Zolpidem and driving impairment

Zolpidem, a non-benzodiazepine hypnotic, was identified in the blood of 29 subjects arrested for impaired driving. Zolpidem concentrations ranged from 0.05 to 1.4 mg/L (mean 0.29 mg/L, median 0.19 mg/L). In the subjects whose cases we reviewed where zolpidem was present with other drugs and/or alcohol, symptoms reported were generally those of CNS depression. Symptoms included slow movements and reactions, slow and slurred speech, poor coordination, lack of balance, flaccid muscle tone, and horizontal and vertical gaze nystagmus. In five separate cases, where zolpidem was the only drug detected (0.08-1.40 mg/L, mean 0.65 mg/L, median 0.47 mg/L), signs of impairment included slow and slurred speech, slow reflexes, disorientation, lack of balance and coordination, and "blacking out." Although no quantitative relationship between blood concentrations and degree of driving impairment is currently possible, it is reasonable to conclude that because of its specific activity as a sleep inducer, blood concentrations consistent with therapeutic doses of zolpidem have the potential to affect driving in a negative way, and that concentrations above the normal therapeutic range would further impair a person's level of consciousness and driving ability.     

Definition of "positional isomer" as it pertains to the control of schedule I controlled substances. Final rule

On May 25, 2006, DEA published a Notice of Proposed Rulemaking which proposed the addition of a specific definition for the term "positional isomer" to allow for the systematic determination of which isomers of schedule I substances would be considered to be "positional," and therefore, subject to schedule I control. This rulemaking finalizes that definition. The Controlled Substances Act (CSA) and its implementing regulations specify which hallucinogenic substances are considered schedule I controlled substances. The CSA states that all salts, isomers, and salts of isomers of these substances are also schedule I controlled substances. In non-technical terms, an isomer of a substance is a different compound, but a compound which has the same number and kind of atoms. The terms "optical isomer" and "geometric isomer" are specific scientific terms and it is easy to determine whether one substance is an optical or geometric isomer of another. The term "positional isomer," however, is subject to scientific interpretation. The addition of a definition for the term "positional isomer" will assist legitimate research[ers] and industry in determining the control status of materials that are "positional isomers" of schedule I hallucinogens. While the DEA will remain the authority for ultimately determining the control status of a given material, providing a specific definition for "positional isomer" will ensure consistent criteria are utilized in making these determinations. This rule does not change existing laws, regulations, policies, processes, and procedures regarding the determination of control status for schedule I hallucinogenic substances. This rule merely makes available to the public the longstanding definition of "positional isomer" which DEA has used when making these scheduling determinations. This rule is relevant only to specialized forensic or research chemists. Most of these individuals are existing DEA registrants who are authorized by the DEA to handle schedule I hallucinogenic substances.     

Toxicology and characteristics of deaths involving zolpidem in new South wales, australia 2001-2010*

Abstract: All cases presenting to the New South Wales Department of Forensic Medicine between January 1, 2001 and September 31, 2010 in which zolpidem was detected, were retrieved. A total of 91 cases were identified. The mean age was 49.4 years, 65.9% were male, and 61.5% were suicides. Zolpidem was a factor contributing to death in 35 (37.3%) cases, of which 31 (34.1%) involved zolpidem toxicity. The median blood zolpidem concentration was 0.20 mg/L (range 0.05–3.50 mg/L), with no significant gender difference. Drug toxicity cases involving zolpidem had significantly higher median blood zolpidem concentrations than other cases (0.50 vs. 0.10 mg/L). In 83.5% of cases, psychoactive substances other than zolpidem were detected, most commonly antidepressants (46.2%), benzodiazepines (35.2%), opioids (26.4%), and alcohol (39.6%). In summary, zolpidem was a factor contributing to death in a large proportion of cases, predominately involving drug toxicity and suicide.     

赛洛新和赛洛西宾分析方法研究进展

致幻剂是一类低剂量就使人意识、知觉和视觉异常,引起幻觉和情绪障碍的精神活性物质.赛洛新和赛洛西宾是一类具有致幻作用的色胺类化合物,存在于裸盖伞属和斑褶菇属的致幻蘑菇中.当前滥用及娱乐性使用含此类物质的致幻蘑菇的现象日趋严重,由此引起的危害公共安全案(事)件不断增多.因此,对于致幻蘑菇滥用的鉴定是当前司法鉴定领域的重要需...     

