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In the area of psychotropic drugs, tryptamines are known to be a broad class of classical or serotonergic hallucinogens. These drugs are capable of producing profound changes in sensory perception, mood and thought in humans and act primarily as agonists of the 5-HT 2A receptor. Well-known tryptamines such as psilocybin contained in Aztec sacred mushrooms and N , N -dimethyltryptamine (DMT), present in South American psychoactive beverage ayahuasca, have been restrictedly used since ancient times in sociocultural and ritual contexts. However, with the discovery of hallucinogenic properties of lysergic acid diethylamide (LSD) in mid-1900s, tryptamines began to be used recreationally among young people. More recently, new synthetically produced tryptamine hallucinogens, such as alpha-methyltryptamine (AMT), 5-methoxy- N , N -dimethyltryptamine (5-MeO-DMT) and 5-methoxy- N , N -diisopropyltryptamine (5-MeO-DIPT), emerged in the recreational drug market, which have been claimed as the next-generation designer drugs to replace LSD (‘legal’ alternatives to LSD). Tryptamine derivatives are widely accessible over the Internet through companies selling them as ‘research chemicals’, but can also be sold in ‘headshops’ and street dealers. Reports of intoxication and deaths related to the use of new tryptamines have been described over the last years, raising international concern over tryptamines. However, the lack of literature pertaining to pharmacological and toxicological properties of new tryptamine hallucinogens hampers the assessment of their actual potential harm to general public health. This review provides a comprehensive update on tryptamine hallucinogens, concerning their historical background, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics and their physiological and toxicological effects on animals and humans.

High-resolution mass spectrometry and accurate mass measurement by liquid chromatography/quadrupole-time of flight mass spectrometry (LC/Q-TOFMS) was applied to postmortem plasma and urine specimens from an autopsy of a fatal case involving synthetic cannabinoid use, resulting in the detection of three synthetic cannabinoids: MAM-2201, AM-1220, and AM-2232. We searched for their metabolites existing in postmortem plasma or urine by LC/Q-TOFMS and were able to detect N -dealkylated metabolites, defluorinated and further oxidized metabolites of MAM-2201, and some hydroxylated metabolites. Postmortem plasma concentrations of the parent drugs, N -dealkylated metabolites, and fluorinated and further oxidized metabolites of MAM-2201 were measured, and quantitation results revealed site differences between heart and femoral postmortem plasma concentrations of parent drugs and some metabolites, suggesting postmortem redistribution of the synthetic cannabinoids and their metabolites. Quantitation results suggest that defluorination is a major metabolic pathway for MAM-2201, and N -dealkylation is a common but minor pathway for the naphthoylindole-type synthetic cannabinoids in human.

Abstract Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo. Design. Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. Methods. During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics. Results. Insufflation of both HYD coarse and fine particles led to lower “At this Moment” Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists. Conclusions. HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder.

•The fungus Cunninghamella elegans can metabolize JWH-018, JWH-073 and AM2201.•The majority of the metabolites was produced via phase I metabolism.•The fungal metabolites were found to be in good agreement with the human metabolites. Being marketed as “legal” smoking blends or mixtures, synthetic cannabinoids are abused widely owing to its cannabis-like effect. Due to the rapid introduction of new generation analogues of synthetic cannabinoids to escape from legislative/judicial control, the investigation of the metabolic pathways of these substances is of particular importance for drug control, abstinence and forensic toxicology purposes. In this study, the in vitro metabolism of JWH-018, JWH-073 and AM2201 by the fungus Cunninghamella elagans has been investigated with the purpose of validating its potential as a complementary model for investigating synthetic cannabinoid metabolism. JWH-018, JWH-073 and AM2201 were incubated for 72h with C. elegans. Detection of metabolites was based on liquid chromatography–tandem mass spectrometry and high resolution mass spectrometry analysis. C. elegans was found capable of producing the majority of the phase I metabolites observed in earlier in vitro and in vivo mammalian studies as a result of monohydroxylation, dihydroxylation, carboxylation, dehydrogenation, ketone formation, dihydrodiol formation, dihydrodiol formation with N-dealkylation and combinations thereof. C. elegans can thus be a useful and economic model for studying synthetic cannabinoid metabolism.

Wastewater-based epidemiology is a promising approach worldwide, and its application is currently being developed in non-advanced economies. This technology, based on known toxicokinetic data initially used to detect illicit drugs in well-managed and maintained local sewer networks, has been extended to assess other products such as pesticides, alcohol, flame retardants, nicotine, and other substances. This technology is also used in countries with non-advanced economies. The present review aims to support future wastewater-based epidemiology in such countries by providing toxicokinetic data for locally used narcotic drugs that are expected or known to be emerging in developed countries, outlining the excretion differences due to human polymorphism, and summarising the practical obstacles due to the coverage, maintenance efficiency, or type of local sewage network.Case study feedback from Martinique is presented as an example; the Martinique field study complies with the Organisation for Economic Co-operation and Development standards for health issues, but not with regard to population and urban dynamics.

