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Abstract
The 2025 revision of the World Anti-Doping Agency (WADA) Prohibited List introduces significant updates grounded in recent pharmacological developments, emerging therapeutic compounds, and shifting patterns of misuse in sport. This scientific brief outlines key changes, including the addition of novel agents such as ryanodine receptor-1-calstabin complex stabilizers (e.g., S-107, ARM210) to the S0 category, the estrogen receptor degrader elacestrant to S4.2, and MOTS-c to the metabolic modulators section (S4.4). Other revisions include formal recognition of insulin mimetics (S519, S597), the naming of xipamide as a masking agent, and stricter dosing intervals for inhaled formoterol. Classification updates affect stimulants such as hydrafinil (reallocated to S6.A), and newly listed specified stimulants including midodrine and tesofensine. The revised policy also clarifies the permissibility of blood donation via apheresis procedure under strict oversight and introduces notable sport-specific changes, which is removal of β-blockers from the Prohibited List for selected skiing and snowboarding disciplines, following recommendations by the International Ski Federation (FIS). These changes underscore WADA’s commitment to preemptive regulation based on emerging risks, ensuring fairness and athlete safety. Where applicable, clinical rationale, therapeutic use implications, and detection methodologies are discussed to support implementation and compliance across sports.
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MICHALIK, Maciej, LORENC, Tomasz, MURAS, Mateusz, MARCINKOWSKI, Krzysztof, MIKSZTA, Natalia, MIKSZTA, Jakub
and MARCINKOWSKA, Julia. Key Updates in the WADA 2025 Prohibited List: Implications for Competitive Sports. Quality in Sport.
2025;42:61192. eISSN 2450-3118.
https://doi.org/10.12775/QS.2025.42.61192
https://apcz.umk.pl/QS/article/view/61192
The journal has been awarded 20 points in the parametric evaluation by the Ministry of Higher Education and Science of Poland. This is
according to the Annex to the announcement of the Minister of Higher Education and Science dated 05.01.2024, No. 32553. The journal has a
Unique Identifier: 201398. Scientific disciplines assigned: Economics and Finance (Field of Social Sciences); Management and Quality
Sciences (Field of Social Sciences).
Punkty Ministerialne z 2019 - aktualny rok 20 punktów. Załącznik do komunikatu Ministra Szkolnictwa Wyższego i Nauki z dnia 05.01.2024
Lp. 32553. Posiada Unikatowy Identyfikator Czasopisma: 201398. Przypisane dyscypliny naukowe: Ekonomia i finanse (Dziedzina nauk
społecznych); Nauki o zarządzaniu i jakości (Dziedzina nauk społecznych). © The Authors 2025.
This article is published with open access under the License Open Journal Systems of Nicolaus Copernicus University in Torun, Poland. Open
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The authors declare that there is no conflict of interest regarding the publication of this paper.
Received: 19.05.2025. Revised: 25.06.2025. Accepted: 25.06.2025. Published: 27.06.2025.
1
Key Updates in the WADA 2025 Prohibited List: Implications for Competitive Sports
Maciej Michalik
https://orcid.org/0009-0009-7799-7252
Tomasz Lorenc
Warszawski Szpital Południowy
https://orcid.org/0009-0008-9902-469X
Mateusz Muras
Wojewódzki Szpital Specjalistyczny nr 2 w Jastrzębiu-Zdroju
https://orcid.org/0009-0005-1392-3773
Krzysztof Marcinkowski
Śląski Uniwersytet Medyczny
https://orcid.org/0009-0002-5759-7285
Natalia Mikszta
Śląski Uniwersytet Medyczny
https://orcid.org/0009-0003-8444-7650
Jakub Mikszta
Uniwersytet Opolski
https://orcid.org/0009-0000-4194-9915
Julia Marcinkowska
Śląski Uniwersytet Medyczny w Katowicach
https://orcid.org/0009-0005-7006-4303
2
Abstract
The 2025 revision of the World Anti-Doping Agency (WADA) Prohibited List introduces
significant updates grounded in recent pharmacological developments, emerging therapeutic
compounds, and shifting patterns of misuse in sport. This scientific brief outlines key changes,
including the addition of novel agents such as ryanodine receptor-1-calstabin complex
stabilizers (e.g., S-107, ARM210) to the S0 category, the estrogen receptor degrader elacestrant
to S4.2, and MOTS-c to the metabolic modulators section (S4.4). Other revisions include formal
recognition of insulin mimetics (S519, S597), the naming of xipamide as a masking agent, and
stricter dosing intervals for inhaled formoterol. Classification updates affect stimulants such as
hydrafinil (reallocated to S6.A), and newly listed specified stimulants including midodrine and
tesofensine. The revised policy also clarifies the permissibility of blood donation via apheresis
procedure under strict oversight and introduces notable sport-specific changes, which is
removal of β-blockers from the Prohibited List for selected skiing and snowboarding disciplines,
following recommendations by the International Ski Federation (FIS). These changes
underscore WADA’s commitment to preemptive regulation based on emerging risks, ensuring
fairness and athlete safety. Where applicable, clinical rationale, therapeutic use implications,
and detection methodologies are discussed to support implementation and compliance across
sports.
