benzofurans and Substance-Related-Disorders

Benzofurans, also known by users as benzo fury or benzofury, are synthetic phenethylamines and constitute the third most prominent group of new psychoactive substances (NPS). As the use of these substances has been spread as an alternative to the classic illicit psychostimulants, such as amphetamines, their legal status was reviewed, resulting in an utter prohibition of these NPS in many countries worldwide. Herein, the prevalence of abuse, chemistry, biological effects, metabolism, and the potential harms and risky behaviors associated with the abuse of benzofurans are reviewed. The congeners of this group are mainly consumed recreationally at electronic dance music parties, in polydrug abuse settings. Benzofurans preferentially act by disturbing the functioning of serotonergic circuits, which induces their entactogenic and stimulant effects and is the reason behind the considerable number of recent benzo fury-related deaths. The slight interaction of these drugs with the dopaminergic system justifies the rewarding effects of these drugs. To date, published evidence on the mechanisms of toxicity of benzo fury is very limited but a body of research is now beginning to emerge revealing an alarming public health threat regarding the abuse of these NPS.

Topics: Benzofurans; Drug Misuse; Health Risk Behaviors; Humans; Illicit Drugs; Psychotropic Drugs; Substance-Related Disorders

5-(2-ethylaminopropyl)benzofuran (5-EAPB) and 5,6-methylenedioxy-2-aminoindane (MDAI) are two new psychoactive substances (NPS) exhibiting MDMA-like properties. In this paper, we report the case of a 28-years old man, known as drug addict, found dead at home, with two unidentified powders next to him. External examination by the forensic pathologist was unremarkable but no autopsy was performed. Powders, blood and urine (which were the only samples available) were submitted to general unknown screening by high pressure liquid chromatography with a diode array detector (HPLC-DAD) and ultra high pressure liquid chromatography with a time-of-flight detector (UPLC-TOF-MS), after liquid-liquid extraction for biological samples, or simple dilution for powders. Analysis revealed 68% of MDAI in one powder and 87% of 5-EAPB in the other one. Significant levels of the same substances were found in blood (MDAI: 2.09 mg/L and 5-EAPB: 6.45 mg/L). The cause of death was therefore attributed to the consumption of these NPS since screening for other drugs of abuse and for alcohol was negative (oxazepam was found in urine only). 5-methylaminopropylbenzofuran (5-MAPB) and 5-aminopropylbenzofuran (5-APB) were also found in blood (0.089 and 0.546 mg/L, respectively) and urine (1.00 and 4.88 mg/L, respectively). In addition to the inherent complexity of NPS identification by itself, another analytical difficulty in this case was the identification of the EAPB positional isomer. Our routine screening methods were not able to distinguish the positional isomer, but an additional classical gas chromatography technique was able to make the distinction. Anyway, in our case, this issue was simplified thanks to the availability of a relatively pure powder that was analyzed by nuclear magnetic resonance (NMR).

Topics: Adult; Benzofurans; Chromatography, Gas; Chromatography, High Pressure Liquid; Humans; Indans; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Molecular Structure; Psychotropic Drugs; Substance Abuse Detection; Substance-Related Disorders

For the new psychoactive drug 5-(2-aminopropyl) benzofuran (5-APB), very limited knowledge is available regarding lethal concentrations. We present a case and report the post mortem blood concentration of a fatal outcome for a 25 year old man related to the consumption of 5-APB. After intake, he became unconscious and stopped breathing. Cardiopulmonary resuscitation was started without success. After 30min he was declared dead at the scene. During autopsy, whole blood from the femoral vein was collected and screened for a wide range of medicinal drugs and drugs of abuse. 5-APB was initially identified by ultra high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) and subsequently confirmed by using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The only toxicological findings were ethanol 0.6g/L, tetrahydrocannabinol (THC) 0.0024mg/L and 5-APB 0.86mg/L. The cause of death was attributed to intake of 5-APB. Only one previous report of a fatal 5-APB concentration as the main toxicological agent exist in the literature, and the present concentration indicated that 5-APB could be lethal in lower concentrations than previously reported.

Topics: Adult; Benzofurans; Chromatography, High Pressure Liquid; Designer Drugs; Fatal Outcome; Humans; Male; Mass Spectrometry; Molecular Structure; Propylamines; Pulmonary Edema; Substance-Related Disorders

