Pharmacological profiles of compounds in preworkout supplements ("boosters").

Preworkout supplements ("boosters") are used to enhance physical and mental performance during workouts. These products may contain various chemical substances with undefined pharmacological activity. We investigated whether substances that are contained in commercially available athletic multiple-ingredient preworkout supplements exert amphetamine-type activity at norepinephrine, dopamine, and serotonin transporters (NET, DAT, and SERT, respectively). We assessed the in vitro monoamine transporter inhibition potencies of the substances using human embryonic kidney 293 cells that expressed the human NET, DAT, and SERT. The phenethylamines ß-phenethylamine, N-methylphenethylamine, ß-methylphenethylamine, N-benzylphenethylamine, N-methyl-ß-methylphenethylamine, and methylsynephrine inhibited the NET and less potently the DAT similarly to D-amphetamine. ß-phenethylamine was the most potent, with IC50 values of 0.05 and 1.8 µM at the NET and DAT, respectively. These IC50 values were comparable to D-amphetamine (IC50 = 0.09 and 1.3 µM, respectively). The alkylamines 1,3-dimethylbutylamine and 1,3-dimethylamylamine blocked the NET but not the DAT. Most of the phenethylamines interacted with trace amine-associated receptor 1, serotonin 5-hydroxytryptamine-1A receptor, and adrenergic α1A and α2A receptors at submicromolar concentrations. None of the compounds blocked the SERT. In conclusion, products that are used by athletes may contain substances with mainly noradrenergic amphetamine-type properties.

The Use of Prescription Drugs, Recreational Drugs, and "Soft Enhancers" for Cognitive Enhancement among Swiss Secondary School Students.

The use of prescription or recreational drugs for cognitive enhancement (CE) is prevalent among students. However, the prevalence of CE among Swiss school students is unknown. We therefore performed a cross-sectional online survey including ≥ 16-year-old students from bridge-year schools (10th grade), vocational schools, and upper secondary schools (10th-12th grade) in the Canton of Zurich to investigate the prevalence of and motives for the use of prescription drugs, recreational drugs, and/or freely available soft enhancers for CE. A total of 1,139 students were included. Of these, 54.5% reported the use of prescription drugs (9.2%), recreational drugs including alcohol (6.2%), or soft enhancers (51.3%) explicitly for CE at least once in their lives. The last-year and last-month prevalence for CE considering all substances was 45.5% and 39.5%, respectively. Soft enhancers were the substances that were most commonly used (ever, last-year, and last-month, respectively), including energy drinks (33.3%, 28.4%, and 24.6%), coffee (29.8%, 25.1%, and 21.9%), and tobacco (12.6%, 9.3%, and 8.3%). CE with methylphenidate was less prevalent (4.0%, 2.8%, and 2.0%). However, the use of prescription drugs, alcohol, or illegal drugs for CE was reported by 13.3% of the participants. The most common motives for use were to stay awake and improve concentration. CE was more prevalent among students who reported higher levels of stress or performance pressure and students with psychiatric disorders. In conclusion, half of the school students had used a substance at least once in their lives to improve school performance. Soft enhancers were most commonly used. Prevalence rates were similar to those reported by Swiss university students, indicating that the use of prescription or recreational drugs for CE already occurs before starting higher education. Performance pressure, stress, and psychiatric disorders may be associated with CE.

Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs).

BACKGROUND: N-2-methoxybenzyl-phenethylamines (NBOMe drugs) are newly used psychoactive substances with poorly defined pharmacological properties. The aim of the present study was to characterize the receptor binding profiles of a series of NBOMe drugs compared with their 2,5-dimethoxy-phenethylamine analogs (2C drugs) and lysergic acid diethylamide (LSD) in vitro. METHODS: We investigated the binding affinities of 2C drugs (2C-B, 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4, 2C-T-7, and mescaline), their NBOMe analogs, and LSD at monoamine receptors and determined functional 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2B receptor activation. Binding at and the inhibition of monoamine uptake transporters were also determined. Human cells that were transfected with the respective human receptors or transporters were used (with the exception of trace amine-associated receptor-1 [TAAR1], in which rat/mouse receptors were used). RESULTS: All of the compounds potently interacted with serotonergic 5-HT2A, 5-HT2B, 5-HT2C receptors and rat TAAR1 (most Ki and EC50: <1 µM). The N-2-methoxybenzyl substitution of 2C drugs increased the binding affinity at serotonergic 5-HT2A, 5-HT2C, adrenergic α1, dopaminergic D1-3, and histaminergic H1 receptors and monoamine transporters but reduced binding to 5-HT1A receptors and TAAR1. As a result, NBOMe drugs were very potent 5-HT2A receptor agonists (EC50: 0.04-0.5 µM) with high 5-HT2A/5-HT1A selectivity and affinity for adrenergic α1 receptors (Ki: 0.3-0.9 µM) and TAAR1 (Ki: 0.06-2.2 µM), similar to LSD, but not dopaminergic D1-3 receptors (most Ki:>1 µM), unlike LSD. CONCLUSION: The binding profile of NBOMe drugs predicts strong hallucinogenic effects, similar to LSD, but possibly more stimulant properties because of α1 receptor interactions.