Keywords: WADA, World Anti-Doping Agency, Prohibited List, Prohibited List 2025, Doping,
Olympics
3
Introduction:
The World Anti-Doping Agency (WADA) annually revises its Prohibited List to reflect
advances in biomedical research, emerging trends in pharmacology, and evolving patterns of
substance misuse in competitive sport. These updates are critical to ensuring both fair play and
athlete safety, as well as maintaining the integrity of sport at all levels. The 2025 revision
introduces several important modifications, many of which are not based on the addition of
entirely new substances but rather on refined classifications and clarifications regarding
existing compounds, especially those developed under or structurally related to already banned
pharmacological classes. Such revisions are incredibly important, given the dynamic landscape
of pharmaceutical innovation and the continued emergence of grey-zone compounds or
procedures, that challenge regulatory definitions. This brief communication outlines the key
updates to the 2025 WADA Prohibited List, with particular focus on changes in substance
classification (e.g., the reclassification of certain stimulants), specification clarifications (e.g.,
inhaled β2-agonists), and sport-specific exemptions or adjustments (e.g., the removal of β-
blockers for certain winter sports disciplines). Furthermore, this update highlights underlying
scientific and clinical rationale where available, including efficacy data, potential for abuse, and
impact on performance, as well as implications for therapeutic use exemptions (TUEs), athlete
monitoring, and anti-doping enforcement policy [1,2].
Ryanodine receptor-1-calstabin complex stabilizers inclusion to the Prohibited at all times – in
and out of competition substance (S0)
WADA prohibits any pharmacological substance that is not explicitly listed but lacks approval
from regulatory health authorities for human therapeutic use. This includes investigational
drugs, discontinued medications, designer substances, and compounds not intended for human
use, such as veterinary medications. This class includes numerous substances, among which
are: BPC-157, 2,4-Dinitrophenol (DNP), and troponin activators (e.g., Reldesemtiv and
Tirasemtiv). Since 2025, additional substances have been named under this section: “ryanodine
receptor-1-calstabin complex stabilizers [such as S-107, S48168 (ARM210)]”[1].
S-107 has been shown to stabilize calstabin1 binding to ryanodine receptor-1, the skeletal
muscle sarcoplasmic reticulum calcium release channel required for muscle contraction. This
interaction leads to a reduction in intracellular calcium leakage and oxidative stress (ROS).
Additionally, it improves tetanic Ca2+ release while limiting calcium channel leakage associated
4
with certain diseases and aging. Moreover, it has been observed to increase muscle-specific
force production and elevate overall exercise capacity in mice, while simultaneously reducing
fatigue [1-5],
Inclusion in the S0 category (substances prohibited at all times, both in- and out-of-competition)
is likely intended to prevent potential misuse before it becomes widespread in the sporting
community. Although the S-107 ryanodine receptor-1-calstabin complex stabilizer (RyR1) has
been recognized for its potential risk of misuse [6], the specific classification of this substance
under the S0 category coincides with the emergence of another novel RyR1 compound –
S48168 (ARM210). The S48168/ARM210 compound has shown therapeutic potential for
neuromuscular diseases such as dystrophinopathies in preclinical studies using animal models
[7]. More recent reports suggest that daily administration of 200 mg of ARM210 leads to
reduced fatigue and increased proximal muscle strength in patients with RYR1-related
myopathies [8].
It is worth noting that while this update does not signal a radical shift in WADA’s overall policy,
it further reinforces its commitment to the principle of prohibiting substances “at all times.”
The theoretical risk of misuse, their unknown or poorly understood influence on physical
performance, and unresolved safety concerns constitute sufficient justification for their explicit
inclusion in the S0 category of WADA’s 2025 Prohibited List [1].
Elacestrant naming to the Prohibited at all times (in- and out-of-competition) S4.2. Anti-
estrogenic substances [Anti-Estrogens and Selective Estrogen Receptor Modulators (SERMs)]
Tamoxifen acts as an estrogen antagonist at the level of the hypothalamus and pituitary,
stimulating the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In
our experience, it mildly increases endogenous testosterone production and enhances
spermatogenesis [9].Related elacestrant – a receptor degrader rather than modulator, approved
by the FDA in 2023, has been shown to inhibit the expression of estrogen receptor alpha (ERα)
in cultured breast tumor cell lines, leading to complete degradation of the receptor [10,11].
Given that estrogen receptors are also expressed in non-tumor tissues, there is a theoretical risk
of misuse. In particular, reduction in estrogen receptor signaling within the hypothalamus may
falsely signal a low-estrogen state, leading to reactivation of the hypothalamic-pituitary-
gonadal (HPG) axis and the resumption of endogenous testosterone production. While this may
promote muscle hypertrophy, the increase in serum testosterone concentrations remains modest
5
[12]. Suppression of spermatogenesis is a frequent consequence of androgen (AAS) use, due to
negative feedback inhibition of the HPG axis. Recovery of this axis can take several months.
Although no robust clinical evidence currently supports their use, anecdotal reports suggest that
selective estrogen receptor modulators (SERMs) may facilitate faster restoration of gonadal
function [9,12-14]. These properties position elacestran alongside other anti-estrogens and
SERMs already included on the WADA Prohibited List [2], as a theoretical indirect anabolic
agent and a potential masking substance following prior testosterone or AAS use.
