

This definition highlights that trauma encompasses not only sudden physiological injury but also a significant psychological insult, both requiring immediate intervention. The study emphasizes that trauma care extends beyond initial resuscitation, incorporating strategies aimed at minimizing long-term sequelae such as PTSD and chronic pain.

Acute stress disorder (ASD) is characterized by disrupted sleep, recurring nightmares, distressing flashbacks, heightened arousal, and increased autonomic activity following a traumatic event. Symptoms persist for more than 48 hours but resolve within one month. The severity of ASD can influence the likelihood of developing PTSD, which is typically diagnosed between 3 and 6 months after a traumatic incident. PTSD is marked by four main symptom clusters: intrusive memories, avoidance of trauma reminders, negative changes in mood and cognition, and heightened physiological arousal [6]. Trauma can trigger a cascade of molecular events leading to lasting alterations in brain morphology and physiology, ranging from inflammation-driven synaptic remodelling to reductions in hippocampal volume [7,8].

As an uncompetitive NMDA receptor antagonist, ketamine modulates excitatory neurotransmission and synaptic plasticity—mechanisms central to both its anaesthetic effects and potential psychiatric outcomes [9]. These neurobiological actions intersect with the pathophysiology of PTSD, which involves dysregulated glutamatergic signalling, neuroinflammation, and hippocampal atrophy. This distinctive pharmacological profile enables ketamine to act as a fast-acting anaesthetic and analgesic while also showing potential as a treatment for depression and PTSD [10]. However, ketamine’s psychotomimetic effects can induce symptoms resembling psychosis in healthy individuals, including hallucinations, confusion, sensory distortions, depersonalization, paranoia, and emotional instability [11]. These effects mirror core features of both acute and chronic PTSD, raising important concerns about ketamine’s capacity to either alleviate or worsen posttraumatic stress responses.

Given that ASD often precedes PTSD, early pharmacological intervention may significantly influence long-term psychiatric outcomes. Ketamine’s NMDA receptor modulation and its potential to reduce neuroinflammation prompt a critical question: Can ketamine prevent the progression from ASD to PTSD, or does it exacerbate stress-related pathology by reinforcing trauma memory consolidation?

The long-term psychological effects of ketamine in trauma care remain contentious. Some studies suggest that administering ketamine immediately after trauma may amplify early stress reactions, such as dissociation and hyperarousal. In contrast, other research indicates that ketamine can facilitate fear extinction and reduce the subsequent development of PTSD symptoms. These conflicting results highlight the need for individualized clinical decision-making and a cautious approach to ketamine use, particularly among vulnerable populations.

To clarify ketamine’s role in trauma-related psychiatric outcomes, this review synthesizes findings from both clinical and preclinical research. Given the variability in methodological rigor among the included studies, we employed the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework [12] to systematically assess the certainty of evidence for key outcomes. This framework evaluates study design, risk of bias, consistency, indirectness, and precision, thereby clarifying the robustness and clinical relevance of the available findings. Overall, the evidence reviewed was generally rated as having low to moderate certainty, underscoring the urgent need for high-quality RCTs to inform evidence-based guidelines for ketamine use in trauma care (Table 1) [1–4,8,11,13–25].

TIMING OF ADMINISTRATION: PERIOPERATIVE VS. IMMEDIATE POST-TRAUMA

Studies on perioperative ketamine use

Several studies suggest that ketamine may play a protective role in reducing PTSD incidence or alleviating its symptoms. One study reported that prehospital ketamine administration was associated with significantly lower odds of developing PTSD within the first year following injury, but only in individuals who had not sustained a TBI [26]. This finding indicates that ketamine’s potential benefits may depend on the specific nature of the trauma and the patient’s injury profile.