GC/MS determination of zolpidem in postmortem specimens in a voluntary intoxication

An ingestion of an unknown quantity of Ivadal (zolpidem) tablets in a case of drug abuse is described. The authors report a new and fast method of analysing and determining the zolpidem concentration in postmortem specimens. Quantitation of zolpidem was performed by ethyl acetate extraction from alkalinized body fluids before GC/MS analysis. The analyses were performed without any complex sample clean-up steps and with little sample material. Postmortem concentrations of zolpidem in body fluids are given. The proposed method is a rapid procedure of analysis in cases of deliberate poisoning with the sedative-hypnotic drug, zolpidem.     

The determination of psilocin and psilocybin in hallucinogenic mushrooms by HPLC utilizing a dual reagent acidic potassium permanganate and tris(2,2'-bipyridyl)ruthenium(II) chemiluminescence detection system

This paper describes a procedure for the determination of psilocin and psilocybin in mushroom extracts using high-performance liquid chromatography with postcolumn chemiluminescence detection. A number of extraction methods for psilocin and psilocybin in hallucinogenic mushrooms were investigated, with a simple methanolic extraction being found to be most effective. Psilocin and psilocybin were extracted from a variety of hallucinogenic mushrooms using methanol. The analytes were separated on a C12 column using a (95:5% v/v) methanol:10 mM ammonium formate, pH 3.5 mobile phase with a run time of 5 min. Detection was realized through a dual reagent chemiluminescence detection system of acidic potassium permanganate and tris(2,2'-bipyridyl)ruthenium(II). The chemiluminescence detection system gave improved detectability when compared with UV absorption at 269 nm, with detection limits of 1.2 x 10(-8) and 3.5 x 10(-9) mol/L being obtained for psilocin and psilocybin, respectively. The procedure was applied to the determination of psilocin and psilocybin in three Australian species of hallucinogenic mushroom.     

Zolpidem distribution in postmortem cases

Zolpidem is the prototype of a class of sedative hypnotic drugs that are derivatives of imidazopyridine and is sold in the United States under the trade name Ambien. Over a four-year period, zolpidem was identified in eight cases investigated by the Office of the Chief Medical Examiner, State of Maryland. Zolpidem was identified by gas chromatography-nitrogen-phosphorus detection (GC-NPD) following an alkaline extraction and was confirmed by full-scan electron impact gas chromatography/mass spectrometry. Zolpidem was quantitated by GC-NPD in all specimens received. Five of the cases presented were deaths due to drug intoxication. In three of these cases, zolpidem was an incidental finding because the drug fatalities resulted from other drugs. In the other two cases of drug intoxication, zolpidem was present in elevated concentrations and was a contributing, but not exclusive cause of the drug intoxication. The remaining three cases were deaths that were not caused by drugs. The blood zolpidem concentrations in these cases were therapeutic (0.28, 0.12 and 0.19 mg/L, respectively). In six of the eight cases where both blood and urine were analyzed, the blood concentration was higher than the urine concentration. The distribution of zolpidem into the liver and kidney failed to identify any sequestration of the drug into either specimen.     

Zaleplon and driving impairment

Zaleplon, a sedative-hypnotic, was identified in the blood of a subject arrested for impaired driving. Symptoms reported were those of central nervous system (CNS) depression. The zaleplon concentration was determined to be 0.13 microg/mL. Symptoms included slow movements and reactions, poor coordination, and lack of balance. Although no quantitative relationship between blood concentrations and degree of driving impairment is currently possible, it is reasonable to conclude that because of its specific activity as a sedative-hypnotic, blood concentrations consistent with doses exceeding therapeutic concentrations of zaleplon have the potential to cause impairment of psychomotor function, and would impair a person's level of consciousness and driving ability.     