Inclusion of Mitochondrial Open Reading Frame of the 12S rRNA-c (MOTS-c) to the Metabolic
Modulators S4.4 subgroup
A novel member of the mitochondrial-derived peptide family, mitochondrial open reading
frame of the 12S rRNA-c (MOTS-c), functions not only as a cell-autonomous peptide but also
acts systemically as a “hormone,” influencing numerous metabolic processes. Among its effects
is the reduction of insulin resistance – MOTS-c systemically regulates in vivo glucose
metabolism and enhances muscle insulin sensitivity [15]. Insulin enhances glucose uptake and
maximizes glycogen storage prior to exercise, potentially improving performance. It also
augments amino acid transport, thereby indirectly contributing to anabolic processes [16,17].
Improved insulin sensitivity of skeletal muscle cells supports enhanced glucose metabolism
[15], while MOTS-c has also been associated with obesity prevention, improved muscle
function, bone metabolism support, immune regulation, and delayed aging. In addition, MOTS-
c contributes to nuclear–mitochondrial signaling and exerts cytoprotective properties within
cells [18,19]. MOTS-c naturally targets skeletal muscle tissue, where it may accelerate energy-
generating metabolic processes [18]. Moreover, it has been shown to increase glycolysis and
ATP levels in dystrophic muscle cells, improving the absorption and activity of
phosphorodiamidate morpholino oligomers [20]. MOTS-c is frequently advertised by wellness
and anti-aging clinics as a “weight-loss peptide,” despite its status as an experimental compound
not approved for human therapeutic use [21]. Given its potential anabolic and performance-
enhancing properties, alongside its uncertain safety profile, MOTS-c was added to the World
Anti-Doping Code International Standard Prohibited List 2025, under the category of
Metabolic Modulators [1].
6
Insulin Mimetic example listing of S519, S597 analogues
The influence of insulin and its synthetic analogues on carbohydrate metabolism and their anti-
catabolic effects has led to their prohibition in sports at all times, according to the regulations
of the World Anti-Doping Agency [1]. Insulin mimetics imitate the biological action of insulin
by binding to the insulin receptor. [22]. Insulins and insulin mimetics have been included in
Article S4.4.1 as non-specified substances since the year 2000. In the latest revision of WADA
Prohibited List 2025, S519 and S597 are listed as examples of insulin analogues; however, the
regulation also applies to all unnamed compounds that fall within this category.
S519 and S597 are the most extensively studied and well-characterized insulin mimetics. A
validated method exists to detect these substances in plasma, utilizing advanced solid-phase
extraction (SPE) and liquid chromatography coupled with high-resolution tandem mass
spectrometry (LC-HRMS/MS). This method enables the detection of S519 and S597 at
concentrations exceeding 0.5 ng/mL [22-24].
Inclusion of Xipamide as a diuretic example
Xipamide is a diuretic derived from salicylic acid which structure resemblance to chlorthalidone.
Despite its similarity to thiazide diuretic, xipamide works mainly in the distal tubule and shows
a diuretic efficacy compared to furosemide at doses up to 40mg [25,26]. The main factor that
leaded to banning xipamide were its similarities to other diuretics which are described by
WADA as masking agents, that potentially can be used to falsify the results of doping controls
and to conceal doping [1,27].
In 2012 during Tour de France Frank Schleck sample A showed presence of xipamide and the
cyclist was withdrawn by his team. At that time, the list of substances prohibited by WADA did
not specifically include the name xipamide; however, the substance was indirectly banned due
to its structural similarity to other classes of diuretics [28]. In the revised Prohibited List,
xipamide was mentioned by name for the first time to emphasize the fact that it is a prohibited
substance due to its structure and functions being analogous to other diuretics.
7
Manipulation of Blood and Blood Components - liberalisation for donation purposes
WADA strictly prohibits manipulation of Blood and Blood Components (BBC), including any
form of intravascular manipulation of blood components by physical or chemical means, as
well as artificially enhancing the uptake, transport, or delivery of oxygen. While plasmapheresis
was exempted from this rule [2], as no signs of doping activity from the procedure were
observed [29], the 2025 revision clarifies that donation of BBC by apheresis would not be
prohibited when performed in an accredited collection center under strict regulatory oversight.
The concern arises because red blood cell (RBC) collection and reinfusion – which is the basis
of apheresis – can enhance oxygen delivery, potentially improving endurance performance; this
practice is known as blood doping [30]. The M1.1category strictly prohibits blood component
reinfusion. The donation of RBCs via apheresis is permitted under specific conditions, ensuring
that the components are not reinfused [1]. The shift from permitting only plasmapheresis to
allowing broader apheresis procedures reflects WADA's recognition of the importance of
facilitating blood donations for medical and humanitarian purposes. By enabling athletes to
donate various blood components under strict regulatory oversight, WADA balances the need
to prevent doping with the ethical imperative to support blood donation initiatives. In
conclusion, while apheresis includes the collection of components that could theoretically pose
a threat of doping, the 2025 WADA Prohibited List maintains prohibitions on reinfusion
practices that enhance performance, further reinforcing the need for strict supervision of the
procedure at accredited centers. This policy change allows for ethical blood donations without
compromising the integrity of competitive sports [1,21].
