The occurrence of non-anatomical therapeutic chemical-international nonproprietary name molecules in suspected illegal or illegally traded health products in Europe: A retrospective and prospective study.

The General European Official Medicines Control Laboratory (OMCL) Network (GEON), co-ordinated by the European Directorate for the Quality of Medicines & HealthCare (EDQM), regularly organises market surveillance studies on specific categories of suspected illegal or illegally traded products. These studies are generally based on a combination of retrospective and prospective data collection over a defined period of time. This paper reports the results of the most recent study in this context with the focus on health products containing non-Anatomical Therapeutic Chemical-International Nonproprietary Name (ATC-INN) molecules. In total 1104 cases were reported by 16 countries for the period between January 2017 and the end of September 2019. The vast majority of these samples (83%) were collected from the illegal market, while only 3% originated from a legal source. For the rest of the samples, categorisation was not possible. Moreover, 69% of all the reported samples were presented as medicines, including sexual performance enhancers, sports performance enhancers, physical performance enhancers and cognitive enhancers or nootropic molecules that act on the central nervous system (CNS). Although the popularity of anabolics, PDE-5 inhibitors and CNS drugs in illegal products has already been reported, the study showed some new trends and challenges. Indeed, 11% of the samples contained molecules of biological origin, that is, research peptides, representing the second most reported category in this study. Furthermore, the study also clearly shows the increasing popularity of Selective Androgen Receptor Modulators and nootropics, two categories that need attention and should be further monitored.

Rapid assessment of the illegal presence of 1,3-dimethylamylamine (DMAA) in sports nutrition and dietary supplements using 1H NMR spectroscopy.

1,3-Dimethylamylamine (DMAA) is a stimulant that can be found in pre-workout sports nutrition and dietary supplements. This practice is illegal because DMAA is not a safe food ingredient but rather an unapproved medicinal compound due to its pharmacological action. In order to determine the DMAA content in such products, a nuclear magnetic resonance (NMR) spectroscopic method was developed and validated (DMAA was quantified as DMAA-HCl). For quantification, the collective integral from two of the methyl groups of the molecule in the range δ 0.92-0.84 ppm was used. The method was linear over the examined range of 1-21 g/kg (R(2) = 0.9937). The recoveries from spiked concentrations (0.1-6 g/kg) ranged between 85% and 105% (96% on average), with a relative standard deviation (RSD) of 1% for an authentic sample. The detection limit was 0.03 g/kg and the quantification limit was 0.08 g/kg (calculated for 75 mg sample weight). The actual DMAA-HCl content in the sample was quantified using calibration curves (external standardization) or 3,5-dinitrobenzoic acid as single-point internal standard. The developed NMR methodology was applied for the analysis of 16 products, from which 9 samples were found positive (the DMAA-HCl concentration varied between 3.1 g/kg and 415 g/kg). The method can be recommended for routine use in food testing, customs or doping control laboratories.

What is a food and what is a medicinal product in the European Union? Use of the benchmark dose (BMD) methodology to define a threshold for "pharmacological action".

The decision criterion for the demarcation between foods and medicinal products in the EU is the significant "pharmacological action". Based on six examples of substances with ambivalent status, the benchmark dose (BMD) method is evaluated to provide a threshold for pharmacological action. Using significant dose-response models from literature clinical trial data or epidemiology, the BMD values were 63mg/day for caffeine, 5g/day for alcohol, 6mg/day for lovastatin, 769mg/day for glucosamine sulfate, 151mg/day for Ginkgo biloba extract, and 0.4mg/day for melatonin. The examples for caffeine and alcohol validate the approach because intake above BMD clearly exhibits pharmacological action. Nevertheless, due to uncertainties in dose-response modelling as well as the need for additional uncertainty factors to consider differences in sensitivity within the human population, a "borderline range" on the dose-response curve remains. "Pharmacological action" has proven to be not very well suited as binary decision criterion between foods and medicinal product. The European legislator should rethink the definition of medicinal products, as the current situation based on complicated case-by-case decisions on pharmacological action leads to an unregulated market flooded with potentially illegal food supplements.