Sympathomimetic agents are a group of chemical compounds that are able to activate the sympathetic nervous system either directly via adrenergic receptors or indirectly by increasing endogenous catecholamine levels or mimicking their intracellular signaling pathways. Compounds from this group, both used therapeutically or abused, comprise endogenous catecholamines (such as adrenaline and noradrenaline), synthetic amines (e.g., isoproterenol and dobutamine), trace amines (e.g., tyramine, tryptamine, histamine and octopamine), illicit drugs (e.g., ephedrine, cathinone, and cocaine), or even caffeine and synephrine. In addition to the effects triggered by stimulation of the sympathetic system, the discovery of trace amine associated receptors (TAARs) in humans brought new insights about their sympathomimetic pharmacology and toxicology. Although synthetic sympathomimetic agents are mostly seen as toxic, natural sympathomimetic agents are considered more complacently in the terms of safety in the vision of the lay public. Here, we aim to discuss the pharmacological and mainly toxicological aspects related to sympathomimetic natural agents, in particular of trace amines, compounds derived from plants like ephedra and khat, and finally cocaine. The main purpose of this review is to give a scientific and updated view of those agents and serve as a reminder on the safety issues of natural sympathomimetic agents most used in the community.

Department of Pharmacology and Toxicology Faculty of Pharmacy Charles University 500 05 Hradec Králové Czech Republic

Laboratório Associado i4HB Instituto para a Saúde e a Bioeconomia Laboratório de Toxicologia Departamento de Ciências Biológicas Faculdade de Farmácia Universidade do Porto Rua Jorge Viterbo 228 4050 313 Porto Portugal

Post Graduation Program in Bioexperimentation University of Passo Fundo BR 285 Passo Fundo São José 99052 900 RS Brazil

UCIBIO REQUIMTE Laboratory of Toxicology Faculty of Pharmacy University of Porto Rua Jorge Viterbo Ferreira 228 4050 313 Porto Portugal

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The psychostimulant drug, fenethylline (captagon): Health risks, addiction and the global impact of illicit trade