β2 Agonists - dosing intervals update for Formoterol
All selective and non-selective beta-2 agonists, including all optical isomers, are prohibited
both in- and out-of-competition. Exemptions apply, including the use of Formoterol – a long-
acting β2-agonist (LABA) with a duration of action of 12 hours [31] – when inhaled at a
maximum delivered dose of 54 micrograms over 24 hours [2]. Administration of this
medication within this regimen does not require a Therapeutic Use Exemption (TUE).
Formoterol acts as a bronchodilator and, at supratherapeutic doses, may have performance-
8
enhancing effects such as increased endurance, bronchodilation beyond therapeutic need, and
stimulation of muscle function [31,32]. Since 2025, the maximum inhaled dose of 54 μg over
24 hours must be divided into doses that do not exceed 36 micrograms over any 12-hour period
[1]. The scientific basis for this change is grounded in studies showing dose-response
relationships for β2-agonists. Supratherapeutic dosing – even within short timeframes – may
yield systemic effects such as increased aerobic capacity or muscle strength, especially when
doses are clustered [33]. It was shown that a single 54 μg dose of formoterol has performance-
enhancing potential on sprint ability and short, intense performance [31]. With the 2025 revision
of the Prohibited List, potential risks of misuse are minimized, limiting the possibility of β2-
agonist exploitation [1].
Hydrafinil reallocation to the stimulant group (S6)
Hydrafinil (fluorenol, also known as 9-hydroxyfluorene) is structurally related to modafinil,
which is an approved drug for the treatment of narcolepsy and attention deficit hyperactivity
disorder (ADHD), with cognitive enhancement activity [34].
After in vivo trials on rats, where it demonstrated wake-promoting properties surpassing those
of modafinil, [35,36] the drug candidate was not further developed. Consequently, preclinical
and clinical trial plans were abandoned. Hydrafinil has since appeared on some markets as a
cheap and readily available substance [37].
The substance was included in the 2024 WADA Prohibited List in the S6.B section as a
specified stimulant (prohibited in-competition). The revised List shifted the compound to the
S6.A section as a non-specified stimulant [1,2]. A non-specified stimulant is a substance that is
most likely used deliberately with the intention to dope, whereas a specified stimulant is
recognized as more susceptible to inadvertent use [1]. The shift was largely based on WADA’s
notice that hydrafinil is more potent than modafinil and is not licensed for medical use; thus,
there are no recognized therapeutic applications. These factors suggest that hydrafinil is more
likely to be used for performance enhancement rather than for legitimate medical reasons [1,36].
Midodrine and Tesofensine inclusion in the Specified Stimulant (S6.B) section
Midodrine is a peripheral α-adrenergic agonist commonly used to reduce the effects of
orthostatic hypotension. It is a prodrug that requires enzymatic hydrolysis to form its
pharmacologically active metabolite, de-glymidodrine. Midodrine acts non-selectively on α1-
and α2-adrenergic receptors, increasing standing blood pressure and decreasing venous capacity
9
[38]. In the latest edition of WADA Prohibited List [1], midodrine is named and classified as a
specified stimulant (S6.B). Its inclusion was not particularly groundbreaking, as the ban mainly
reflects the potential risk of hypertension and related complications, along with the theoretical
possibility of enhancing sports performance.
Tesofensine is a triple monoamine reuptake inhibitor that inhibits the reuptake of dopamine,
noradrenaline, and 5-HT. Tesofensine was originally developed and investigated for
Alzheimer’s and Parkinson’s disease, but early results showed limited efficacy; however,
weight loss was observed in those patients. The main mechanism leading to this effect is its
appetite suppressant action. [39] The effectiveness of its impact on weight reduction is still
being studied; however, the substance lacks documented clinical efficacy for WADA to consider
allowing its use. Additionally, tesofensine may potentially enhance sporting performance, pose
an actual or potential health risk, and violate “the spirit of sport.” The combination of potential
performance enhancement, health risks, and lack of documented clinical efficacy led WADA to
include this substance by name in the newest list of prohibited substances [1].
Guanfacine status clarification as not prohibited
Guanfacine, an α2A-adrenergic receptor agonist, is primarily used to treat ADHD and certain
anxiety disorders. The α2A-adrenoreceptors are highly concentrated in the locus coeruleus and
prefrontal cortex – areas most heavily implicated in ADHD [40]. In the 2025 Prohibited List, it
was explicitly included as an exemption in the S6 stimulant section. It does not possess
stimulant properties and lacks evidence suggesting performance-enhancing effects.
Additionally, it is not associated with significant health risks when used as prescribed. Therefore,
it does not meet the necessary criteria for inclusion on the Prohibited List [1,41,42].
Adjustments to the regulations regarding β-blockers in certain disciplines following the
International Ski and Snowboard Federation’s endorsement
In the 2025 revision of the World Anti-Doping Agency Prohibited List, β-blockers were
removed from the list of substances prohibited in-competition for specific skiing and
snowboarding disciplines: ski jumping, freestyle aerials/halfpipe, and snowboard halfpipe/big
air. This change was implemented based on information provided by the International Ski and
Snowboard Federation (FIS) [1]. The rationale behind this decision likely stems from a
reassessment of the actual performance-enhancing effects of β-blockers in these disciplines. β-
blockers are known to reduce heart rate and tremors, which can be advantageous in sports
10
requiring precision and steadiness, such as shooting or archery [43]. However, in dynamic and
acrobatic events like ski jumping and freestyle snowboarding, the benefits of β-blockers are
less clear, and they may even impair performance due to their sedative and muscle-weakening
effects. A few reports from the 20th century discussed a theoretical performance advantage of
β-blockade in ski jumpers. However, these studies were limited by small sample sizes,
subjective performance measures, inconsistent outcomes due to side effects, lack of long-term
assessment, and overgeneralized conclusions [44,45].
