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New generations of novel synthetic opioids (NSOs) have emerged to fill a void in the illicit drug markets left by the decline in popularity of fentanyl analogs subsequent to core-structure scheduling of fentanyl-related substances in the United States and China. These new opioids include members of the 2-benzyl benzimidazole (eg, isotonitazene, metonitazene, N-pyrrolidino etonitazene, protonitazene, etodesnitazene), benzimidazolone (eg, brorphine), and cinnamylpiperazine (eg, AP-238, 2-methyl AP-237) subclasses. Novel synthetic opioids continue to be detected in opioid-related fatal overdoses, demonstrating the harms associated with exposure to these drugs. Between January 2020 and December 2021, 384 casework blood samples were reported by our laboratory to contain 1 or more of the prior listed 8 NSOs. Isotonitazene (n = 144), metonitazene (n = 122), and brorphine (n = 91) were the 3 most prevalent substances, with positivity for isotonitazene and brorphine peaking just before the announcement of emergency scheduling. These NSOs have been documented as significant drivers of drug mortality, and this case series described here highlights the challenges medical examiners and coroners face in staying current with emerging drugs. Challenges include regional differences, rapid turnover, short lifecycles, variable toxicology testing, and difficulty in assessing individual drug toxicity in polydrug cases.

We report the case of a young adult who became unresponsive after insufflating what he believed to be “crushed Xanax.” Naloxone was administered, reversing his altered mental status and respiratory depression. Clinicians suspected opioid toxicity; however, the patient adamantly denied opioid use. Because of unclear etiology of his symptoms, blood and urine specimens were obtained. A urine specimen was split and then submitted for a clinical comprehensive drug screen using gas chromatography–mass spectrometry. The blood specimen and the remaining urine specimen were sent to a reference laboratory for analysis using liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography tandem mass spectrometry. The standard, clinical gas chromatography–mass spectrometry urine drug testing procedure only detected caffeine; however, analysis by liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography tandem mass spectrometry confirmed the presence of U-47700 (a high-potency clandestine opioid) and its metabolites in the urine and blood. These findings implicate U-47700 as the agent responsible for the patient's signs of opioid toxicity. In this case, a young adult intending to use alprazolam encountered U-47700 with life-threatening effect. Clinicians must remain vigilant for symptoms consistent with opioid overdose, especially with increasing prevalence of counterfeit drugs containing clandestine opioids. Clinicians must also consider obtaining specimens for appropriate analytical testing to improve surveillance and facilitate public health interventions.

Random samples from normal distributions are an important assumption for many statistical methods. The present study evaluates this assumption with regard to quantitative breath alcohol analyses. Eight individuals (six male and two female) consumed alcoholic beverages and subsequently provided replicate (n ranging from 22 to 69) breath samples to an infrared breath alcohol instrument within short time intervals. The serially collected data were treated with several descriptive and inferential methods. Descriptive results among the eight individuals included: mean 0.0420–0.1175 g/210L, SD 0.0008–0.0045 g/210L and CV: 1.9%–4.7%. Statistical tests for normality showed seven of the distributions to be reasonably normal (p ≥ 0.25) and the other marginal (p = 0.051). A test for runs about the median showed random results (p ≥ 0.10) for four individuals and non-random (p ≤ 0.01) for the other four. The results suggest an individual's breath alcohol measurement, when appropriately collected and analysed, should be considered a random sample from a normal within-subject distribution. The existing variability in breath alcohol analysis, due largely to biological and sampling considerations, is acceptably minimized to warrant forensic application.

Methamphetamine is currently enjoying a resurgence of popularity as a recreational drug. It presents a number of challenges to the forensic toxicologist both analytically and interpretively, and these latter interpretive issues are considered here. This review also discusses the current popular syntheses which account for the widespread domestic synthesis of the drug; the demographics of methamphetamine use in the United States as assessed from the Drug Abuse Warning Network (DAWN) data; developments in research of the neurotransporter pharmacology of the drug and its implications for interpretive forensic toxicology; the psychomotor effects of the drug and its potential for cognitive and functional impairment; interpretive issues related to postmortem blood drug concentrations and how these are impacted by evidence for incomplete distribution and the potential for postmortem redistribution; and, finally, concerns caused by designer methamphetamine analogues. All data indicate that methamphetamine and its analogues will present significant interpretive challenges to forensic toxicologists as the popularity of the drug continues to grow.

