According to the EU Early Warning System (EWS), synthetic cathinones (SCs) are the second largest new psychoactive substances (NPS) class, with 162 synthetic cathinones monitored by the EU EWS. They have a similar structure to cathinone, principally found in Catha Edulis; they have a phenethylamine related structure but also exhibit amphetamine-like stimulant effects. Illegal laboratories regularly develop new substances and place them on the market. For this reason, during the last decade this class of substances has presented a great challenge for public health and forensic toxicologists. Acting on different systems and with various mechanisms of action, the spectrum of side effects caused by the intake of these drugs of abuse is very broad. To date, most studies have focused on the substances’ cardiac effects, and very few on their associated neurotoxicity. Specifically, synthetic cathinones appear to be involved in different neurological events, including increased alertness, mild agitation, severe psychosis, hyperthermia and death. A systematic literature search in PubMed and Scopus databases according to PRISMA guidelines was performed. A total of 515 studies published from 2005 to 2022 (350 articles from PubMed and 165 from Scopus) were initially screened for eligibility. The papers excluded, according to the criteria described in the Method Section (n = 401) and after full text analyses (n = 82), were 483 in total. The remaining 76 were included in the present review, as they met fully the inclusion criteria. The present work provides a comprehensive review on neurotoxic mechanisms of synthetic cathinones highlighting intoxication cases and fatalities in humans, as well as the toxic effects on animals (in particular rats, mice and zebrafish larvae). The reviewed studies showed brain-related adverse effects, including encephalopathy, coma and convulsions, and sympathomimetic and hallucinogenic toxidromes, together with the risk of developing excited/agitated delirium syndrome and serotonin syndrome.

Our understanding of tryptamines is poor due to the lack of data globally. Tryptamines currently are not part of typical toxicology testing regimens and their contribution to drug overdoses may be underestimated. Although their prevalence was low, it is increasing. There are few published data on the many new compounds, their mechanisms of action, onset and duration of action, toxicity, signs and symptoms of intoxication and analytical methods to identify tryptamines and their metabolites. We review the published literature and worldwide databases to describe the newest tryptamines, their toxicology, chemical structures and reported overdose cases. Tryptamines are 5-HT_2A receptor agonists that produce altered perceptions of reality. Currently, the most prevalent tryptamines are 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 5-methoxy-N,N- diallyltryptamine (5-MeO-DALT) and dimethyltryptamine (DMT). From 2015 to 2020, 22 new analytical methods were developed to identify/quantify tryptamines and metabolites in biological samples, primarily by liquid chromatography tandem mass spectrometry. The morbidity accompanying tryptamine intake is considerable and it is critical for clinicians and laboratorians to be informed of the latest data on this public health threat.

Sexual enhancers increase sexual potency, sexual pleasure, or libido. Substances increasing libido alter the concentrations of specific neurotransmitters or sex hormones in the central nervous system. Interestingly, the same pathways are involved in the mechanisms underlying many psychiatric and neurological disorders, and adverse reactions associated with the use of aphrodisiacs are strongly expected. However, sexual enhancers of plant origin have gained popularity over recent years, as natural substances are often regarded as a safer alternative to modern medications and are easily acquired without prescription. We reviewed the psychiatric and neurological adverse effects associated with the consumption of herbal aphrodisiacs Areca catechu L., Argemone Mexicana L., Citrus aurantium L., Eurycoma longifolia Jack., Lepidium meyenii Walp., Mitragyna speciosa Korth., Panax ginseng C. A. Mey, Panax quinquefolius L., Pausinystalia johimbe (K. Schum.) Pierre ex Beille, Piper methysticum G. Forst., Ptychopetalum olacoides Benth., Sceletium tortuosum (L.) N. E. Brown, Turnera diffusa Willd. ex. Schult., Voacanga africana Stapf ex Scott-Elliot, and Withania somnifera (L.) Dunal. A literature search was conducted on the PubMed, Scopus, and Web of Science databases with the aim of identifying all the relevant articles published on the issue up to June 2020. Most of the selected sexual enhancers appeared to be safe at therapeutic doses, although mild to severe adverse effects may occur in cases of overdosing or self-medication with unstandardized products. Drug interactions are more concerning, considering that herbal aphrodisiacs are likely used together with other plant extracts and/or pharmaceuticals. However, few data are available on the side effects of several plants included in this review, and more clinical studies with controlled administrations should be conducted to address this issue.

Licit and illicit drugs affecting the central nervous system have the potential to impair driving ability. The effects of drugs on driving performance should be checked with drug concentration in the brain and at the same time with the evaluation of both the behavioural and neurophysiological effects. The best accessible indicator of this information is the concentration of the drug and/or metabolites in blood and, to a certain extent, oral fluid. Neurocognitive tasks under the influence of drugs should be also monitored. Up to 2010, no epidemiological studies were available on this matter and International scientists suggested that even minimal amounts of parent drugs in blood and oral fluid could affect driving impairment. More recently, epidemiological data, systematic reviews and meta-analysis on drugged drivers allowed the suggestion of impairment concentration limits for the most common illicit drugs. These values were obtained comparing driving disability induced by psychotropic drugs with that of established blood alcohol limits. Differently from ethyl alcohol where both detection methods and concentration limits have been well established even with inhomogeneity of ranges within different countries, in case of drugs of abuse no official cut-offs have yet been established, nor any standardized analytical protocols. Furthermore, few studies systematically evaluated cognitive ability and performance when drugged. In this scenario, we sought to review international studies on correlation between blood and oral fluid drug concentrations, neurological correlates and cognitive impairment in driving under the influence of drugs (DUID).

Melatonin (MEL) is an indoleamine produced mainly by the pineal gland in vertebrates. It plays a significant role in the regulation of circadian rhythms, mitigation of sleeping disorders, and jet lag. This compound is synthetized from tryptophan (TRP) and it has been found in seeds, fruits, and fermented beverages, including wine. Wine is also a source of other tryptophan derivatives, the tryptophan ethylester (TEE) and MEL isomers (MISs), for which the biological properties need to be elucidated. An analytical method for the simultaneous quantification of TRP, TEE, and MEL was developed by a Solid Phase Extraction (SPE) of a preconcentration of wine followed by high performance liquid chromatography (HPLC) analysis either with fluorescence or mass spectrometer detectors. The analytical method showed a relative standard deviation (RSD) lower than 8%, except for TRP (RSD 10.5% in wine). The recovery was higher than 76%. The versatility of SPE preconcentrations allowed for the adequate preconcentration of wine sample as well as detection of low concentrations, an important aspect especially for MEL (detection limit 0.0023 µg/L). The proposed method proved to be suitable for assessing the investigated compounds in some red wine samples, where 74.4–256.2 µg/L and 0.038–0.063 µg/L of TEE and MEL were detected, respectively. Five MISs were also found in wine samples in concentrations up to 1.97 µg/L.