The change, endorsed through FIS expertise, may lay the groundwork for a closer investigation
into the effects of β-blockers in the aforementioned disciplines, as large-scale, carefully
designed, and up-to-date trials are still lacking. An interesting opportunity for such research
may arise during the Milano-Cortina 2026 XXV Olympic Winter Games, starting on the 6th of
February. The potentially large sample size available for retrospective studies across multiple
disciplines could provide a solid foundation for further evaluating the impact of β-blockers on
performance in certain winter sports.
Conclusions
The transition from the 2024 to the 2025 WADA Prohibited List marks a significant evolution
in anti-doping regulations, reflecting advances in scientific understanding and emerging
challenges in sports integrity. Notably, the 2025 list introduces several novel substances and
revises existing frameworks to better address potential performance-enhancing
methods.Among the most prominent additions is MOTS-c, a mitochondrial-derived peptide
with promising anabolic and metabolic effects, now explicitly prohibited due to its unapproved
status and theoretical performance-enhancing potential. Similarly, the inclusion of ARM210
and other next-generation metabolic modulators underscores WADA’s commitment to
monitoring cutting-edge compounds that may evade detection yet provide unfair advantages.
Regulatory updates extend to blood manipulation controls, where the 2025 list broadens the
scope of apheresis procedures, endorsing honorary blood donation in sportsmen. While WADA
maintains a strict ban on reinfusion practices to prevent blood doping, it permits certain blood
donations under tightly controlled conditions, balancing athlete health and ethical blood
donation initiatives. Dosing adjustments in the realm of β2-agonists, with introduction of a 12-
hour maximum dosing window aims to curb misuse while preserving therapeutic access,
showcasing WADA’s nuanced approach to substances with legitimate medical uses and reactive
decision-making in response to the novel reports. Finally, the International Ski and Snowboard
Federation’s (FIS) endorsement of more permissive β-blocker regulations in selected
11
disciplines exemplifies an evolving attitude toward sport-specific doping risks. This
liberalization acknowledges the differential impact of β-blockers across sports, offering a
tailored regulatory framework that supports athlete safety and fairness. The competitors’
performance is set to be under the close monitoring by the experts during upcoming Milano-
Cortina 2026 XXV Olympic Winter Games.
In summary, the 2025 WADA Prohibited List demonstrates a proactive stance toward emerging
doping strategies, incorporating novel compounds, refining dosage guidelines, and adjusting
sport-specific policies. These changes collectively enhance the effectiveness of anti-doping
efforts while striving to uphold the integrity and spirit of competitive sport.
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... Anti-doping considerations are critical for competitive athletes [152]. The agent cross-referenced all supplement recommendations against the World Anti-Doping Agency prohibited substance list [153]. This would warn athletes that supplements carry contamination risks, even when the primary ingredient is permitted. ...
Ismail Dergaa Sabri Barbaria
Wissem Dhahbi
Helmi Ben Saad
Despite widespread artificial intelligence (AI) adoption in sports science for predictive analytics, current systems operate as passive tools requiring continuous human monitoring and intervention at every decision point. Autonomous AI agent systems capable of 24/7 monitoring, independent reasoning, and proactive action execution remain academically unexplored in sports science contexts. Unlike passive analytics that await human analysis or conversational interfaces requiring explicit prompting, autonomous agents operate continuously, detecting patterns and implementing interventions without human initiation. Our review distinguished autonomous agents from existing AI applications, proposes modular implementation frameworks, develops theoretical application workflows across eight priority domains, and establishes empirical validation pathways. Current (i.e., April 23, 2026) literature lacks peer-reviewed research on autonomous agent systems in sports science. This review connects computer science with exercise physiology. We integrate modern agent architectures with established sports science concepts. The outcome is a practical, multi-domain implementation roadmap. Our three-phase framework progresses from specialized single-domain agents through coordinated multi-agent systems to fully integrated platforms. Phase 1 develops autonomous agents for training load management, exercise prescription, biomechanical analysis, nutrition optimization, sleep monitoring, injury prevention, mental skills training, and rehabilitation, each operating independently within defined safety boundaries. Phase 2 stablishes coordination protocols enabling information exchange across domains while maintaining modular independence. Phase 3 integrates fully autonomous agent systems across all domains into a unified platform with comprehensive cross-domain reasoning. This framework aimed to advance autonomous agent research from conceptual proposal to a structured implementation and validation pathway in evidence-based athlete management.
