The Paradox of Ketamine and the Clinical Manifestations of Acute and Chronic Toxicity

Eli Brennan MS3, NREMT-B, FF
University of Massachusetts Medical School
Mid-Atlantic Representative – EMRA MSC

Introduction

Ketamine, a phencyclidine derivative, is known for its dissociative anesthetic effects and has been the subject of great interest and debate in the medical community.

Ketamine was first derived from phencyclidine in the 1960s and was used during the Vietnam war as a battlefield anesthetic, allowing analgesia without the same risk of respiratory depression as others existing anesthetics (1). Over the decades, ketamine’s applications have expanded, moving beyond anesthesia to roles in emergency medicine, pain management, and psychiatry, particularly for treatment-resistant depression. This drug exerts a range of dose-dependent effects, but the scientific community still debates its safety profile and potential for toxicity.

Recently, the drug has been of much controversy and has been involved in several high-profile medical malpractice cases as well as the subject of legal debate regarding its use in psychiatry.

Mechanism of Action

(R,S) Ketamine is a racemic mixture that acts as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors in the central nervous system (CNS) (2). Ketamine’s blockade of NMDA receptors results in decreased excitatory neurotransmission, resulting in a characteristic “dissociative amnesia.”

Consciousness is thought to depend on proper functioning of the connection between the thalamus, which processes stimuli, and the cortex, which interprets it (3). Most anesthetics interrupt consciousness via direct enhancement of inhibitory GABAergic pathways (3). NMDA receptors are receptors that modulate glutamate release, an excitatory neurotransmitter. Ketamine binds to the phencyclidine site inside GABAergic neurons’ NMDA receptor ion channels, blocking calcium influx and inhibiting synaptic neurotransmission (4). However, its effects depend on its impact on both pyramidal neurons and interneurons which express the NMDA receptors. Pyramidal neurons primarily function as excitatory units by releasing glutamate, while interneurons act as inhibitory regulators through GABA release, modulating the activity of pyramidal neurons to maintain neural balance. Ketamine binds to both neuron types, leading to both inhibition and excitation. To explain this paradoxical effect, studies have shown that NMDA receptors on inhibitory GABAergic interneurons are more sensitive to ketamine than excitatory ones, leading to net disinhibition (5). By disrupting cortical activity, ketamine induces an excited yet uncoordinated state. On a macroscopic level, this leads to the characteristic preservation of functional consciousness, owing to the intact thalamocortical axis, while impairing the patient’s ability to integrate sensory information into conscious awareness (5). This disruption, coupled with heightened psychoactivity, can manifest as hallucinations at certain doses. Clinically, this translates into analgesia and anesthesia without a true loss of consciousness.

Ketamine also interacts with mu and kappa opioid receptors. This mechanism is thought to contribute to its analgesic properties. However, it has been shown that this occurs to a much lesser extent than the interaction with NMDA receptor (4), rendering pure analgesia without anesthesia a very complicated process.

Ketamine indirectly also boosts serotonin and dopamine levels in the CNS, fascinating and poorly understood mechanisms that likely underlie its antidepressant effects (6). While this is of primary importance to its use for psychiatric reasons, it is beyond the scope of this work to discuss.

Acute Ketamine Toxicity

Acute toxicity with ketamine, particularly through intravenous administration, results from its dose-dependent pharmacologic effects. Like many other commercially available anesthetics, ketamine exists as an isomeric mixture of R and S enantiomers. Studies have shown that S-Ketamine is responsible for the psychoactive impacts of the drug whereas R-Ketamine more readily induces analgesia, a mechanism that is still being explored (7).

While ketamine is considered relatively safe in therapeutic doses, toxic effects emerge with excessive dosing or rapid administration.

• Dose Ranges and Toxicity Thresholds: In clinical settings, ketamine is administered at doses tailored to its desired effect:
  • Sub-anesthetic Doses: 0.1-0.5 mg/kg for analgesia.
  • Anesthetic Doses: 1-2 mg/kg for sedation and dissociation.
  • Toxic Doses: Toxic effects may occur at doses exceeding 2 mg/kg IV, though they are influenced by factors such as the speed of administration and individual susceptibility. Notably, given ketamine’s frequent recreational use in non-clinical settings, its narrow therapeutic index becomes particularly significant, heightening concerns about toxicity when the drug is abused.

