Clinical Update

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It is FDA approved for the induction and maintenance of anesthesia.¹ When used for this indication, ketamine induces a “dissociative anesthesia” characterized by involuntary movement and spontaneous breathing.² It was developed as an alternative to phencyclidine (PCP) as an anesthetic with less dysphoria and psychosis post-surgery.¹ At lower doses, ketamine provides pain relief without producing anesthesia.¹ Ketamine is commercially available as an injectable solution. It can also be administered orally, topically, intranasally, and rectally.^2,3 Ketamine is also available as a compound prescription in various dosage forms – tablet, troche, injection, intranasal spray. Although originally approved as an anesthetic, compounded ketamine formulations have been used recently to treat psychiatric disorders, triggering an FDA warning in October 2023 about the use of compounded ketamine for the treatment of psychiatric disorders. ²⁰ This has the potential to be harmful to patients because of risk for ischemia and dissociation especially in unmonitored use.

Ketamine is a Schedule III controlled substance with a long history of abuse dating back to the 1970s and remains popular as a “club drug” today.^4-5 In the 2022 Monitoring the Future survey, ketamine abuse was prevalent among 1.2% of 12th graders in the United States.⁶ Psychostimulant effects of ketamine are dose-dependent and include hallucinations, perceptual disturbances, and dissociative states. Ketamine may be abused through snorting, smoking, injecting or ingesting orally. At high doses, users experience feelings of complete sensory detachment often referred to as “K-hole.” During these sensory distortions, users describe out of body experiences and an altered perception of time and space.^4-5 While the psychoactive effects of ketamine last approximately an hour, modifications of the user’s senses, judgment, and coordination may persist for up to 24 hours.⁵

Ketamine in Mental Health

Clinically, antidepressant effects have been observed in multiple studies following a low dose ketamine infusion. Zarate et al. reported significant improvement over placebo in depression symptoms within 110 minutes. One day after the infusion, 71% and 29% met response and remission criteria, respectively. The response was maintained for a week in 35% of subjects.⁷  Thakurta and colleagues reported significant improvement at 80 minutes post-infusion and found 77% of subjects met response criteria at one-day post-infusion with no subjects meeting remission criteria; the response was maintained for a week in 13% of patients.⁸ Common side effects noted in these studies were perceptual disturbances, increased blood pressure, euphoria, confusion, headache, and dizziness. While these findings are promising, one limitation is that the antidepressant effects of ketamine have not been sustained long term. Participants typically returned to their baseline depressive state seven days after treatment.^7-8 As a result, a recent study focused on extending the duration of ketamine’s effects by administering ketamine three times a week over the course of 12 days. This dosing regimen extended ketamine’s effects to a median of 18 days following the last infusion.⁹ Limitations of ketamine studies for resistant depression included small sample sizes, lack of active comparators, and the potential for abuse in an already susceptible patient population. In 2019, an intranasal formulation of esketamine – Spravato^® – an enantiomer of ketamine, was approved for the treatment of treatment-resistant depression in adults.¹⁰ This medication is administered by a clinician and is not dispensed directly to the patient for self-administration.  Thus, it may not be listed on a patient’s prescription drug monitoring program history.¹⁰

There is a current phase two trial underway for arketamine (“R-ketamine” and “PCP-101”) for treatment resistant depression. Arketamine has less dissociative effects, sedation, and risk for psychosis compared to eskatamine.²¹ Ketamine is associated with upregulation of dopamine receptors that can cause psychosis-like symptoms, but it is unknown if the r- or s-isomer have differing activity at dopamine receptors.

Ketamine in Pain Treatment

Ketamine’s analgesic effects are mainly attributed to its interaction with NMDA receptors. While many studies have been published, results are complicated by the multiple types of pain evaluated, various doses utilized, side effects limiting therapy and inconsistencies in patient outcomes. An additional complicating factor is the subjective nature of pain, making it difficult to determine a dose-response association when ketamine is administered for this indication.^3,11 Despite these limitations, ketamine may have potential to improve analgesia in poor opioid responsiveness, which may be influenced by NMDA overactivity. The use of an NMDA antagonist, like ketamine, is advocated by some in multimodal pain treatment and to improve opioid responsiveness. Several studies have established the efficacy of low-dose ketamine for patients with opioid-resistant pain.¹²

Ketamine in Substance Use Disorder

People with alcohol, opioid, cannabis, and cocaine use disorders are reported to have higher rates of depression than the general population. Recently, clinical studies have shown the rapid antidepressant effects of ketamine provide substantial support for its potential use for the treatment of addiction. Research has also shown the effects of ketamine on the expression of drug-related memories. Ketamine has been shown to prolong abstinence in alcohol and heroin dependence and reduce cocaine cravings and self-administration.¹³ A benefit of ketamine for addiction treatment is daily dosing is not required. However, studies have limitations, and further randomized controlled trials are needed to confirm the efficacy of ketamine for treating addiction.¹³

Potential Clinical Uses of Ketamine

Recently, ketamine clinics have gained popularity and are able to provide ketamine to patients for off-label indications. The use of ketamine for the treatment of unapproved indications is met with hesitancy as clinical trials have been inconclusive and lack long-term data establishing safety and efficacy. The need for additional studies has been identified.^11,14 Arketamine has shown evidence of success in treating major depressive disorder and bipolar depression.²¹ Ketamine and its isomers should not be used to treat schizophrenia or schizoaffective disorder due to the risk of psychosis.²¹ Despite showing promise in treating depression and pain in clinical trials, ketamine is not recommended as first-line therapy for these indications and requires careful monitoring for adverse effects and substance abuse.

