A review of current chemistry, pharmacology, and regulation of endogenous anabolic steroids testosterone, boldenone, and nandrolone in horses.

Anabolic androgenic steroids are synthetic substances related to the male sex hormones (androgens). These agents promote the growth of skeletal muscle (anabolic effects) and the development of male sexual characteristics (androgenic effects). Anabolic steroids have been illegally used for many years as performance-enhancing drugs in human, equine, and canine sports and as growth promoters in livestock reared to provide meat for human consumption. The analytical challenge to developing effective means of control within these fields has been exacerbated by the reported endogenous nature of some of these steroids. Anabolic steroids have been employed extensively in equine practice over the past 50 years. Their usefulness is largely dependent on subjective opinions, as only minimal studies investigating pharmacodynamics have been carried out in horses. Therefore, their use will vary markedly between practitioners depending on their personal experiences and pressures by trainers to use them. They form part of rational therapy in a variety of conditions. In addition to their use for increasing muscle mass, they are used to varying extents in the raising of yearlings and in the training and racing of horses with the view of improving performance. The use of these agents is prohibited in the horseracing industry by the Association of Racing Commissioners International (ARCI), International Federation of Horseracing Authorities (IFHA), and Fédération Equestre Internationale (FEI).

Discovery of 3-amino-4-{(3S)-3-[(2-ethoxyethoxy)methyl]piperidin-1-yl}thieno[2,3-b]pyridine-2-carboxamide (DS96432529): A potent and orally active bone anabolic agent.

The continuing investigation of SAR of 3-aminothieno[2,3-b]pyridine-2-carboxamide derivatives has been described. In this study, C4-piperidine derivatives with polar functional groups were synthesized to develop orally available bone anabolic agents. The optimized compound 9o (DS96432529), which exhibited the best PK profile and high in vitro activity, showed the highest in vivo efficacy in this series. Moreover, significant synergistic effects were observed following co-administration of DS96432529 and alendronate or parathyroid hormone. The mechanism of action is most likely mediated through CDK8 inhibition.

New Insights into the Metabolism of Methyltestosterone and Metandienone: Detection of Novel A-Ring Reduced Metabolites.

Metandienone and methyltestosterone are orally active anabolic-androgenic steroids with a 17α-methyl structure that are prohibited in sports but are frequently detected in anti-doping analysis. Following the previously reported detection of long-term metabolites with a 17ξ-hydroxymethyl-17ξ-methyl-18-nor-5ξ-androst-13-en-3ξ-ol structure in the chlorinated metandienone analog dehydrochloromethyltestosterone ("oral turinabol"), in this study we investigated the formation of similar metabolites of metandienone and 17α-methyltestosterone with a rearranged D-ring and a fully reduced A-ring. Using a semi-targeted approach including the synthesis of reference compounds, two diastereomeric substances, viz. 17α-hydroxymethyl-17ß-methyl-18-nor-5ß-androst-13-en-3α-ol and its 5α-analog, were identified following an administration of methyltestosterone. In post-administration urines of metandienone, only the 5ß-metabolite was detected. Additionally, 3α,5ß-tetrahydro-epi-methyltestosterone was identified in the urines of both administrations besides the classical metabolites included in the screening procedures. Besides their applicability for anti-doping analysis, the results provide new insights into the metabolism of 17α-methyl steroids with respect to the order of reductions in the A-ring, the participation of different enzymes, and alterations to the D-ring.

Pharmacological Characterization of a Novel 5-Hydroxybenzothiazolone-Derived ß 2-Adrenoceptor Agonist with Functional Selectivity for Anabolic Effects on Skeletal Muscle Resulting in a Wider Cardiovascular Safety Window in Preclinical Studies.

The anabolic effects of ß 2-adrenoceptor (ß 2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of ß 2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived ß 2-AR agonist in comparison with formoterol as a representative ß 2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human ß 2-AR and selectivity over the ß 1-AR and ß 3-AR. 5-HOB also shows potent agonistic activity at the ß 2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue-derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional ß 2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects.

Selective Array-Based Sensing of Anabolic Steroids in Aqueous Solution by Host-Guest Reporter Complexes.

Arrayed complexes of a water-soluble deep cavitand and two fluorescent indicators show selective sensing of anabolic-androgenic steroids in aqueous environments. By combining the host-guest complexes with small amounts of heavy metal ions, discrimination between steroids that vary in structure by only a single π bond is possible. The sensing occurs through a triggered aggregation mechanism, which can be mediated by both the presence of metal ions and the steroids. The use of both "turn-on" and "turn-off" fluorophores is essential for good discrimination. As low as 10 µm steroid can be detected, and the discrimination is selective in steroid samples spiked into human urine.