The acute and chronic toxicity of several new psychoactive substances (NPS) is unknown, and only little information is available on the pharmacology and toxicology, toxicokinetics, and detectability in body samples of such new compounds. We here propose analytical methods to disclose acute and chronic use of two types of new psychostimulants: benzofurans and ethylphenidate and we applied them to a real case of a subject attending Emergency Department with signs of acute intoxication due to psychotropic drug(s). After a urinary immunoassay screening which gave a positivity to amphetamines, general unknown gas chromatography-mass spectrometry (GC-MS) urine analysis identified 5-(2-methylaminopropyl)benzofuran (5-MAPB), 5-(2-aminopropyl)benzofuran (5-APB), 5-(2-ethylaminopropyl)benzofuran (5-EAPB), ethylphenidate, and ritalinic acid. All these substances were confirmed and quantified not only in urine but also in serum samples at different times after hospitalization by GC-MS and ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Two subsequent 2-cm hair segments were also analyzed and tested positive for the above reported substances, evidencing repeated use. The matching quantitative results in all the analyzed biological matrices demonstrated that both analytical methodologies were suitable to correctly quantify NPS involved in the current intoxication. The objective assessment of acute and chronic intoxication by the above reported compounds demonstrate that the development of analytical methods aiming at the detection of a broad spectrum of compounds in conventional and non-conventional biological matrices is helpful when facing the new challenging threat of intoxications caused by NPS.

Topics: Benzofurans; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Hair; Humans; Immunoassay; Male; Methylphenidate; Psychotropic Drugs; Substance Abuse Detection; Substance-Related Disorders; Tandem Mass Spectrometry; Young Adult

Intoxication cases involving new psychoactive substances (NPS) provide several challenges for forensic toxicologists as data on pharmacodynamic and pharmacokinetic properties are lacking, especially on potency and toxicity. Furthermore, reference values and information on postmortem redistribution (PMR) do not exist so far for most NPS. A fatal case involving the amphetamine-derivatives MDAI (5,6-methylenedioxy-2-aminoindane) and 2-MAPB (1-(benzofuran-2-yl)-N-methylpropan-2-amine) was investigated at the Zurich Institute of Forensic Medicine. At admission at the institute approx. 11h after death (first time point, t1), femoral and heart blood (right ventricle) was collected using computed tomography (CT)-guided biopsy sampling. At autopsy (t2), samples from the same body regions as well as various tissue samples were collected manually. In addition, an antemortem blood sample collected 6h before death was available. MDAI and 2-MAPB were quantified using a validated LC-MS/MS method. A significant concentration decrease between the antemortem and the first peripheral postmortem blood sample was observed, which most probably can be explained by remaining metabolism and excretion within the last 6h prior to death. No significant concentration change was observed between the two postmortem heart blood and peripheral blood samples. Accordingly, MDAI and 2-MAPB did not seem to undergo relevant postmortem redistribution in peripheral and heart blood in the presented case. This is the first study on postmortem redistribution of the new psychoactive substances MDAI and 2-MAPB. However, more studies covering more cases are necessary to generate universal statements on the PMR with these two NPSs.

Topics: Adipose Tissue; Adult; Benzofurans; Cerebellum; Chromatography, Liquid; Frontal Lobe; Humans; Indans; Kidney; Liver; Male; Mass Spectrometry; Muscle, Skeletal; Myocardium; Postmortem Changes; Psychotropic Drugs; Spleen; Substance-Related Disorders

Although 5-(2-aminopropyl)benzofuran (5-APB) and 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (phenazepam) are being used as recreational drugs, research on their dependence liability or mechanisms of action is lacking. The present study aimed to evaluate the behavioral effects and dependence liability of these drugs using conditioned place preference and self-administration paradigms in rodents. Additionally, biochemical techniques were used to assess the substance-induced alterations in synaptosome-released dopamine. While both of the tested substances elicited increases in conditioned place preference and dopamine, neither of them facilitated self-administration, suggesting that 5-APB and phenazepam have rewarding effects, rather than reinforcing effects.

Topics: Animals; Benzodiazepines; Benzofurans; Brain; Designer Drugs; Dopamine; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Propylamines; Rats; Rats, Sprague-Dawley; Self Administration; Substance-Related Disorders

To characterise the patterns of presentation and clinical features of toxicity following reported recreational use of benzofuran compounds ((2-aminopropyl)-2,3-dihydrobenzofurans) in the UK, as reported to the National Poisons Information Service (NPIS), and to compare clinical features of toxicity with those after reported mephedrone use.. NPIS patient-specific telephone enquiries and user sessions for TOXBASE(®), the NPIS online information database, related to (2-aminopropyl)-2,3-dihydrobenzofurans and associated synonyms were reviewed from March 2009 to August 2013. These data were compared with those of mephedrone, the recreational substance most frequently reported to NPIS, collected over the same period.. There were 63 telephone enquiries concerning 66 patients and 806 TOXBASE(®) user sessions regarding benzofuran compounds during the period of study. The first telephone enquiry was made in July 2010 and the highest numbers of enquiries were received in August 2010 (33 calls, 112 TOXBASE(®) sessions). Patients were predominantly male (82%) with a median age of 29 years; 9 reported co-ingestion of other substances. Comparing the 57 patients who reported ingesting benzofuran compounds alone with 315 patients ingesting mephedrone alone, benzofurans were more often associated with stimulant features, including tachycardia, hypertension, mydriasis, palpitation, fever, increased sweating, and tremor, (72% vs. 38%, odds ratio [OR] 4.2, 95% confidence interval [CI] 2.27-7.85, P < 0.0001) and mental health disturbances (58% vs. 38%, OR 2.3, 95% CI 1.29-4.07, P = 0.006). Other features reported after benzofuran compound ingestion included gastrointestinal symptoms (16%), reduced level of consciousness (9%), chest pain (7%), and creatinine kinase elevation (5%).. Reported ingestion of benzofuran compounds is associated with similar toxic effects to those of amphetamines and cathinones. Mental health disturbances and stimulant features were reported more frequently following reported ingestion of benzofuran compounds than after ingestion of mephedrone.

