Anabolic steroid and new psychoactive compounds (Smart Drugs) abuse and dependence as a social evil that interests both the health care and legal systems. Organ damage in healthy young athletes: epidemiologic, biochemical, pathological, toxicologi

Research project

Description

Self-administration of high doses of anabolic androgenic steroids (AAS) is widespread among young athletes to optimize strength and gain muscle mass. AAS abuse has increased in last decades, particularly among non-athletes at fitness centers for aesthetic purposes and it is estimated that more than ﰓ3 million individuals in the United States and 1 milion in Europe currently abuse AAS, including nandrolone decanoate, methandienone, stanozolol, androsterone, and androstane. AAS are synthetic derivatives of the male sex hormone testosterone and have androgenic (development and sustainment of secondary sex characteristics), anabolic (tissue-building) and hedonic effects. The anabolic effects cannot be separated entirely from the androgenic ones even if many efforts have been made to alter the relative anabolic androgenic potency, slow the rate of inactivation, and change the pattern of metabolism through structural modifications of testosterone molecule which is the most important androgen secreted in eugonadal man. The various clinical effects are determined by the type and concentrations of androgen receptors and enzymes controlling steroid metabolism in a given organ. Other mechanisms include an anticatabolic effect by interfering with glucocorticoid receptor expression. In summary the classical pathway of androgen action involves steroid binding to the androgen receptors (ARs), a ligand-activated transcription factor, and single copy member of the nuclear receptor superfamily, acting on the genome. The genomic action of ARs is modulated by a large variety of coregulators, which are proteins that target gene expression by enhancing (coactivator) or restraining (corepressor) transcription. Finally, AAS may also have direct rewarding or hedonic properties, mediated not so much by their genomic effects (although these may well contribute) but more directly by the effects of AAS and their metabolites on plasma membranes. Rapid, nongenomic effects of steroid androgens are distinguished from genomic ones by 1) rapid onset (seconds to minutes) which is faster than genomic mechanisms, 2) insensitivity to inhibition of RNA and protein synthesis, 3) effects produced by steroids unable to access the nucleus (either covalently linked to membrane im- permeable macromolecules or in cells lacking a nucleus), and 4) not usually blocked by classical antagonists due to different steroidal specificity from classical cognate nuclear receptors. As for other steroids, nongenomic androgen effects characteristically involve the rapid induction of conventional second messenger signal transduction cascades, including increases in cytosolic calcium and activation of protein kinase A, protein kinase C, and MAPK (mitogen- activated protein kinase), leading to diverse cellular effects including smooth muscle relaxation, neuromuscular and junctional signal transmission and neuronal plasticity. Most nongenomic effects involve a membrane receptor, and putative binding sites are described for androgens. The mechanisms of AAS toxicity are not yet completely understood since the adverse effects of AAS are known to be complex and likely to arrise from effects on several organ systems in humans. Moreover the negative health consequences of AAS are also dependent on the sex, the dose and the duration of administration and many of the side effects may be reversible. Many individuals who use only a few cycles of AAS in their careers, in fact, often report few adverse medical or psycho- logical effects from AAS since most of the more severe side effects appear to develop during prolonged use. A number of clinical and experimental studies have investigated the somatic and psychological consequences associated with these drugs and have provided strong evidence of increase morbility and mortality in humans. A review of the literature reveals a AAS – induced side effects on cardiovascular system, the liver, the kidney, the musculoskeletal and the endocrine systems. Similar considerations can be formulated for the, so called, Smarts Drugs. In recent times within the European Union and in the USA the availability of new products sold as “Legal Highs” or “Herbal Highs” (psychoactive compounds not included in the list of Controlled Substances) has been reported. This new heterogeneous class of products is also named “Smart Drugs” (SD) and includes several types of preparations such as teas, herbal mixtures, incenses, ambient scents, energetic drinks and food additives. Because of the lack of legal restrictions to their marketing, SDs are easily available in herbalist shops, in the so-called “Smart Shops” or through e-commerce. It is widely reported that the use of SDs is associated with dissociate mental states and mild psychedelic sensations. Moreover, SDs may induce amphetamine-like effects on both fatigue and mood as well as performance enhancement. In the most recent years numerous cases of acute intoxications and a few deaths associated to SDs have been reported, many of which were caused by the consumption of synthetic analogue of cannabinoids (JWH-018,HU-210, CP- 47, 497, JWH-073, JWH-398 and JWH 250). Moreover cases of consumption of phenethylamines (analogues of amphetamine and mescaline), tryptamine (allucinogenic molecules similar to psylocine) and phenylpirazines have been reported. These compounds, and particularly that with ampthetamine-like effects, are classifiable as performance-enhancing drugs. At present, almost all the diagnoses of SD consumption/intoxications are based on the medical history of subjects, due to the difficulty to determine these compounds in biological fluids depending on the novelty and variety of the active principles and on their brief stay on the market. As a result the traditional analytical approaches are scarcely suitable for the analysis of the SDs for the following reasons: immunochemical methods base their selectivity on the specific affinity of antibodies directed towards known compounds used in the immunization process; both liquid and gas chromatography base their identification capability on the match of the chromatographic retention of known compounds; the usual identification techniques based on low resolution mass spectrometry (single or triple quadruples or ion traps) mainly depend on the fragmentation pattern of the molecules, which under standard conditions is reproducible. In practice, they permit the identification of the unknown compounds by comparison with the fragmentation spectra available in databases or experimentally obtained with reference standards. Consequently, if the fragmentation spectra are unknown and the reference standards are not available, such as with the most recently introduced SDs, any identification is impossible. On these grounds, it is clear that at present the determination of SDs in clinical contexts and in most forensic situations is hardly possible with the existing instrumentation and methodologies. The use of anabolic androgenic steroids (AAS) among athletes as well as non-athletes has been associated with abuse of these additional substances.
The major goal of our proposed research is (1) to employ animal models to study the specific organ pathology associated with long term of AAS administration which could ehnance our understandanding of the mechanisms which may underlie sudden death, liver intoxication or kidneys necrosis in humans and (2) to develop new analytical strategies for the determination of so-called Smart Drugs (SD) and anabolic steroids in biological samples to support the diagnosis of dependence/abuse and also (3) to assess the extent of the phenomenon in relation to cases of suspicious deaths at the same time to draw a first map of the epidemiological phenomenon in Italy in populations of young athletes by analyzing the causes of psychological models and trying to envisage legal models able to counter the illicit traffic.
StatusActive
Effective start/end date1/1/12 → …

Funding

  • MIUR - FIRB

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Athletes
Substance-Related Disorders
Steroids
Delivery of Health Care
Androgens
Androgen Receptors
Pleasure
Amphetamine
Cytoplasmic and Nuclear Receptors
Testosterone
Psychology
Kidney
Membranes
Liver
Performance-Enhancing Substances
Stanozolol
Methandrostenolone
Fitness Centers
Mescaline
Controlled Substances