Doping substances in dietary supplements. / Dopingmidler i kosttilskudd.

BACKGROUND: International studies have shown that 12-58 % of all dietary supplements intended for people who exercise and engage in sports contain substances prohibited by the World Anti-Doping Code (WADC). In some cases, the doping substances are not declared on the product label, and the consumer may therefore be unaware of what he/she ingests. Many of the substances may cause adverse health effects, and sale of such products is illegal in Norway. MATERIAL AND METHOD: To investigate the prevalence of doping substances in dietary supplements sold on the Norwegian market, a total of 93 high-risk products from online shops targeting Norwegian consumers were analysed for substances on the WADC Prohibited List and pharmaceutical drugs. All supplements were marketed as able to boost energy levels and/or having a muscle-building or fat-burning effect. The products were selected on the basis of tips received, online forums and/or international lists. RESULTS: Altogether 21 of 93 (23 %) products analysed contained prohibited substances, pharmaceutical drugs and/or illegal amounts of caffeine. Substances on the WADC Prohibited List were detected in 8 of the 93 (9 %) dietary supplements. All products containing doping substances were declared as containing one or more banned substances. INTERPRETATION: The results show that using apparently legal dietary supplements purchased in online shops targeting Norwegian consumers involves a risk of inadvertent doping and adverse health effects.

Computational Assessment of Pharmacokinetics and Biological Effects of Some Anabolic and Androgen Steroids.

PURPOSE: The aim of this study is to use computational approaches to predict the ADME-Tox profiles, pharmacokinetics, molecular targets, biological activity spectra and side/toxic effects of 31 anabolic and androgen steroids in humans. METHODS: The following computational tools are used: (i) FAFDrugs4, SwissADME and admetSARfor obtaining the ADME-Tox profiles and for predicting pharmacokinetics;(ii) SwissTargetPrediction and PASS online for predicting the molecular targets and biological activities; (iii) PASS online, Toxtree, admetSAR and Endocrine Disruptomefor envisaging the specific toxicities; (iv) SwissDock to assess the interactions of investigated steroids with cytochromes involved in drugs metabolism. RESULTS: Investigated steroids usually reveal a high gastrointestinal absorption and a good oral bioavailability, may inhibit someof the human cytochromes involved in the metabolism of xenobiotics (CYP2C9 being the most affected) and reflect a good capacity for skin penetration. There are predicted numerous side effects of investigated steroids in humans: genotoxic carcinogenicity, hepatotoxicity, cardiovascular, hematotoxic and genitourinary effects, dermal irritations, endocrine disruption and reproductive dysfunction. CONCLUSIONS: These results are important to be known as an occupational exposure to anabolic and androgenic steroids at workplaces may occur and because there also is a deliberate human exposure to steroids for their performance enhancement and anti-aging properties.

Benzofuran-pyran hybrids: A new class of potential bone anabolic agents.

Benzofuran moiety is an important pharmacophore showing positive effects on bone health. In the present study, sixteen benzofuran-pyran hybrids were synthesized and were evaluated for their osteogenic effects on primary osteoblast cells isolated from calvaria. Compounds 22 and 24 were found potent in stimulating osteoblast differentiation as assessed by the alkaline phosphatase activity. These compounds were also found to be nontoxic to osteoblast cells as compared to the control cells in MTT assay. Further, Alizarin Red-S staining for visualization of calcium nodules demonstrated compounds 22 and 34 as active in enhancing mineralization in osteoblast cells. Additionally, transcriptional analysis of these compounds on osteoblast cells revealed that compound 22 up-regulated the expression of osteogenic genes RUNX2, BMP-2, COL-1, thus substantiating that compound 22 having two geminal methyl groups in its R3 position is a potent osteogenic agent. Additionally, compound 22 enhanced the ability of bone marrow stromal cells to differentiate towards osteoblast lineage and therefore can be further studied in vivo in bone loss model.

Structural elucidation of major selective androgen receptor modulator (SARM) metabolites for doping control.