Md. Rabiul Islam
Asef Raj Mehedi Islam
Eva Rahman Kabir
Salbutamol (albuterol) is a short-acting β2-agonist and primary reliever for reversible airflow obstruction. This chapter reviews its chemistry, receptor pharmacology and signaling, pharmacokinetics, and device-based delivery, and evidence-based dosing across ages and special populations. We summarize adverse effects, toxicity mechanisms and management, and clinically relevant interactions, additives, and impurities. Pharmacogenomic influences, second-generation outcomes (fertility, pregnancy, lactation, epigenetics), and the long-term consequences of overuse are integrated with current guideline strategies that pair reliever therapy with anti-inflammatory control. The chapter further summarizes current evidence into clear, pragmatic recommendations across dosing, safety, interactions, and special populations. Used judiciously within guideline-based care, inhaled salbutamol remains the pivotal component of advanced respiratory management.
Rastegar Hoseini
Zahra Hoseini Behzad Heydarpour Mahtab Faraji
Exercise physiology is evolving from an organ-based framework toward a systems-level understanding, where molecular interactions between muscle, brain, and the gut microbiome critically influence performance and health. This review systematically examines the genetic, molecular, and cellular bases of this triad, with a focus on translational insights for disease prevention and human optimization. A systematic search of PubMed, Embase, and Web of Science was conducted up to October 2023 to identify studies exploring molecular pathways linking skeletal muscle, cognitive/affective function, and gut microbiota in exercise contexts. Inclusion criteria were original research articles investigating at least two components of the muscle-brain-gut axis. Exclusion criteria included non-English articles, conference abstracts, and studies without molecular data. The PRISMA 2020 guidelines were followed. The search strategy is detailed in Supplementary Material. Evidence was categorized into Grades 1 through 4 based on methodological rigor, omics integration, reproducibility, and translational relevance to human physiology and disease models. Analysis included 154 studies encompassing 987 molecular associations. Among these, 59 associations (Grades 1–2) provided robust evidence for genetically and functionally validated pathways, including myokine-mediated (e.g., irisin, BDNF) and microbially derived metabolites (e.g., SCFAs, tryptophan derivatives) that modulate neuroplasticity, mitochondrial function, inflammation, and HPA axis activity. Psychobiological factors influenced microbial composition, illustrating bidirectional gut-brain-muscle signaling. Most associations (n = 952) were limited by methodological variability or insufficient mechanistic depth. The integration of multi-omics platforms (metagenomics, metabolomics, proteomics) emerges as a key tool for personalized exercise interventions and biomarker discovery. This review synthesizes molecular evidence for the muscle-gut-brain axis as an integrative determinant of exercise responsiveness and disease resilience. We highlight genetic and metabolic pathways with diagnostic and therapeutic potential, aligning with the development of molecular tools for precision medicine. Future interdisciplinary research should leverage artificial intelligence and longitudinal omics to translate these mechanisms into targeted strategies for performance enhancement and disease prevention.
Claudia I. Perez
Jorge Luis
Axel Lopez
Ranier Gutierrez
Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine’s food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine’s appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.
Filippo Giorgio Di Girolamo Chiara Biasinutto
Alessandro Mangogna
Gianni Biolo
Background Hormonal doping in recreational sports is a public-health concern. The World Anti-Doping Agency (WADA) promoted the creation of the Athlete Biological Passport, aiming to monitor athlete’s biological variables over time to facilitate indirect detection of doping. Detection tests for anabolic androgenic steroids (AAS) and growth hormone (GH) are available while insulin abuse cannot be revealed. We have determined in recreational bodybuilders the metabolic effects associated with different patterns of hormone abuse. All analyses were conducted using Statistical Package for Social Sciences (SPSS) 21.0 software (SPSS Chicago, IL). Results We have assessed plasma concentrations of selected metabolic markers and fatty acid content in erythrocyte membranes of 92 male bodybuilders and in 45 healthy controls. Hormonal abuse was identified by anonymous questionnaires. 43% (%) of recruited bodybuilders regularly abused hormones, i.e., anabolic androgenic steroids (95%) often associated with GH (30%) and/or insulin (38%). HDL-cholesterol was lower in insulin and/or GH abusers. Alanine (ALT) and aspartic (AST) transaminases were greater in hormone abusing bodybuilders than in non-doping bodybuilders and controls. Insulin doping was selectively associated with increased plasma ALT-to-AST ratio. In erythrocyte membranes, elongase activity (i.e., stearic-to-palmitic ratio) was lower in insulin and/or growth hormone doping, whereas increased Δ-9 desaturase activity (i.e., palmitoleic-to-palmitic ratio) was selectively associated with insulin doping. Conclusions In conclusion, our study demonstrates that insulin and GH abuse are characterized by multiple alterations of specific metabolic markers. Although further studies are needed to test whether longitudinal monitoring of selected metabolic marker such as muscle contraction time, HDL levels, ALT-AST ratio as well as the activities of selected enzymes (e.g. Δ-9 desaturase and elongase), could contribute to the detection of insulin and GH abuse in sport.
