Ketamine, a racemic mixture consisting of (S)- and (R)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine’s pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of N-methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

https://pharmrev.aspetjournals.org/content/pharmrev/70/3/621.full.pdf

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Congratulations to Dr. Baselt for the publication of his 10th edition and the expansion of his classic toxicology text to cover over 1,500 medications and chemicals. This enduring work provides a c...

Disposition of Toxic Drugs and Chemicals in Man

Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB1 (EC50 = 0.45–36 nM) and CB2 (EC50 = 4.6–128 nM) receptors in a fluorometric assay of membrane potential, with a general preference for CB1 activation. The cannabimimetic properties of two prevalent compounds with confirmed toxicity in humans, 5F-AMB and MDMB-FUBINACA, were demonstrated in vivo using biotelemetry in rats. Bradycardia and hypothermia were induced by 5F-AMB and MDMB-FUBINACA doses of 0.1–1 mg/kg (and 3 mg/kg for 5F-AMB), with MDMB-FUBINACA showing the most dramatic hypoth...

Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues.

This review describes the medical, research and recreational uses of ketamine, an anaesthetic derivative of phencyclidine that has dissociative, analgesic and psychedelic properties. Ketamine has a complex mechanism of action that is further complicated by stereoselectivity; however, antagonism of glutamate NDMA receptors is thought to underlie its analgesic, dissociative and neuroprotective effects. While ketamine use in medical and veterinary settings is well documented and has a good safety record, the increase in its unregulated use outside of such controlled environments is a cause for concern. The impact on higher centres in the brain, particularly altered perception of auditory, visual and painful stimuli, results in a general lack of responsive awareness that puts the recreational user at (often unrecognised) risk of personal harm. The perceptual and mood changes observed in those who have consumed ketamine are highly sensitive to age, dose, route of administration, previous experience and setting. At low doses, stimulant effects predominate and the effect of environmental conditions are significant; with higher doses, psychedelic effects predominate and the effect of the environment diminishes. The potential of ketamine as a novel clinical and research tool is matched by its abuse potential outside medical settings.

Ketamine - From medicine to misuse

Designer cathinones--an emerging class of novel recreational drugs.

In recent years, many new psychoactive substances (NPS) from several drug classes have appeared on the drug market. These substances, also known as 'legal highs', belong to different chemical classes. Despite the increasing number of NPS, there are few comprehensive screening methods for their detection in biological specimens. In this context, the purpose of this study was to develop a fast and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) screening procedure for NPS in blood. The elaborated method allows the simultaneous screening of 143 compounds from different groups (number of compounds): cathinones (36), phenethylamines (26), tryptamines (18), piperazines (9), piperidines (2), synthetic cannabinoids (34), arylalkylamines (7), arylcyclohexylamines (3), aminoindanes (2), and other drugs (6). Blood samples (0.2 mL) were precipitated with acetonitrile (0.6 mL). The separation was achieved with gradient mobile phase of 0.1% formic acid in acetonitrile and 0.1% formic acid in water in 14 min. Detection of all compounds was based on multiple reaction monitoring (MRM) transitions. The total number of transitions monitored in dynamic mode was 432. The whole procedure was rapid and simple. The limits of detection (LODs) estimated for 104 compounds were in the range 0.01-3.09 ng/mL. The extraction recoveries determined for 32 compounds were from 1.8 to 133%. The procedure was successfully applied to the analysis of forensic blood samples in routine casework. The developed method should have wide applicability for rapid screening of new drugs of abuse in forensic or clinical samples. The procedure can be easily expanded for more substances. Copyright © 2015 John Wiley & Sons, Ltd.

Simple and rapid screening procedure for 143 new psychoactive substances by liquid chromatography-tandem mass spectrometry

New psychoactive substances (NPS) pose a challenge for forensic and clinical toxicologists, as well as for legislators. We present our findings from cases where NPS have been detected in biological material. During the three-year period 2012-2014 we found NPS in 112 cases (out of 1058 analyzed), with 75 cases in 2014 alone. The prevalence of all NPS (15.1-17.6%) was similar to amphetamine alone that was detected in 15.1-16.5% of cases. The new drugs found belonged to the following classes: cathinones (88%), synthetic cannabinoids (5%), phenethylamines (3%), piperazines and piperidines (3%), arylalkylamines (1%) and other (1%). The drugs detected were (in the order of decreased frequency): 3-MMC (50), α-pyrrolidinopentiophenone (α-PVP) (23), pentedrone (16), 3',4'-methylenedioxy-α-pyrrolidinobutyrophenone (MDPBP) (12), synthetic cannabinoid UR-144 (7), ethcathinone (5), mephedrone (5), methylenedioxypyrovalerone (MDPV) (4), 4-methylethcathinone (4-MEC) (3), buphedrone (3), desoxypipradrol (2-DPMP) (3), methylone (2) and 2C-B (2). In single cases, 2-methylmethcathinone (2-MMC), 2C-P, eutylone, 25I-NBOMe, meta-chlorophenylpiperazine (mCPP), ephedrone, methiopropamine (MPA), and 5-(2-aminopropyl)benzofuran (5-APB) were found. One NPS was the sole agent in 35% of all cases, and two or more NPS were present in 19% of cases. NPS (one or more) with other conventional drugs (like amphetamines, cannabinoids, cocaine, and benzodiazepines) were detected in most (65%) of the cases. NPS were very often detected in the blood of drivers which was a challenge for toxicologists due to a lack of data on their influence on psychomotor performance. A review of concentrations showed a wide range of values in different types of cases, especially driving under the influence of drugs (DUID) and intoxication.

The prevalence of new psychoactive substances in biological material – a three‐year review of casework in Poland

Simultaneous screening for and determination of 128 date-rape drugs in urine by gas chromatography-electron ionization-mass spectrometry

Fatal intoxication with synthetic cannabinoid MDMB-CHMICA.

A death caused by a new designer drug, 4-methylmethcathinone (mephedrone), is reported. Eight small plastic bags containing white powder were found in the jacket of a young dead male. Spot tests conducted by the police officer indicated the presence of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in the powders. Laboratory routine screening analyses of blood and vitreous humor did not reveal any positive results; therefore, 2C-B was excluded. Analysis of powders was conducted using gas chromatography – mass spectrometry and high-pressure liquid chromatography with diode array detection. The purity of mephedrone found in all powder samples was in the range of 80.4– 87.3%. In connection with these findings, blood and vitreous humor samples were analyzed for mephedrone. Analyses were conducted using liquid chromatography – tandem mass spectrometry. Mephedrone was found in blood and vitreous humor at the concentrations of 5.5 and 7.1 mg/ mL, respectively, revealing that this was a fatal mephedrone

/pdf/fatal-mephedrone-intoxication-a-case-report-3am9m18466.pdf

Piotr Adamowicz

Papers

Simple and rapid screening procedure for 143 new psychoactive substances by liquid chromatography-tandem mass spectrometry

The prevalence of new psychoactive substances in biological material – a three‐year review of casework in Poland

Simultaneous screening for and determination of 128 date-rape drugs in urine by gas chromatography-electron ionization-mass spectrometry

Fatal intoxication with synthetic cannabinoid MDMB-CHMICA.

Fatal Mephedrone Intoxication—A Case Report