Selective androgen receptor modulators (SARMs) are a class of androgen receptor drugs, which have a high potential to be performance enhancers in human and animal sports. Arylpropionamides are one of the major SARM classes and get rapidly metabolized significantly complicating simple detection of misconduct in blood or urine sample analysis. Specific drug-derived metabolites are required as references due to a short half-life of the parent compound but are generally lacking. The difficulty in metabolism studies is the determination of the correct regio and stereoselectivity during metabolic conversion processes. In this study, we have elucidated and verified the chemical structure of two major equine arylpropionamide-based SARM metabolites using a combination of chemical synthesis and liquid chromatography-mass spectrometry (LC-MS) analysis. These synthesized SARM-derived metabolites can readily be utilized as reference standards for routine mass spectrometry-based doping control analysis of at least three commonly used performance-enhancing drugs to unambigously identify misconduct.

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part II: Optimization of 4-(pyrrolidin-1-yl)benzonitrile derivatives.

We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay.

Benzofuran-dihydropyridine hybrids: A new class of potential bone anabolic agents.

A series of novel benzofuran-dihydropyridine hybrids were designed by molecular hybridization approach and evaluated for bone anabolic activities. Among the screened library, ethyl 4-(7-(sec-butyl)-2-(4-methylbenzoyl)benzofuran-5-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (compound 21) significantly enhanced the ALP production and mineralized nodule formation, which are primary requisites in the process of in vitro osteogenesis. Oral administration of compound 21 at 10 mg.kg-1 day-1 for two weeks led to restoration of trabecular bone microarchitecture in drill hole fracture model by significantly increasing BV/TV and Tb.N. Furthermore, histological and molecular studies showed compound 21 triggering the new bone regeneration in a drill hole defect site by increasing BMP expression. Furthermore, molecular modeling studies were performed to gain insight into the binding approach, which revealed that both benzofuran and dihydropyridine moieties are essential to show similar binding interactions to fit into the active site of BMP2 receptor, an important target of the osteogenic agents. Our results suggest that compound 21 stimulates BMP2 synthesis in osteoblast cells that promotes new bone formation (∼40%) at the fracture site which helps in shorten the healing period.

Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet.

Importance: Recent reports have described the increasing use of nonsteroidal selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration (FDA), to enhance appearance and performance. The composition and purity of such products is not known. Objective: To determine the chemical identity and the amounts of ingredients in dietary supplements and products marketed and sold through the internet as selective androgen receptor modulators and compare the analyzed contents with product labels. Design and Setting: Web-based searches were performed from February 18, 2016, to March 25, 2016, using the Google search engine on the Chrome and Internet Explorer web browsers to identify suppliers selling selective androgen receptor modulators. The products were purchased and the identities of the compounds and their amounts were determined from April to August 2016 using chain-of-custody and World Anti-Doping Association-approved analytical procedures. Analytical findings were compared against the label information. Exposures: Products marketed and sold as selective androgen receptor modulators. Main Outcomes and Measures: Chemical identities and the amount of ingredients in each product marketed and sold as selective androgen receptor modulators. Results: Among 44 products marketed and sold as selective androgen receptor modulators, only 23 (52%) contained 1 or more selective androgen receptor modulators (Ostarine, LGD-4033, or Andarine). An additional 17 products (39%) contained another unapproved drug, including the growth hormone secretagogue ibutamoren, the peroxisome proliferator-activated receptor-δ agonist GW501516, and the Rev-ErbA agonist SR9009. Of the 44 tested products, no active compound was detected in 4 (9%) and substances not listed on the label were contained in 11 (25%). In only 18 of the 44 products (41%), the amount of active compound in the product matched that listed on the label. The amount of the compounds listed on the label differed substantially from that found by analysis in 26 of 44 products (59%). Conclusions and Relevance: In this limited investigation involving chemical analyses of 44 products marketed as selective androgen receptor modulators and sold via the internet, most products contained unapproved drugs and substances. Only 52% contained selective androgen receptor modulators and many were inaccurately labeled.

C-H Acetoxylation-Based Chemical Synthesis of 17 ß-Hydroxymethyl-17 α-methyl-18-norandrost-13-ene Steroids.

Palladium-catalyzed C-H acetoxylation has been proposed as a key transformation in the first chemical synthesis of steroids bearing a unique 17ß-hydroxymethyl-17α-methyl-18-nor-13-ene D-fragment. This C-H functionalization step was crucial for inverting the configuration at the quaternary stereocenter of a readily available synthetic intermediate. The developed approach was applied to prepare the metandienone metabolite needed as a reference substance in anti-doping analysis to control the abuse of this androgenic anabolic steroid.

Gas chromatography/chemical ionization triple quadrupole mass spectrometry analysis of anabolic steroids: ionization and collision-induced dissociation behavior.