Joshua J. Todd
Tokunbor Lawal Irene C. Chrismer Payam Mohassel
Background RYR1-related myopathies (RYR1-RM) are caused by pathogenic variants in the RYR1 gene which encodes the type 1 ryanodine receptor (RyR1). RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to RYR1-RM pathogenesis. Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1-RM patient skeletal muscle biopsies and improved following ex vivo treatment with Rycal compounds. Thus, we initiated a first-in-patient trial of Rycal S48168 (ARM210) in ambulatory adults with genetically confirmed RYR1-RM. Methods Participants received 120 mg (n = 3) or 200 mg (n = 4) S48168 (ARM210) daily for 29 days. The primary endpoint was safety and tolerability. Exploratory endpoints included S48168 (ARM210) pharmacokinetics (PK), target engagement, motor function measure (MFM)-32, hand grip and pinch strength, timed functional tests, PROMIS fatigue scale, semi-quantitative physical exam strength measurements, and oxidative stress biomarkers. The trial was registered with clinicaltrials.gov (NCT04141670) and was conducted at the National Institutes of Health Clinical Center between October 28, 2019 and December 12, 2021. Findings S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile. Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle strength on physical examination. Interpretation S48168 (ARM210) demonstrated favorable safety, tolerability, and PK, in RYR1-RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key symptom of RYR1-RM. These results set the foundation for a randomized, double-blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) in RYR1-RM.
Alexandre Mortier Jina Khoudary Sophie van Dooslaer de Ten Ryen
Louise Deldicque
Background and Objectives Most research studies on the effects of repeated plasma donation are observational with different study limitations, resulting in high uncertainty on the link between repeated plasma donation and health consequences. Here, we prospectively investigated the safety of intensive or less intensive plasma donation protocols. Materials and Methods Sixty‐three male subjects participated in this randomized controlled trial and were divided into low‐frequency (LF, once/month, n = 16), high‐frequency (HF, three times/month, n = 16), very high‐frequency (VHF, two times/week, n = 16) and a placebo (P, once/month, n = 15) groups. Biochemical, haematological, clinical, physiological and exercise‐related data were collected before (D0), after 11⁄2 months (D42) and after 3 months (D84) of donation. Results In VHF, red blood cells, haemoglobin and haematocrit levels decreased while reticulocyte levels increased from D0 to D84. In both HF and VHF, plasma ferritin levels were lower at D42 and D84 compared to D0. In VHF, plasma levels of albumin, immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM) dropped from D0 to D42 and remained lower at D84 than at D0. In HF, plasma IgG, IgA and IgM were lower at D42, and IgG and IgM were lower at D84, compared to D0. Few adverse events were reported in HF and VHF. Repeated plasma donation had no effect on blood pressure, body composition or exercise performance. Conclusion VHF plasmapheresis may result in a large reduction in ferritin and IgG levels. HF and VHF plasmapheresis may result in little to no difference in other biochemical, haematological, clinical, physiological and exercise‐related parameters.
Jan Sommer Jeppesen
Søren Jessen
Martin Thomassen
Morten Hostrup
Purpose: Many athletes use long-acting beta2 -agonist formoterol in treatment of asthma. However, studies in non-athlete cohorts demonstrate that inhaled formoterol can enhance sprint performance calling into question whether its use in competitive sports should be restricted. We investigated whether formoterol at upper recommended inhaled doses (54 μg) would enhance sprint ability and intense exercise performance in elite cyclists. Methods: Twenty-one male cyclists (V̇O2max : 70.4 ± 4.3 mL × min-1 × kg-1 , mean ± SD) completed two 6-s all-out sprints followed by 4-min all-out cycling after inhaling either 54 μg formoterol or placebo. We also assessed cyclists' leg muscle mass by dual-energy X-ray absorptiometry and muscle fiber type distribution of vastus lateralis biopsies. Results: Peak and mean power output during the 6-s sprint was 32 W (95% CI, 19-44 W, p < 0.001) and 36 W (95% CI, 24-48 W, p < 0.001) higher with formoterol than placebo, corresponding to an enhancing effect of around 3%. Power output during 4-min all-out cycling was 9 W (95% CI, 2-16 W, p = 0.01) greater with formoterol than placebo, corresponding to an enhancing effect of 2.3%. Performance changes in response to formoterol were unrelated to cyclists' VO2max and leg lean mass, whereas muscle fiber Type I distribution correlated with change in sprinting peak power in response to formoterol (r2 = 0.314, p = 0.012). Conclusion: Our findings demonstrate that an inhaled one-off dose of 54 μg formoterol has a performance-enhancing potential on sprint ability and short intense performance in elite male cyclists, which is irrespective of training status but partly related to muscle fiber type distribution for sprint ability.
Morten Hostrup Erik Søren Halvard Hansen Søren M. Rasmussen
Vibeke Backer
Athletes often experience lower airway dysfunction, such as asthma and exercise-induced bronchoconstriction (EIB), which affects more than half the athletes in some sports, not least in endurance sports. Symptoms include coughing, wheezing, and breathlessness, alongside airway narrowing, hyperresponsiveness, and inflammation. Early diagnosis and management are essential. Not only because untreated or poorly managed asthma and EIB potentially affects competition performance and training, but also because untreated airway inflammation can result in airway epithelial damage, remodeling, and fibrosis. Asthma and EIB do not hinder performance, as advancements in treatment strategies have made it possible for affected athletes to compete at the highest level. However, practitioners and athletes must ensure that the treatment complies with general guidelines and anti-doping regulations to prevent the risk of a doping sanction because of inadvertently exceeding specified dosing limits. In this review, we describe considerations and challenges in diagnosing and managing athletes with asthma and EIB. We also discuss challenges facing athletes with asthma and EIB, while also being subject to anti-doping regulations.