We present data from the analysis of the alcohol content of 391 beers and malt beverages available for sale in the State of Washington. The beverages were tested by gas chromatography for their alcohol content. Considerable variability in the alcoholic strength was found, even within the same class. Overall, the range of concentrations was 2.92% (v/v) to 15.66% (v/v). The alcohol content of beverages consumed is a critical factor in Widmark or volume-of-distribution-type calculations used to estimate blood or breath alcohol content from patterns of alcohol consumption. Using the correct alcohol content for beer, when the brand is known, can make a significant difference in the reliability of the calculation, and the data presented here should assist with optimizing the accuracy of the calculation.

A simple liquid-liquid extraction procedure for the analysis of γ-hydroxybutyrate (GHB) in biological fluids without conversion to its lactone, γ-hutyrolactone, is described. Following derivatization to its di-TMS derivative, GHB was detected using gas chromatography-electron impact mass spectrometry. Diethylene glycol was used as the internal standard. The limit of quantitation in 1 mL of blood was 1 mg/L, and a linear response was observed over the concentration range 1 to 100 mg/L. Coefficients of variation for both intra-assay precision and interassay reproducibility ranged between 3.9 and 12.0%. GHB was detected in the blood of a sexual assault victim (3.2 mg/L), in the blood of two driving (DUI) cases (33 and 34 mg/L), and in the blood and urine of two nonfatal GHB-overdose cases (blood 130 and 221 mg/L; urine 1.6 and 2.2 g/L). The observed clinical symptoms ranged from confusion, disorientation, vomiting, and nystagmus to ataxia, sinus bradycardia, unconsciousness, and apnea.

Methylphenidate is the most commonly prescribed psychostimulant in clinical use today.Known methylphenidate metabolites include ritalinic acid, corresponding lactams, and p-hydroxymethylphenidate. Recent in vitro work using rat liver preparations has indicated that the methylphenidate ethyl ester, ethylphenidate, is formed upon incubation with ethanol. This report describes the first detection of ethylphenidate in human blood and liver samples obtained from two suicide victims who had overdosed on methylphenidate and coingested ethanol. Amounts of ethylphenidate detected in whole blood specimens in these two cases (8 ng/mL and 1 ng/mL, respectively) were small relative to methylphenidate and ritalinic acid concentrations. Nonetheless, given the high likelihood that methylphenidate and ethanol coingestion frequently occurs, the detection of ethylphenidate in humans warrants further investigation into the extent of its formation as well as into any associated toxicity in nonoverdose situations. (J Clin Psychopharmacol 1999;19:362-366)

Information Resources Useful in Forensic Toxicology. STAFFORD, D. T., AND LOGAN, B. K. (1990). Fundam. Appl. Toxicol. 15, 411–419.This paper addresses information resources available to forensic toxicologists. The approach taken here is to discuss those resources found useful in problem solving situations. First, attempt to obtain information from someone familiar with the problem. This is generally the most efficient mechanism to use. The next most efficient mechanism is to search the published literature, electronically using bibliographic databases, if possible. The least efficient method of obtaining information is to go into the laboratory and generate the desired information. In many situations, however, the problem must be solved, or the information confirmed, in the laboratory. Suggested sources of information have been listed in the appendices. These are not intended to be exhaustive, but rather to stimulate and direct the access to information resources.