Clinical Manifestations of Acute Toxicity:

• CNS Toxicity: The CNS effects of acute ketamine toxicity are the hallmarks of toxicity; frequently presenting as agitation, hallucinations, dissociation, and, in severe cases, seizures (8). These neuropsychiatric symptoms arise from NMDA receptor blockade and ketamine’s influence on monoaminergic pathways, leading to excitotoxicity and altered neurotransmission in the CNS.
• Cardiovascular Toxicity: Ketamine stimulates sympathetic outflow by blocking inhibitory NMDA receptors in the CNS, leading to increased release of norepinephrine and epinephrine (10). This can cause hypertension, tachycardia, and, in patients with underlying cardiac conditions, potential myocardial ischemia. The risk is heightened with rapid IV administration or high doses, which may provoke hypertensive crisis or arrhythmias.
• Respiratory Depression: Although ketamine is often considered “respiratory-sparing,” high doses or co-administration with other depressants can lead to hypoventilation, apneic episodes, or even full respiratory arrest. This risk is particularly relevant in non-clinical use or when ketamine is administered in an uncontrolled setting.
• Serotonin Syndrome: The interaction of ketamine with serotonin receptors has been associated with cases of serotonin syndrome (SS), particularly in patients concurrently using other serotonergic agents. SS typically manifests with a constellation of symptoms indicative of heightened autonomic activity, including restlessness, tachycardia, and tremors, along with hallmark features such as clonus and hyperthermia. 

Like any other substance commonly abused in non-clinical settings, physicians should also have a low threshold for suspicion for contamination with other illicit substances.

Management of Acute Ketamine Toxicity:

• Supportive Care: There are currently no drugs primarily approved specifically for the use of ketamine drug. As such, primary management for ketamine toxicity is supportive, including continuous monitoring of vital signs, intravenous fluids for cardiovascular support, and airway protection if respiratory depression occurs.
• Pharmacologic Interventions:
  • Benzodiazepines can be effective in treating ketamine-induced agitation, dissociation, and seizures by enhancing GABAergic inhibition in the CNS (8).
  • Clonidine: Clonidine, an a2 agonist, has been shown in multiple studies to be beneficial in treating acute ketamine toxicity by reducing psychomimetic symptoms (11). This can be particularly helpful in patients who have contraindications to benzodiazepines or other antipsychotics.
  • Antihypertensive Agents: For severe hypertension, beta-blockers or calcium channel blockers can be used to manage sympathetic overactivity, though caution is warranted to avoid hypotension in cases where cardiovascular compromise is a concern.
  • Airway and Respiratory Support: In cases of respiratory depression, oxygen supplementation and, if necessary, positive pressure ventilation or intubation may be required.
  • Serotonin syndrome: In this case of the development of SS, supportive care, cooling measures, and cyproheptadine, a potent serotonin antagonist, are crucial for treatment (12). If rhabdomyolysis develops, aggressive fluid resuscitation and potassium management is critical.

Chronic Effects of Ketamine Use

While acute toxicity is often self-limiting and reversible, chronic ketamine use, particularly in recreational settings, has been associated with more severe and irreversible complications, although these are subject to much debate.

• Urological Complications: Ketamine-induced cystitis (KIC) has been heavily documented as a chronic effect of use (13). Symptoms include dysuria, urgency, hematuria, and urinary frequency. Studies have shown over 90% of chronic users can experience some components of ketamine cystitis (14). While the mechanism is debated, ketamine metabolites are thought to directly disrupt the bladder mucosa as well as cause microvascular damage, causing chronic inflammation and fibrosis (15).
• Neurological and Cognitive Impairments: The neurologic impacts of chronic ketamine exposure have been heavily debated in literature. Preliminary research has explored the use of ketamine for neuroprotection in traumatic brain injuries or cardiac arrest due its impacts on neuronal excitability (16). Conversely, it has also been associated with cognitive impairments, particularly in memory and executive functions (17). Several mechanisms have been proposed and multiple studies have shown different negative impacts of the drug metabolites on neuronal function. Animal models have shown that ketamine can induce the formation of the hyperphosphorylated tau protein, a key structure in the development of Alzheimer’s disease (18).
• Cholangiopathy: While less documented in literature, chronic ketamine use has been associated with cholangiopathy since the 1980s (19). NMDA receptors have been found to exist in the smooth muscle cells of bile ducts (20). It is believed that chronic use of ketamine can lead to inflammation, manifesting as both intra and extrahepatic strictures (19).

Conclusion

Ketamine exists as a potent pharmacological agent with significant clinical utility across various specialties, including emergency medicine, anesthesia, and psychiatry. However, its paradoxical mechanisms and dose-dependent effects underscore its complexity and the necessity for judicious use. Acute ketamine toxicity, while often reversible with prompt supportive care, presents with diverse and potentially severe manifestations, including neuropsychiatric disturbances, cardiovascular dysregulation, and respiratory compromise. Chronic use introduces risks of irreversible complications, such as ketamine-induced cystitis, cognitive impairments, and cholangiopathy, highlighting the importance of education on its safe use.

The expanding interest in ketamine’s therapeutic potential demands further research into its long-term safety profile, optimal dosing strategies, and novel applications. As the medical community continues to explore its benefits, healthcare providers must remain vigilant to its risks and foster a comprehensive understanding of its pharmacological intricacies to ensure patient safety and maximize therapeutic outcomes.

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