Further evidence comes from a study involving 241 soldiers who had experienced burns in Operation Iraqi Freedom and Operation Enduring Freedom [27]. Among the 147 individuals who underwent surgery, 119 received perioperative ketamine and had a PTSD incidence rate of 27%, compared to 46% in those who did not receive ketamine . Notably, this lower PTSD prevalence occurred despite the ketamine group having more severe injuries and longer intensive care unit stays, suggesting a possible protective effect against trauma-related psychological distress.

Furthermore, a retrospective study by McGhee et al. [14] examined intraoperative ketamine use in burn patients and reported a correlation between ketamine administration and decreased PTSD incidence. Although the study’s retrospective design and small sample size were significant limitations, the findings support the emerging view that ketamine’s analgesic and dissociative properties may contribute to PTSD prevention. However, in a follow-up study involving a larger cohort of burned service members, McGhee et al. [15] found no significant effect of ketamine on PTSD development. While this later study did not replicate the earlier protective association, it confirmed that ketamine use in burn patients does not appear to increase PTSD risk.

Clinical trial data also align with these positive observations. A study comparing ketamine to midazolam found that ketamine infusion significantly reduced PTSD symptoms within 24 hours, with benefits persisting even after adjusting for baseline psychological conditions such as depression [13]. The rapid onset and sustained symptom reduction highlight ketamine’s potential as a fast-acting intervention for PTSD.

Studies on immediate post-trauma ketamine use

In contrast, Schönenberg et al. [11] raised concerns about ketamine administration in the immediate aftermath of trauma. Their study found that ketamine given 3 days after trauma was associated with heightened dissociation, re-experiencing, hyperarousal, and avoidance, which are core PTSD symptom domains. These results suggest that while ketamine can provide rapid analgesia, it may also intensify psychological distress in the early post-trauma period.

Contrast in findings

Despite differing perspectives, some research indicates that ketamine neither significantly prevents nor exacerbates PTSD in trauma-exposed individuals. For example, an analysis of PTSD and ASD prevalence among 277 injured soldiers found no direct causal relationship between ketamine use and PTSD risk [18]. Although PTSD patients in this cohort had received higher doses of ketamine, morphine, and midazolam, the association did not establish causation. These findings imply that factors such as injury severity and concurrent medication use may confound observed relationships between ketamine and PTSD outcomes.

NEUROBIOLOGICAL MECHANISMS

Neurobiological research has shed light on ketamine’s mechanism of action in trauma resilience.

Synaptic stability

A recent study explored the role of glial and neuroinflammatory markers in determining vulnerability versus resilience after trauma, suggesting that ketamine may interrupt the cascade of neuroinflammatory changes triggered by stress [8]. This disruption could help maintain synaptic stability and protect against PTSD development.

Furthermore, another recent study on ketamine’s immediate effect on neurotransmitter systems explains this in greater detail [17]. Ketamine triggers the release of gamma-aminobutyric acid, glutamate, and glutamine, which regulate brain-derived neurotrophic factor (BDNF). BDNF, in turn, promotes synaptic plasticity through pathways involving TrkB and PSD-95. Ketamine’s acute effects also involve the modulation of molecular markers such as c-Fos, GSK-3, HDAC, and HCN1, as well as hormonal factors including corticotropin-releasing hormone and adrenocorticotropic hormone, both of which are implicated in the stress response and neuroinflammation. Additionally, ketamine increases levels of proinflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumour necrosis factor α, all of which are associated with trauma-induced stress and contribute to the neuroinflammatory environment seen in PTSD. While these immediate actions may enhance neuroplasticity and protect against stress-related damage in some individuals, their net impact on PTSD remains complex.

Beyond its immediate actions, ketamine produces sustained molecular changes that alter gene expression and neuronal activity over time. These include activation of the mTOR pathway, which regulates BDNF expression, as well as modifications in GSK-3β, FKBP5, and GFAP—molecules linked to neuroinflammation and glial activation. The ERK phosphorylation pathway plays a key role in long-term synaptic plasticity and memory consolidation, while epigenetic modifications involving DNMT3, MECP2, H3K27me3, mir-132, mir-206, and HDAC influence gene regulation and contribute to lasting structural and functional changes in the brain. These adaptations may stabilize synaptic connections and support recovery in brain regions critical for memory, emotion, and stress regulation.