Tramadol is a centrally acting, binary analgesic that is neither an opiate-derived nor a nonsteroidal anti-inflammatory drug and that was approved for use in the United States in 1995. It is used to control moderate pain in chronic pain settings such as osteoarthritis and postoperative cases. Used in therapy as a racemic mixture, the (+)-enantiomer weakly binds to the µ-opioid receptor, and both enantiomers inhibit serotonin and norepinephrine reuptake. Tramadols major active metabolite, O-desmethyltramadol (ODT), shows higher affinity for the µ-opioid receptor and has twice the analgesic potency of the parent drug. The synergism of these effects contributes to tramadols analgesic properties with the (+)-enantiomer exhibiting 10-fold higher analgesic activity than the (−)-enantiomer. Although tramadol was initially thought to exhibit low abuse potential, Ortho-McNeil, the drugs manufacturer, recently reported a large number of adverse events attributed to tramadol including abuse by opioid-dependent patients, allergic reactions, and seizures. The high number of adverse reactions has prompted the company to update the prescribing information for the drug. An analytical method using gas chromatography-mass spectrometry (GC-MS) without derivatization for the determination of tramadol and its metabolites is reported. An n-butyl chloride extraction is followed by GC-MS analysis using a 5% phenylmethylsilicone column (30 m × 0.32-µm i.d.). Analysis of 12 blood samples from tramadol-related deaths and four nonfatal intoxications involving tramadol revealed concentrations ranging from 0.03 to 22.59 mg/L for tramadol, from 0.02 to 1.84 mg/L for ODT, and from 0.01 to 2.08 mg/L for N-desmethyltramadol. Three deaths were clearly attributable to acute morphine toxicity, one was a doxepin overdose, and six were multiple drug overdoses. The role of tramadol in each death is explored.

A variety of breads and soft drinks were tested and found to contain low concentrations of alcohol. The potential for these products to generate false readings on an evidential breath-alcohol instrument was evaluated. Alcohol-free subjects ingested these products and then provided breath samples into a DataMaster. It was found that breath samples provided immediately after consumption of some of these products, or with them still present in the mouth, did produce low levels of apparent breath alcohol, which may or may not be rejected as invalid by the breath-test instrument. If the subject swallowed or expectorated the food or beverage and then observed a 15-min deprivation period during which nothing was introduced into the mouth, the apparent effect was eliminated. These findings emphasize the need for the mandatory pretest alcohol-deprivation period and the benefits of duplicate breath sampling.

Bupropion is a “second generation” antidepressant agent structurally related to the phenethylamines. Postmortem toxicology data are presented from three suicidal drug overdoses in which bupropion was detected. In two cases in which bupropion was the major toxicology finding, peripheral blood levels of the parent drug were 4.0 and 4.2 mg/L and total metabollte levels were 15 and 16.6 mg/L. Lethal doses in both cases were estimated by history to be less than 10 g.

In a case involving a fatal shooting, toxicology tests on blood and urine demonstrated the presence of cocaine metabolites and a large amount of an unidentified compound. This compound was subsequently identified by mass spectral, gas chromatographic, and thin layer chromatographic tests as laudanosine, a metabolite of the skeletal muscle relaxant atracurium which was administered during emergency surgery. Identification was confirmed by comparison with commercially available standards. Because of the difficulty associated with isolating and chromatographing highly water-soluble compounds, recognition of this artifact is a useful tool in identifying these cases.

This paper describes analytical methods using high-performance liquid chromatography and gas chromatography-mass spectrometry (GC-MS) for the isolation of the nonsteroidal anti-inflammatory drug, ketorolac. The drug is isolated from postmortem blood using a hatched solid-phase extraction method on Amberlite XAD-2 resin. Derivatization of ketorolac using diazopropane was necessary prior to GC-MS analysis. The methods were applied in the investigation of a death occurring shortly after the administration of an intramuscular injection of ketorolac tromethamine. Death was attributed to an adverse reaction to the drug, resulting in anaphylaxis and cardiac arrest.

Ecgonine is formed by the hydrolysis of both ester linkages in cocaine and is of interest as both a potential metabolite and a postmortem and postcollection artifact in biological specimens. Its extreme polarity and water solubility make its isolation very difficult, particularly from complex matrices such as postmortem whole blood. This procedure describes an initial protein precipitation followed by two derivatization steps, the first of which is to propylate organic acids and primary and secondary amines and the second of which is to form the p-nitrobenzoyl ester of organic alcohols. The resultant derivatized products are then subjected to cleanup using a standard extraction with n-butyl chloride as the solvent. Analysis of the extracts is performed by gas chromatography-mass spectrometry using deuterated internal standards, although the adducts would also be suitable for analysis by high-performance liquid chromatography. Significant quantities of ecgonine have been identified in postmortem whole blood samples using this method.