RATIONALE: The detection of new anabolic steroid metabolites and new designer steroids is a challenging task in doping analysis. Switching from electron ionization gas chromatography triple quadrupole mass spectrometry (GC/EI-MS/MS) to chemical ionization (CI) has proven to be an efficient way to increase the sensitivity of GC/MS/MS analyses and facilitate the detection of anabolic steroids. CI also extends the possibilities of GC/MS/MS analyses as the molecular ion is retained in its protonated form due to the softer ionization. In EI it can be difficult to find previously unknown but expected metabolites due to the low abundance or absence of the molecular ion and the extensive (and to a large extent unpredictable) fragmentation. The main aim of this work was to study the CI and collision-induced dissociation (CID) behavior of a large number of anabolic androgenic steroids (AAS) as their trimethylsilyl derivatives in order to determine correlations between structures and CID fragmentation. Clarification of these correlations is needed for the elucidation of structures of unknown steroids and new metabolites. METHODS: The ionization and CID behavior of 65 AAS have been studied using GC/CI-MS/MS with ammonia as the reagent gas. Glucuronidated AAS reference standards were first hydrolyzed to obtain their free forms. Afterwards, all the standards were derivatized to their trimethylsilyl forms. Full scan and product ion scan analyses were used to examine the ionization and CID behavior. RESULTS: Full scan and product ion scan analyses revealed clear correlations between AAS structure and the obtained mass spectra. These correlations were confirmed by analysis of multiple hydroxylated, methylated, chlorinated and deuterated analogs. CONCLUSIONS: AAS have been divided into three groups according to their ionization behavior and into seven groups according to their CID behavior. Correlations between fragmentation and structure were revealed and fragmentation pathways were postulated.

Investigation of the selective androgen receptor modulators S1, S4 and S22 and their metabolites in equine plasma using high-resolution mass spectrometry.

RATIONALE: Selective androgen receptor modulators (SARMs) are prohibited in sports due to their performance enhancing ability. It is important to investigate the metabolism to determine appropriate targets for doping control. This is the first study where the equine metabolites of SARMs S1, S4 (Andarine) and S22 (Ostarine) have been studied in plasma. METHODS: Each SARM was administered to three horses as an intravenous bolus dose and plasma samples were collected. The samples were pretreated with protein precipitation using cold acetonitrile before separation by liquid chromatography. The mass spectrometric analysis was performed using negative electrospray, quadrupole time-of-flight mass spectrometry operated in MS(E) mode and triple-quadrupole mass spectrometry operated in selected reaction monitoring mode. For the quantification of SARM S1, a deuterated analogue was used as internal standard. RESULTS: The numbers of observed metabolites were eight, nine and four for the SARMs S1, S4 and S22, respectively. The major metabolite was formed by the same metabolic reactions for all three SARMs, namely amide hydrolysis, hydroxylation and sulfonation. The values of the determined maximum plasma concentrations were in the range of 97-170 ng/mL for SARM S1, 95-115 ng/mL for SARM S4 and 92-147 ng/mL for SARM S22 and the compounds could be detected for 96 h, 12 h and 18 h, respectively. CONCLUSIONS: The maximum plasma concentration of SARMs S1, S4 and S22 was measured in the first sample (5 min) after administration and they were eliminated fast from plasma. The proposed targets to be used in equine doping control are the parent compounds for all three SARMs, but with the metabolite yielding the highest response as a complementary target. Copyright © 2016 John Wiley & Sons, Ltd.

Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis.

Preptin is a 34-residue pancreatic hormone shown to be anabolic to bone in vitro and in vivo. The bone activity of preptin resides within the (1-16) N-terminal fragment. Due to its peptidic nature, the truncated fragment of preptin is enzymatically unstable; however it provides an attractive framework for the creation of stable analogues using various peptidomimetic techniques. An alanine scan of preptin (1-16) was undertaken which showed that substitution of Ser at position 3 or Pro at position 14 did not inhibit the proliferative activity of preptin in primary rat osteoblasts (bone-forming cells). Importantly, Ser-3 to Ala substitution also showed a significant activity on osteoblast differentiation in vitro and increased the formation of mineralised bone matrix. Additional modifications with non-proteinogenic amino acids at position 3 improved the stability in liver microsomes, but diminished the osteoblast proliferative activity. In addition, to provide greater structural diversity, a series of macrocyclic preptin (1-16) analogues was synthesised using head-to-tail and head-to-side chain macrolactamisation as well as ring-closing metathesis. However, a detrimental effect on osteoblast activity was observed upon macrocyclisation.