However, while ketamine’s acute neurobiological effects may foster resilience by enhancing plasticity and neuroprotection, its sustained influence on memory and emotional processing could, in some cases, promote maladaptive memory consolidation. This raises an important question: does ketamine protect against PTSD by improving trauma memory processing and emotional regulation, or does it increase risk by reinforcing maladaptive memory encoding? Current evidence suggests that its effects likely depend on the timing of administration, dosage, and individual neurobiological factors—underscoring the need for personalized treatment strategies to optimize therapeutic benefits while minimizing risks.

Glutamate signalling and the hypothalamic-pituitary-adrenal axis

Ketamine has also been associated with attenuation of the hypothalamic-pituitary-adrenal axis response, further linking its effects to dysregulated stress adaptation mechanisms. These findings raise concerns that early postexposure ketamine treatment could inadvertently reinforce maladaptive trauma responses, thereby underscoring the importance of timing in determining its psychiatric outcomes [16].

Hippocampal volume

Adding to the complexity, studies examining the relationship between ketamine, hippocampal volume, and PTSD symptoms have produced paradoxical results. Some research indicates that ketamine use is linked to increased right hippocampal volumes, suggesting a possible neuroprotective effect; however, it also correlates with heightened PTSD symptom severity. This paradox highlights that potential neurobiological benefits, such as structural preservation, do not necessarily translate into psychological symptom relief [20].

Fear memory and PTSD

Animal studies suggest that ketamine may increase early memory consolidation of traumatic events, possibly increasing susceptibility to PTSD. A 2017 study contrasts with more recent research associating ketamine’s therapeutic effects with BDNF modulation [27]. In this experiment, rodents received ketamine at doses of 0.5, 5, or 15 mg/kg for 3 consecutive days following stress exposure. Results showed a pronounced increase in freezing behaviour in response to trauma-related cues 31 days later, compared to vehicle-treated controls, indicative of persistent, PTSD-like fear memory. Notably, this increased freezing occurred without changes in BDNF expression, suggesting that ketamine may, in certain contexts, reinforce traumatic memory consolidation independently of BDNF-mediated neuroplasticity.

One study investigating the effects of ketamine anaesthesia (125 mg/kg, intraperitoneal) on the basolateral amygdala found that rats receiving immediate post-training ketamine exhibited significantly stronger memory retention at 48 hours compared to those given delayed administration (3 hours later), which showed no measurable effect [4]. In this experiment, rats were trained in an inhibitory avoidance task, learning to associate entry into a dark compartment with an inescapable foot shock (0.35–0.65 mA, depending on the condition). When tested 48 hours later, rats that had received immediate ketamine displayed longer latencies to re-enter the shock compartment, indicating stronger retention of the aversive experience. This effect was time-dependent and mediated by adrenal and noradrenergic activation, as it was abolished by adrenal medullectomy and by β-adrenergic receptor antagonism in the basolateral amygdala. These findings suggest that when administered at anaesthetic doses immediately after trauma, ketamine may enhance the encoding of distressing memories rather than mitigating them, thereby increasing PTSD risk. The absence of similar effects with delayed administration further supports the hypothesis that early post-trauma ketamine can interfere with normal fear extinction processes and contribute to long-term maladaptive memory formation.