Windows of detection of zolpidem in urine and hair: application to two drug facilitated sexual assaults

A LC-MS/MS method for the detection of zolpidem in hair was developed to detect this drug after a single dose in possible drug facilitated sexual assaults. To determine the window of detection of zolpidem in both urine and hair, three volunteers received a 10 mg dose. Urine specimens were collected each 12 h for 144 h. Hair was sampled 3-5 weeks after exposure. Hair and urine extracts were separated on a Xterra MS C18 column using a gradient of acetonitrile and formate buffer. For each compound, detection was related to two daughter ions. Zolpidem was detected for up to 60 h in urine with peak concentrations obtained at 12 h. A single exposure to zolpidem was detected in hair at concentrations ranging from 1.8 to 9.8 pg/mg. Hair analysis was applied to two possible criminal cases. In the first case, zolpidem tested positive in the corresponding hair segment at 4.4 pg/mg. In the other case, zolpidem was detected in all the segments analyzed, demonstrating likely previous drug use in addition to recent exposure associated with a positive blood result.     

HPLC-MS／MS同时检测全血中佐匹克隆、唑吡坦和扎来普隆

目的建立全血中佐匹克隆、唑吡坦和扎来普隆的液相色谱一四级杆飞行时间串联质谱联用同时检测方法。方法采用液液萃取进行提取,提取物以ZorbaxEclipsePlusC18（2．1×50mm,1．8fire）色谱柱分离,以10mmol／L甲酸铵（含0．1％甲酸）一乙腈为流动相梯度洗脱,流速为0．2mL／min,四级杆一飞行时间串联质谱检测。结果全血中佐匹克隆和扎来普隆的线性范围为10ng／mL-500ng／mL,检出限为3ng／mL唑吡坦的线性范围为3ng／mL-300ng／mL,检出限为lng／mL。结论本方法准确、快速、灵敏,可用于全血中佐匹克隆、唑吡坦和扎来普隆的同时定性、定量检测。     

The Appearance,Taste, and Concentrations of Zolpidem Dissolved in Still Water and Carbonated Beverages

Zolpidem is a sedative that could be used to drug victims, but its suitability to dissolve in drinks is unknown. In this small study, we added either crushed or whole tablets of zolpidem hemitartrate to carbonated beverages or still water to observe how this affected the taste and appearance. Also, concentrations were measured by ultra‐high performance liquid chromatography tandem mass spectrometry at different time intervals. Two crushed tablets (20 mg) in cider (250 mL) lead to a maximum concentration of 84 mg/L zolpidem base after 30 min, while the corresponding concentration after adding fifteen tablets (150 mg) was 467 mg/L. There was little change in taste, but froth and turbidity were observed when adding high doses to carbonated beverages. Carbonated beverages spiked with 20 mg of crushed zolpidem hemitartrate tablets reached concentrations that could cause impairment. Spiking with 150 mg could possibly be lethal if several mouthfuls were ingested.     

Distribution profile of 2,5-dimethoxy-4-bromoamphetamine (DOB) in rats after oral and subcutaneous doses

2,5-Dimethoxy-4-bromoamphetamine (DOB) is one of the potent hallucinogenic phenylalkylamines, whose ingestion has already caused several deaths reported all over the world. However, there is unsufficient information on DOB properties based on controlled pharmacokinetic studies available. The aim of this study was to clarify the distribution profile of DOB and its phenolic metabolite 2-methoxy-5-hydroxy-4-bromoamphetamine (2M5H4BA) in blood and biological tissues of experimental rats. The rats were administered a 20 mg/kg dose of DOB·HCl by oral ingestion or subcutaneous injection. Plasma and brain, liver and lung tissues were collected at 0.5, 1, 2, 4, 8, 16, and 32 h after dosing (three animals per time point). The samples were prepared by a liquid–liquid extraction procedure and the extracts were assayed by GC–MS. After per oral application, DOB peak plasma level of 320 ng/mL was reached after one-hour post dosing as well as 2M5H4BA peak concentration of 203 ng/mL. A rapid phase of DOB absorption, 2M5H4BA formation and their tissue distribution during the first two hours after application were followed by a slow decrease rate of the elimination process until 32 h. After subcutaneous application, high plasma levels of the unchanged parent drug and relatively reduced formation of its metabolite 2M5H4BA were observed. DOB maximum plasma concentration of 1143 ng/mL was reached after one-hour post application, whereas its metabolite peak level after 8 h was 213 ng/mL. The concentration profiles of both compounds in plasma after per oral and subcutaneous administration revealed the existence of significant first pass effect after per oral administration that significantly affected DOB bioavailability. DOB tissue concentrations exceeded plasma and the highest values were found in the lungs, where drug accumulation occurred with prolonged retention till 32 h after subcutaneous dose. Although the plasma/tissue transfer was more effective for the lipophilic parent drug than for its hydroxylated metabolite 2M5H4BA, the metabolite tissue levels were significant. The hallucinogenic potential of 2M5H4BA appearing in brain remains unclear as nothing is known about its pharmacological activity at present.     