Topics: Adolescent; Adult; Aged; Benzofurans; Central Nervous System Stimulants; Databases, Factual; Drug Information Services; Drug Overdose; Female; Humans; Illicit Drugs; Internet; Male; Methamphetamine; Middle Aged; Odds Ratio; Poison Control Centers; Prognosis; Severity of Illness Index; Substance-Related Disorders; Telephone; Time Factors; United Kingdom; Young Adult

The emergence of a large number of new psychoactive substances (NPSs) in recent years poses a serious problem to clinical and forensic toxicologists. Here we report a patient who administrated ca. 500mg of 3-MMC (3-methyl-N-methylcathinone) and 400mg of 5-APB (5-(2-aminopropyl)benzofuran) in combination with 80g of ethyl alcohol. The clinical manifestations included agitation, seizures, hypertension, tachycardia, hyperthermia and bradycardia. The patient did not recover and died around 4h after the use of drugs. The cause of death was acute cardiovascular collapse that occurred following mixed intoxication with NPSs and alcohol. Toxicological analysis of post-mortem blood revealed 3-MMC and 5-APB in concentrations of 1.6μg/mL and 5.6μg/mL, respectively. Moreover, the serum alcohol concentration was 1.4g/L in ante-mortem sample collected 1h after admission to the hospital. This is the first report on blood concentration of 3-MMC and 5-APB in fatal intoxication.

Topics: Alcohol Drinking; Benzofurans; Blood Alcohol Content; Central Nervous System Stimulants; Designer Drugs; Drug Overdose; Forensic Toxicology; Humans; Male; Methamphetamine; Propylamines; Substance-Related Disorders; Young Adult

Ketamine is a noncompetitive antagonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor that is used in human and animal medicine as an injectable anesthetic. The illegal use of ketamine as a recreational drug is rapidly growing. Very little is currently known about the consequences of repeated ketamine exposure in the human brain. Animal studies indicate that the prefrontal dopaminergic system is particularly vulnerable to the toxic effects of repeated administration of NMDA antagonists. In this study, dopamine D1 receptor availability was assessed by using positron emission tomography and the selective D1 receptor radioligand [11C]NNC 112 in a group of 14 recreational chronic ketamine users and matched healthy subjects.. History of ketamine abuse was confirmed in subjects by hair analysis. [11C]NNC 112 binding potential was measured with kinetic analysis using the arterial input function.. Dorsolateral prefrontal cortex D1 receptor availability was significantly up-regulated in chronic ketamine users ([11C]NNC 112 binding potential: mean=1.68 ml/g, SD=0.40) relative to comparison subjects (mean=1.35 ml/g, SD=0.35). No significant differences were noted in other cortical, limbic, or striatal regions. In the chronic ketamine user group, dorsolateral prefrontal cortex [11C]NNC 112 binding potential up-regulation was significantly correlated with the number of vials of ketamine (with a vial representing approximately 200-300 mg of ketamine) used per week.. Chronic ketamine users exhibited a regionally selective up-regulation of D1 receptor availability in the dorsolateral prefrontal cortex, a phenomenon observed following chronic dopamine depletion in animal studies. These data suggest that the repeated use of ketamine for recreational purposes affects prefrontal dopaminergic transmission, a system critically involved in working memory and executive function.

Topics: Adult; Analgesics; Benzazepines; Benzofurans; Carbon Radioisotopes; Dopamine; Female; Functional Laterality; Hair; Humans; Illicit Drugs; Ketamine; Male; Memory; Positron-Emission Tomography; Prefrontal Cortex; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Substance Abuse Detection; Substance-Related Disorders; Tissue Distribution; Up-Regulation

Topics: Amphetamine; Benzofurans; Chromatography, Ion Exchange; Chromatography, Thin Layer; Drug Stability; Evaluation Studies as Topic; Fluorescence; Glutethimide; Humans; Indicators and Reagents; Methadone; Methamphetamine; Methods; Microchemistry; Morphine; Pentobarbital; Phenobarbital; Phenothiazines; Quinine; Spiro Compounds; Substance-Related Disorders; Time Factors