Another experimental study examined how the timing of ketamine administration affects fear extinction [21]. The results indicated that ketamine’s impact depends critically on when it is given. Administered before stress exposure, ketamine acted in a “vaccine-like” manner, reducing subsequent fear responses. In contrast, when given after extinction but before fear reinstatement, it heightened attentiveness and reactivity. These findings have important implications for military contexts, where increased alertness may intensify emotional and physiological responses to trauma-related stimuli. They also raise concerns in civilian trauma care. In emergency and perioperative settings, where ketamine is frequently used as an analgesic or sedative, timing of administration may influence long-term psychological outcomes. For example, civilians exposed to motor vehicle accidents, assaults, or medical emergencies may receive ketamine during acute treatment, and if administered too close to trauma recall or memory consolidation windows, it may inadvertently enhance fear memory encoding. This could increase sensitivity to trauma cues, prolong hyperarousal, and elevate PTSD risk in non-combat populations.

BALANCING INNOVATION WITH CAUTION

As ketamine’s role in trauma care continues to be investigated, current research highlights both its potential benefits and its limitations. While some studies demonstrate its capacity to reduce PTSD symptoms and promote neuroprotection, others suggest that it may reinforce traumatic memory consolidation or exacerbate psychological distress under certain conditions. These conflicting findings emphasize the need for a cautious, individualized approach when incorporating ketamine into trauma protocols.

Population-specific differences in psychological response

Population heterogeneity, including differences in injury severity, baseline psychological resilience, and neurological comorbidities, necessitates stratified treatment approaches. For example, studies involving military personnel with burn injuries have yielded inconsistent results [14,15]: some reported protective effects of intraoperative ketamine on PTSD development, whereas later analyses found no statistically significant differences. In civilian trauma cohorts, early post-trauma ketamine administration was associated with increased dissociation and hyperarousal, suggesting that trauma context influences neuropsychiatric responses to ketamine [11]. Evidence indicates that early intervention, particularly in patients without TBI, may reduce PTSD risk by disrupting maladaptive fear memories and enhancing emotional resilience. However, prehospital ketamine appeared protective only in non-TBI military personnel, suggesting that neurological comorbidities may alter its effects on stress processing.

Certain patient groups may benefit more from ketamine therapy, including those without TBI, individuals requiring perioperative analgesia, patients with high pain thresholds or opioid resistance, and those with comorbid depression, who may experience both analgesic and antidepressant effects. Conversely, individuals with a history of dissociative disorders, severe anxiety, or baseline hyperarousal may be at increased risk for adverse psychological reactions, such as intensified perceptual disturbances and psychiatric destabilization. Military personnel or others with repeated trauma exposure could also be more susceptible to worsened PTSD symptoms if ketamine-induced alertness amplifies reactivity to trauma-related cues. Tailoring treatment strategies based on these variables, while considering timing, dosage, neurocognitive status, and psychiatric vulnerability, will be critical for optimizing benefits and minimizing harm.

Given the variability in injury severity, psychological resilience, and neurological comorbidities, tailored treatment strategies are critical to optimize therapeutic outcomes and minimize adverse effects. Clinical decisions should account for timing, dosage, neurocognitive status, and individual susceptibility to psychiatric complications.

Dosing strategies

Dose appears to be a key determinant of psychological risk. Clinical and preclinical studies indicate that low intravenous doses (0.1–0.5 mg/kg) may provide neuroprotection, reduce hyperarousal, and help prevent maladaptive fear memory formation [22,23]. In contrast, higher doses (>1 mg/kg intravenous) or repeated administration have been linked to dissociation, perceptual disturbances, and heightened emotional reactivity, making them less suitable for routine trauma care [24].

Clinical safety recommendations

For safe and effective integration of ketamine into trauma care, routine long-term psychological follow-up should be standard practice. Patients who receive ketamine should be screened for PTSD at 1-, 3-, and 6-month post-trauma to identify emerging symptoms early. Ketamine administration should ideally be combined with evidence-based trauma therapies, such as cognitive behavioural therapy or exposure therapy, to enhance fear extinction and support emotional regulation. Refining patient selection criteria, optimizing administration timing, and instituting structured psychiatric monitoring will help ensure that ketamine is used both effectively and safely in PTSD prevention and trauma management.