Concentrations of zolpidem and zopiclone in venous blood samples from impaired drivers compared with femoral blood from forensic autopsies

The concentrations of zolpidem and zopiclone were determined in peripheral blood samples in two forensic materials collected over a 10-year period (2001-2010). The z-hypnotics were determined in venous blood from living subjects (impaired drivers) and in femoral blood from deceased persons (forensic autopsies), with the latter classified as intoxication or other causes of death. The z-hypnotics were determined in blood by capillary column gas chromatography (GC) with a nitrogen-phosphorous (N-P) detector after solvent extraction with n-butyl acetate. The analytical limit of quantitation (LOQ) was 0.02mg/L for zopiclone and 0.05mg/L for zolpidem and these have remained unchanged throughout the study. When death was attributed to drug intoxication (N=918), the median concentration of zopiclone in blood was 0.20mg/L compared with 0.06mg/L for other causes of death (N=1215) and 0.07mg/L in traffic offenders (N=691) (p<0.001). Likewise, a higher median concentration (0.30mg/L) was found in intoxication deaths involving zolpidem (N=357) compared with 0.13mg/L for other causes of death (N=397) or 0.19mg/L in impaired drivers (N=837) (p<0.001). Median concentration in blood of both z-hypnotics were appreciably higher in intoxication deaths when no other substances were identified; 0 70mg/L (N=12) for zopiclone and 1.35mg/L (N=12) for zolpidem. The median concentrations of z-hypnotics in blood decreased as the number of co-ingested substances increased for intoxication deaths but not other causes of death. The most prevalent co-ingested substances were ethanol in autopsy cases and diazepam in the motorists. This large compilation of forensic cases should prove useful when toxicologists are required to interpret concentrations of z-hypnotics in blood samples in relation to cause of death.     

Solid dosage forms: 1975-1983

The changes in the types and drug content of solid dosage forms as analyzed in the ballistics program at the Drug Enforcement Administration (DEA) Special Testing and Research Laboratory from 1975 to 1983 are discussed. Trends and patterns in stimulants, depressants, and hallucinogenic drugs are explained.     

Morphological and chemical analysis of magic mushrooms in Japan

Morphological and toxicological analyses were performed on hallucinogenic mushrooms that are currently circulated in Japan. Scanning electron microscope (SEM) indicated a three-dimensional microstructures in the mushrooms. The complementary use of SEM with an optical microscope was effective for observing characteristic tissues, such as basidiomycetes, spores, cystidia and basidia. Hallucinogenic alkaloids were extracted with methanol and determined by high performance liquid chromatography (HPLC) with a UV detector set at 220 nm. The psilocin/psilocybin contents in Psilocybe cubensis were in the range of 0.14-0.42%/0.37-1.30% in the whole mushroom (0.17-0.78%/0.44-1.35% in the cap and 0.09-0.30%/0.05-1.27% in the stem), respectively. The hallucinogenic alkaloids in Copelandia were 0.43-0.76%/0.08-0.22% in the whole mushroom (0.64-0.74%/0.02-0.22% in the cap and 0.31-0.78%/0.01-0.39% in the stem). It thus appears that P. cubensis is psilocybin-rich, whereas Copelandia is psilocin-rich.     