Other potential clinical uses of ketamine recently studied include:

Misuse of Ketamine

Ketamine and its analogues have a risk of misuse due to the visual hallucinations and dissociative effects. These substances can bind to opioid mu receptors and cause respiratory depression, in addition to hypertension, hypotension, myocardial infarction, and psychosis. In combination with other illicit substances, the risk of serious harm or death due to ketamine exposure increases. An emerging product called “pink cocaine” or “tusi” is a combination of ketamine, MDMA, methamphetamine, opioids, cocaine, and/or other novel psychoactive substances.²⁸

The following substances are analogues of ketamine and can be subject to misuse. Aegis offers testing for numerous ketamine analogs in the Hallucinogens/Dissociatives Novel Psychoactive Substance (NPS) testing:¹⁹

• Phencyclidine (PCP)
• 2F-Deschloroketamine
• Deoxymethoxetamine
• Deschloroketamine
• Fluorexetamine
• 3-methoxy-phencycldine (3-MeO-PCP)
• 4-methoxy phencyclidine (4-MeO-PCP)
• Deschloro-N-ethyl-ketamine (2-oxo-PCE)
• Methoxetamine (MXE)
• Dizocilpine (MK-801)

Pharmacogenomics

Pharmacogenomic studies and drug-drug interaction testing can also lend information to variations in response to ketamine. Ketamine is a major substrate for CYP3A4 and a minor substrate for CYP2B6 and CYP2C9.²⁴ Presence of CYP2B6*6 can cause decreased enzymatic activity and plasma clearance of ketamine.^22,23 As a result, this polymorphism is associated with severe dissociative effects.²² Decreased norepinephrine transport caused by genetic variant rs28386840 is associated with emergent hypertension.²² The Val66Met polymorphism in brain derived neurotropic factor (BNDF) is associated with less antidepressant and anti-suicidal effect.²² Pharmacogenomic testing for CYP450, Val66Met, NET allele rs28386840, and drug-drug interaction testing can prevent severe reactions and non-response to ketamine therapies.

Detection of Ketamine and Metabolites

Major metabolites of ketamine are norketamine, dehydronorketamine, and hydroxyketamine.²⁵ A pharmacokinetic study in 2021²⁶ showed evidence ketamine is a high clearance drug with low (12-19%) bioavailability. There is some variability in renal clearance between isomers, but renal clearance is not significantly influenced by chirality. Changes in renal function were not found to be clinically relevant to plasma concentration, but changes in metabolic status, liver function, and liver blood flow were. Stereoselectivity of CYP450 enzymes can also contribute to the variability in plasma concentration and excretion of ketamine isomers and metabolite isomers.

Extended detection of ketamine and norketamine in urine has been seen in patients undergoing detoxification after chronic, illicit use of ketamine. In a case series looking at ketamine and metabolite urine concentrations during detox ketamine was detected at 61 days, norketamine was detected at 40 days, and dehydronorketamine was detected at 96 days at a threshold of 1ng/ml.²⁷ Ketamine is a lipophilic drug and can accumulate in adipose tissue, contributing to longer periods of detection. In high dose, chronic dose of ketamine there is also evidence of CYP450 self-induction, resulting in variable metabolite excretion.

At Aegis, samples undergo liquid chromatography/ tandem mass spectrometry (LC/MS-MS) analysis to confirm the presence of ketamine. Aegis laboratories will detect ketamine in samples at a threshold of 1 ng/mL, along with dehydronorketamine and norketamine at a threshold of 5 ng/mL with a period of detection up to 3 days in urine specimens and up to 48 hours in oral fluid specimens. When using LC/MS-MS analysis alone, ketamine, esketamine, and arketamine are indistinguishable. The testing does not detect isomers of ketamine or its metabolites, so results should not be used to interpret possible prescription or illicit sources.

NOTICE: The information above is intended as a resource for health care providers. Providers should use their independent medical judgment based on the clinical needs of the patient when making determinations of who to test, what medications to test, testing frequency, and the type of testing to conduct.

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References:

1. Ketamine. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc. http://clinicalpharmacology-ip.com. Updated December 20, 2013. Accessed June 10, 2016.
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20. https://www.fda.gov/drugs/human-drug-compounding/fda-warns-patients-and-health-care-providers-about-potential-risks-associated-compounded-ketamine
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