Relationships between structure, ionization profile and sensitivity of exogenous anabolic steroids under electrospray ionization and analysis in human urine using liquid chromatography-tandem mass spectrometry.

The relationships between the ionization profile, sensitivity, and structures of 64 exogenous anabolic steroids (groups I-IV) was investigated under electrospray ionization (ESI) conditions. The target analytes were ionized as [M + H](+) or [M + H-nH2 O](+) in the positive mode, and these ions were used as precursor ions for selected reaction monitoring analysis. The collision energy and Q3 ions were optimized based on the sensitivity and selectivity. The limits of detection (LODs) were 0.05-20 ng/mL for the 64 steroids. The LODs for 38 compounds, 14 compounds and 12 compounds were in the range of 0.05-1, 2-5 and 10-20 ng/mL, respectively. Steroids including the conjugated keto-functional group at C3 showed good proton affinity and stability, and generated the [M + H](+) ion as the most abundant precursor ion. In addition, the LODs of steroids using the [M + H](+) ion as the precursor ion were mostly distributed at low concentrations. In contrast, steroids containing conjugated/unconjugated hydroxyl functional groups at C3 generated [M + H - H2 O](+) or [M + H - 2H2 O](+) ions, and these steroids showed relatively high LODs owing to poor stability and multiple ion formation. An LC-MS/MS method based on the present ionization profile was developed and validated for the determination of 78 steroids (groups I-V) in human urine.

Characterization of a non-approved selective androgen receptor modulator drug candidate sold via the Internet and identification of in vitro generated phase-I metabolites for human sports drug testing.

RATIONALE: Potentially performance-enhancing agents, particularly anabolic agents, are advertised and distributed by Internet-based suppliers to a substantial extent. Among these anabolic agents, a substance referred to as LGD-4033 has been made available, comprising the core structure of a class of selective androgen receptor modulators (SARMs). METHODS: In order to provide comprehensive analytical data for doping controls, the substance was obtained and characterized by nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography/electrospray ionization high resolution/high accuracy tandem mass spectrometry (LC/ESI-HRMS). Following the identification of 4-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile, the substance was subjected to in vitro metabolism studies employing human liver microsomes and Cunninghamella elegans (C. elegans) preparations as well as electrochemical metabolism simulations. RESULTS: By means of LC/ESI-HRMS, five main phase-I metabolites were identified as products of liver microsomal preparations including three monohydroxylated and two bishydroxylated species. The two most abundant metabolites (one mono- and one bishydroxylated product) were structurally confirmed by LC/ESI-HRMS and NMR. Comparing the metabolic conversion of 4-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile observed in human liver microsomes with C. elegans and electrochemically derived metabolites, one monohydroxylated product was found to be predominantly formed in all three methodologies. CONCLUSIONS: The implementation of the intact SARM-like compound and its presumed urinary phase-I metabolites into routine doping controls is suggested to expand and complement existing sports drug testing methods.

Synthetic androgens as designer supplements.

Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacological effects and metabolism of unapproved steroids due to the absence of clinical studies. The large number of designer steroid findings in dietary supplements and the detection of new compounds combined with legal loopholes for their distribution in many countries show that stricter regulations and better information policy are needed.

Smart drugs and synthetic androgens for cognitive and physical enhancement: revolving doors of cosmetic neurology.

Cognitive enhancement can be defined as the use of drugs and/or other means with the aim to improve the cognitive functions of healthy subjects in particular memory, attention, creativity and intelligence in the absence of any medical indication. Currently, it represents one of the most debated topics in the neuroscience community. Human beings always wanted to use substances to improve their cognitive functions, from the use of hallucinogens in ancient civilizations in an attempt to allow them to better communicate with their gods, to the widespread use of caffeine under various forms (energy drinks, tablets, etc.), to the more recent development of drugs such as stimulants and glutamate activators. In the last ten years, increasing attention has been given to the use of cognitive enhancers, but up to now there is still only a limited amount of information concerning the use, effect and functioning of cognitive enhancement in daily life on healthy subjects. The first aim of this paper was to review current trends in the misuse of smart drugs (also known as Nootropics) presently available on the market focusing in detail on methylphenidate, trying to evaluate the potential risk in healthy individuals, especially teenagers and young adults. Moreover, the authors have explored the issue of cognitive enhancement compared to the use of Anabolic Androgenic Steroids (AAS) in sports. Finally, a brief overview of the ethical considerations surrounding human enhancement has been examined.