Forensic analysis of hallucinogenic fungi: a DNA-based approach

Hallucinogenic fungi synthesize two controlled substances, psilocin and psilocybin. Possession of the fungal species that contain these compounds is a criminal offence in North America. Some related species that are morphologically similar, do not contain the controlled substances. Therefore, unambiguous identification of fungi to the species level is critical in determining if a mushroom is illegal. We investigate a phylogenetic approach for the identification of species that contain the psychoactive compounds. We analyzed 35 North American specimens representing seven different genera of hallucinogenic and non-hallucinogenic mushrooms. We amplified and sequenced the internal transcribed spacer region of the rDNA (ITS-1) and a 5' portion of the nuclear large ribosomal subunit of rRNA (nLSU rRNA or 28S). ITS-1 locus sequence data was highly variable and produced a phylogenetic resolution that was not consistent with morphological identifications. In contrast, the nLSU rRNA data clustered isolates from the same species and separated hallucinogen containing and non-hallucinogen containing isolates into distinct clades. With this information, we propose an approach that combines the specificity of PCR detection and the resolving power of phylogenetic analysis to efficiently and unambiguously identify hallucinogenic fungal specimens for legal purposes.     

Hallucinogenic mushrooms on the German market - simple instructions for examination and identification

'Magic mushrooms' is the name most commonly given to psychoactive fungi containing the hallucinogenic components psilocybin and psilocin. Material confiscated by local authorities was examined using morphologic, microscopic, microchemical, and toxicological methods. Psilocybe cubensis was the most popular mushroom in the sample collective, followed by Psilocybe semilanceata, Panaeolus cyanescens and Psilocybe tampanensis. The alkaloid content was determined with <0.003-1.15% of psilocybin and 0.01-0.90% psilocin. Panaeolus cyanescens was the mushroom with highest levels of psilocybin and psilocin.     

Evaluation of postmortem redistribution phenomena for commonly encountered drugs

We described the findings of a study into the post-mortem redistribution (PMR) of 76 drugs found in 129 drug-related cases between 2006 and 2009. Seventy six drugs (psychotropic drugs (n=14), antidepressants (n=9), sedatives (n=6) and so on) were simultaneously quantified in cardiac and peripheral blood by gas chromatography-mass spectrometry (GC/MS) or liquid chromatography-tandem mass spectrometry (LC/MS/MS). The absence, possibility or presence of PMR of drugs was determined according to the ratios of cardiac to femoral blood concentrations (C/P ratios). Proxyphylline (C/P ratio: 0.85) showed no PMR; carbamazepine was not subject to PMR; a potential for PMR of lorazepam and mirtrazapine cannot be excluded; chlordiazepoxide is subject to PMR; acetaminophen and alprazolam exhibit minimal PMR; amitriptyline and benztropine exhibit PMR. Codeine (C/P ratio: 4.9), zolpidem (C/P ratio: 3.74), chlorpromazine (C/P ratio: 2.97), fluoxetine (C/P ratio: 2.83) and propranolol (C/P ratio: 2.72) had the largest C/P ratios. Postmortem drug concentrations showed variations depending on sampling sites and characteristics of the drugs. It is continuously necessary to analyze commonly used or abused drugs in simultaneously collected cardiac and peripheral blood to establish significant reference values for PMR. These findings can be used to reach a conclusion about the cause and manner of death.     

Forensic analysis of hallucinogenic fungi: a DNA-based approach

Hallucinogenic fungi synthesize two controlled substances, psilocin and psilocybin. Possession of the fungal species that contain these compounds is a criminal offence in North America. Some related species that are morphologically similar, do not contain the controlled substances. Therefore, unambiguous identification of fungi to the species level is critical in determining if a mushroom is illegal. We investigate a phylogenetic approach for the identification of species that contain the psychoactive compounds. We analyzed 35 North American specimens representing seven different genera of hallucinogenic and non-hallucinogenic mushrooms. We amplified and sequenced the internal transcribed spacer region of the rDNA (ITS-1) and a 5′ portion of the nuclear large ribosomal subunit of rRNA (nLSU rRNA or 28S). ITS-1 locus sequence data was highly variable and produced a phylogenetic resolution that was not consistent with morphological identifications. In contrast, the nLSU rRNA data clustered isolates from the same species and separated hallucinogen containing and non-hallucinogen containing isolates into distinct clades. With this information, we propose an approach that combines the specificity of PCR detection and the resolving power of phylogenetic analysis to efficiently and unambiguously identify hallucinogenic fungal specimens for legal purposes.