Pharmacologic and toxic effects of xenobiotics, such as drugs of abuse, depend on the genotype and phenotype of an individual, and conversely on the isoenzymes involved in their metabolism and transport. The current knowledge of such isoenzymes of frequently abused therapeutics such as opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine and codeine), anesthetics ( γ-hydroxybutyric acid, propofol, ketamine and phencyclidine) and cognitive enhancers (methylphenidate and modafinil), and some important plant-derived hallucinogens (lysergide, salvinorin A, psilocybin and psilocin), as well as of nicotine in humans are summarized in this article. The isoenzymes (e.g., cytochrome P450, glucuronyltransferases, esterases and reductases) involved in the metabolism of drugs and some pharmacokinetic data are discussed. The relevance of such data is discussed for predicting possible interactions with other xenobiotics, understanding pharmacokinetic behavior and pharmacogenomic variations, assessing toxic risks, developing suitable toxicological analysis procedures, and finally for interpretating drug testing results.

With respect to the continuous emergence of new synthetic cannabinoids on the market since 2008, evaluation of the metabolism of these compounds and the development of analytical methods for the detection of these drugs including their respective metabolites in biological fluids have become essential. Other than JWH-018 or JWH-073, AM-2201 is one of the frequently identified synthetic cannabinoids in Korea. Recently, in our laboratory, several JWH-018 metabolites have been detected in some urine samples obtained from subjects who were arrested for the possession of herbal mixtures containing only AM-2201 or from those who confessed AM-2201 abuse. In the present study, we identified major urinary metabolites of AM-2201 and several metabolites of JWH-018, i.e., N -5-hydroxylated and carboxylated metabolites from rats administered AM-2201 and found that the metabolic profile in rats was similar to those in human subjects in this study. Analytical results of the urine samples from suspects who had a considerable possibility of AM-2201 or JWH-018 intake were also compared to distinguish between AM-2201 and JWH-018 abuse. The presence of 6-indole hydroxylated metabolites of each drug and N -4-hydroxy metabolite of AM-2201 was found to contribute to the decisive differences in the metabolic patterns of the two drugs. In addition, the concentration ratio of the N -(5-hydroxypentyl) metabolite to the N -(4-hydroxypentyl) metabolite of JWH-018 may be used as a criterion to differentiate between AM-2201 and JWH-018 abuse.

Objective. To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design. Randomized, double-blind, placebo-controlled, crossover study. Setting and Patients. One study site in the United States; adult nondependent, recreational opioid users. Methods. After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was “at the moment” drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results. Mean maximum effect (Emax) for “at the moment” drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (Emax: 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective “at the moment” drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions. The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated.

Opioid-related deaths, abuse, and drug interactions are growing epidemic problems that have medical, social, and economic implications. Drug transporters play a major role in the disposition of many drugs, including opioids; hence they can modulate their pharmacokinetics, pharmacodynamics and their associated drug-drug interactions (DDIs). Our understanding of the interaction of transporters with many therapeutic agents is improving; however, investigating such interactions with opioids is progressing relatively slowly despite the alarming number of opioids-mediated DDIs that may be related to transporters. This review presents a comprehensive report of the current literature relating to opioids and their drug transporter interactions. Additionally, it highlights the emergence of transporters that are yet to be fully identified but may play prominent roles in the disposition of opioids, the growing interest in transporter genomics for opioids, and the potential implications of opioid-drug transporter interactions for cancer treatments. A better understanding of drug transporters interactions with opioids will provide greater insight into potential clinical DDIs and could help improve opioids safety and efficacy.

N -benzylpiperazine (BZP) has become popular among recreational drug users as the major active ingredient of “party pills” due to its stimulant and euphoric properties. Before BZP legal restrictions, these pills were sold as a safe and legal alternative to classical amphetamines like ecstasy. New Zealand, given the size of its legal market prior to BZP control, is the country that most contributed to the knowledge about the patterns of use, motivations and positive and adverse effects resulting from its consumption, though the interest in BZP-party pills was observed all over the world. The use of these pills has been associated with hospitalizations for adverse events and continued availability over the Internet makes this intoxication a continued concern. This paper provides a review on the characteristics of BZP recreational use, specifically the target population, patterns and motivations of use, and evolution of legal status. Moreover, the in vivo and in vitro studies performed in order to understand its pharmacology, toxicology and kinetics are also discussed. Lastly, analytical methodologies for the identification of BZP in clinical and forensic settings are addressed.