Limitations in the current evidence base

Despite growing interest, several methodological limitations constrain interpretation of ketamine’s long-term psychological effects in trauma patients. Sample heterogeneity is a major concern, as many studies combine varied trauma populations—military personnel, civilians, and burn victims—resulting in inconsistent PTSD outcomes. Preexisting psychiatric conditions, trauma severity, and genetic predispositions are often unaccounted for, limiting comparability. Future studies should stratify participants based on these variables to enable more precise and targeted conclusions.

Another challenge involves the inherent biases of retrospective versus prospective study designs. Many existing investigations rely on retrospective chart reviews, which are vulnerable to recall and selection bias, limiting their capacity to establish causality between ketamine use and PTSD risk. To improve reliability, future research must employ prospective, RCTs with extended follow-up periods, enabling a clearer understanding of ketamine’s long-term psychological effects.

A further limitation is the reliance on self-reported PTSD symptoms. These measures are inherently subjective, influenced by patient perception, recall inaccuracies, and social desirability bias. Sole dependence on self-reports may undermine the validity and generalizability of study findings. Incorporating objective biomarkers, such as cortisol levels, neuroimaging measures (e.g., hippocampal volume), salivary cortisol assays, and proinflammatory cytokine profiling, would provide more reliable, quantifiable indicators of PTSD progression and reduce symptom assessment bias.

Future directions

To overcome these methodological shortcomings, future research should prioritize large-scale, prospective RCTs that apply standardized PTSD diagnostic criteria while integrating biomarkers and neuroimaging to complement self-reported symptoms. Improved stratification of study populations based on trauma severity, preexisting psychiatric conditions, and treatment timing will enhance both consistency and accuracy. By refining research methodologies, the medical community can build a clearer picture of ketamine’s long-term psychiatric effects, ultimately optimizing its role in PTSD prevention and treatment while minimizing risks.

CONCLUSIONS

Ketamine remains an important tool in trauma care, offering rapid analgesia and potential neuroprotective benefits. However, its long-term psychological impact remains uncertain, with evidence suggesting both preventive and adverse effects on PTSD depending on timing, dosage, and patient characteristics. While perioperative and early intervention use may reduce PTSD risk, immediate post-trauma administration could reinforce distressing memories and contribute to PTSD development.

Given these mixed findings, clinicians must adopt a cautious, individualized approach when integrating ketamine into trauma protocols. Tailoring administration according to patient-specific risk factors, such as TBI status, psychiatric history, and the timing of exposure, will be essential to minimize adverse psychological outcomes while leveraging its therapeutic potential.

Future research should emphasize longitudinal studies assessing ketamine’s long-term psychiatric effects, as well as mechanistic investigations into its influence on synaptic plasticity, neuroinflammation, and fear extinction processes. In parallel, policymakers must establish ethical and regulatory frameworks that promote responsible use in trauma care, balancing potential benefits against associated risks.

Through refined administration protocols, improved patient selection, and rigorously designed clinical trials, ketamine can be integrated safely and effectively into trauma practice. As research progresses, collaboration among clinicians, neuroscientists, and policymakers will be essential to optimize ketamine’s role in PTSD prevention and treatment, ultimately improving outcomes for trauma-exposed populations.

ARTICLE INFORMATION

Author contributions

Conceptualization: all authors; Data curation: MAM, JC, HH; Formal analysis: MAM, JC, VD, HH, AS; Methodology: MAM, JC, HH, FH, AS; Project administration: MAM, MH, VD, FH; Visualization: all authors; Writing–original draft: MH, JC, FH, AS; Writing–review & editing: MAM, MH, VD, FH, AS. All authors read and approved the final manuscript.

Conflicts of interest

The authors have no conflicts of interest to declare.

Funding

The authors received no financial support for this study.

Data availability

Data sharing is not applicable as no new data were created or analyzed in this study.

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