At this year’s MATT meeting, Dr. Laureen Marinetti spoke to attendees about how to differentiate between ketamine used illicitly versus ketamine used medically.  She also discussed the origin of medical and illicit ketamine. 

Ketamine was developed in 1962 for use as a veterinary anesthetic; it was not approved for human use until 1970.  Ketamine, [2-(ortho-chlorophenyl)-2-methylaminocyclohexanone], is an analog of phencyclidine (PCP), with two resolvable optical isomers, S(+) and R(-), S(+) is the more effective anesthetic, but exhibits a higher incidence of psychotic reactions, brings about a greater increase in blood pressure and pulse, and elicits a greater bronchodilatory response.  Clinically, ketamine is a dissociative anesthetic used to induce and maintain anesthesia and has also been used for severe agitation, excited delirium, acute pain control, acute asthma, and bronchospasm.  Ketamine was approved for the treatment of TRD, which is treatment resistant depression.  The product, Spravato® (S(+) or esketamine), was approved by the FDA in March of 2019.  It is administered as a nasal spray to be used in conjunction with oral antidepressant therapy.  Spravato® should be administered under the guidance of a healthcare provider.  In addition to treatment of TRD, there are other on-going investigative trials for the use of ketamine in post-traumatic stress disorder (PTSD), bipolar depression, cocaine/opiate/alcohol use disorder, and off-label for chronic pain at ketamine clinics.  Emergent reactions from ketamine use include recovery agitation characterized by hallucinations, vivid dreams, fear, severe confusion, laryngospasm, hypertension, tachycardia, emesis, psychoses, delirium, and cardiac arrest.   

Abuse of ketamine was first detected on the US West Coast in 1971.  This abuse continued into the 1980s moving internationally, and to include abuse by physicians.  In the 1990s and 2000s ketamine abuse was popular at Rave Parties where it became known as a club drug.  Nonmedical use of ketamine is becoming popular again.  Ketamine is available as a liquid, dried into crystalline white powder, and is self-administered by smoking, ingestion, insufflation, and as an IV administration when mixed as a solid-dose form with other drugs.  Some street names of illicit ketamine include: Vitamin K’, ‘Special K’, ‘Super K’, ‘Ket’, ‘K’, ‘Super C’, KitKat, ‘Tusi’, ‘Tucibi’, ‘Tuci’, ‘2-C or ‘2-CB’, the phonetic pronunciation of the number “2” and the letters “B”, “C” for “2” “C” “B”.  These products have not been found to contain phenethylamine 2CB.  Ketamine has also been detected in a pink dyed powder called pink cocaine that emerged in Latin America and Europe. This pink powder is a mixture that may contain, but is not limited to; ketamine, cocaine, opioids, methylenedioxymethamphetamine (MDMA), methamphetamine, novel psychoactive substances (NPS), or caffeine. 

Is the ketamine/norketamine in a toxicology report the result of legitimate medical use or is it because of illicit use?  Toxicology testing alone cannot answer this question; other information is needed, such as medicolegal death investigation and autopsy results.  Scene history, medical records, emergency medical services records as well as testing of solid dose form, powders or liquids found at the death scene may also be necessary.  For the data listed in this article, ketamine was screened by LC/QTOF/MS and confirmed by LC/MS/MS.  Toxicology results from ketamine cases containing both illicit and medical ketamine use are shown in the table below.  Group I is from the testing of postmortem blood determined to be from illicit ketamine use cases.  Group II is from the testing of postmortem blood determined to be from medical ketamine use.  Group III is from the testing of ante-mortem hospital blood determined to be from medical ketamine use.  Group IV is from the testing of one ante-mortem hospital serum determined to be from medical ketamine use.  The mean and median concentration of the illicit ketamine cases is significantly lower than that from the medical use ketamine, even though the ranges overlap.  This is not surprising since the medical use of ketamine is usually during an emergency to save the life of the patient.  In this situation there is likely not much time for the patient to metabolize ketamine if the patient does not survive. 

The table below shows the drugs found with illicit ketamine, the most common being fentanyl and fentanyl related.  More information from additional case work is needed to make a conclusion about expected ketamine and norketamine concentrations in illicit vs medical cases.  For more information regarding case demographics and history, please contact Axis Forensic Toxicology ([email protected]) to get a copy of the presentation. 

References 

1. Hoffman, RS, Howland, MA, Lewin, NA, Nelson, LS and Goldfrank, LR. Goldfrank’s Toxicologic Emergencies. 10th ed. New York: McGraw Hill Education; 2015
2. Palamar, JJ. Tusi: a new ketamine concoction complicating the drug landscape. Am J Drug Alcohol Abuse 2023; May 10:1-5
3. Palama, JJ, Wilkinson, ST, Carr, TH, Rutherford and Cottler, LB. Trends in illicit ketamine seizures in the US from 2017 to 2022. JAMA Psychiatry 2023; 80(7):750-751
4. United Nations Office on Drugs and Crime, “Tuci”, “happy water-powdered milk” – is the illicit market for ketamine expanding? Global SMART Update, Vol. 27, December 2022
5. National Drug Intelligence Center, U.S. Department of Justice, Intelligence Bulletin Ketamine, www.usdoj.gov/ndic, July 2004.
6. 6. Mion, and Villevielle T., Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings), CNS Neurosci Ther. 2013 Apr 10;19(6):370–380. doi: 10.1111/cns.12099.