Leticia Varella
Massimo Cristofanilli
Breast cancer remains the second leading cause of cancer mortality in women. Endocrine therapy is the backbone treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the most common subtype. Although several endocrine therapy agents are available, essentially all HR-positive metastatic breast cancers will become resistant to these drugs. ESR1 mutations represent an important mechanism of resistance to aromatase inhibitors. Elacestrant is a novel oral selective estrogen receptor degrader (SERD) that selectively binds to the estrogen receptor in breast cancer cells, inhibiting tumor growth. Preclinical data suggested greater efficacy of elacestrant in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) or everolimus. In a Phase III clinical trial, elacestrant demonstrated a significant although modest improvement in median progression-free survival (PFS) compared to standard of care endocrine therapy in patients with HR-positive, HER2-negative advanced breast cancer. Importantly, there was also a significant benefit in patients with ESR1 mutations, which led to the FDA approval of elacestrant in this patient group. Elacestrant was generally well tolerated, with main side effects being upper gastrointestinal symptoms. There are several ongoing clinical trials evaluating the efficacy of elacestrant in the early setting as well as in combination with other targeted agents in the treatment of metastatic breast cancer. Other novel oral SERDs are also currently being evaluated in the treatment of HR-positive breast cancer. Results of ongoing clinical trials with these drugs will help clinicians decide the best sequence and combination of endocrine therapy agents.
Yue Gao Xinran Wei Pingying Wei Zheng Liu
Mitochondrial-derived peptides are a family of peptides encoded by short open reading frames in the mitochondrial genome, which have regulatory effects on mitochondrial functions, gene expression, and metabolic homeostasis of the body. As a new member of the mitochondrial-derived peptide family, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is regarding a peptide hormone that could reduce insulin resistance, prevent obesity, improve muscle function, promote bone metabolism, enhance immune regulation, and postpone aging. MOTS-c plays these physiological functions mainly through activating the AICAR-AMPK signaling pathways by disrupting the folate-methionine cycle in cells. Recent studies have shown that the above hormonal effect can be achieved through MOTS-c regulating the expression of genes such as GLUT4, STAT3, and IL-10. However, there is a lack of articles summarizing the genes and pathways involved in the physiological activity of MOTS-c. This article aims to summarize and interpret the interesting and updated findings of MOTS-c-associated genes and pathways involved in pathological metabolic processes. Finally, it is expected to develop novel diagnostic markers and treatment approaches with MOTS-c to prevent and treat metabolic disorders in the future.
Andreas Thomas
Sophia Krombholz
Johanna Sternberg Mario Thevis
Because of its influence on carbohydrate metabolism and, at the same time, anti-catabolic effects, the misuse of the peptide hormone insulin and its synthetic analogs is prohibited in sports at all times according to the regulations of the World Anti-Doping Agency (WADA). The biological effects of insulin and its analogs are mediated through binding to the insulin receptor, which was also found to be activated by different peptides structurally largely unrelated to insulin. Such insulin-mimetic peptides or selective-insulin receptor modulators (SIRMs) represent a novel class of potential performance-enhancing agents, which is currently not explicitly mentioned on the WADA Prohibited List. Within this research project, advanced solid-phase extraction (SPE) and liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-HRMS/MS) were employed to develop a fast, reliable, and specific assay for the detection of the insulin-mimetic peptides S597 and S519 from plasma. Method validation demonstrated a detection limit of 0.5 ng/mL and successfully illustrated the applicability of the approach to routine sports drug testing programs. Moreover, sophisticated and comprehensive in vitro metabolism experiments were conducted, and several metabolic degradation products were identified, which will enhance the information generated from future analyses of doping control samples.
Sijie Yu Sihao Shen Ming Tao
Background Non-stimulant guanfacine is a common second-line medication for attention-deficit hyperactivity disorder (ADHD). Numerous randomized controlled trials (RCTs) have explored the efficacy of guanfacine in ADHD treatment. This meta-analysis combined data from selected RCTs to analyze the efficacy and safety of guanfacine in treating ADHD. Methods RCTs were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase (up to February 2022), defining the Clinical Global Impression of Improvement (CGI-I) treatment response score of ≤2 as the primary outcome. Subgroup analysis was performed with a bound treatment duration of 10 weeks. Safety was defined by treatment-emergent adverse events (TEAEs). Results Twelve out of 332 studies with 2653 participants were included. All studies compared guanfacine with placebos. Guanfacine was significantly more effective in treating ADHD (Risk Ratio [RR] 1.78, 95% CI: 1.59–2.01). In the <10 weeks subgroup, the efficacy in the guanfacine group compared with the placebo group was 58.5% versus 29.4%, respectively (RR 1.97, 95% CI: 1.71–2.26). In the >10 weeks subgroup, the efficacy in the guanfacine group compared with the placebo group was 63.6% versus 39.7%, respectively (RR 1.57, 95% CI: 1.37–1.79). Both subgroups lacked heterogeneity ( I 2 = 0), and a funnel plot showed a low publication bias risk. Around 80% of participants in the guanfacine group experienced at least one TEAE, compared with 66.5% in the placebo group (RR 1.23, 95% CI: 1.14–1.32), with low heterogeneity ( I 2 = 46, p = 0.05). The most common TEAEs in the guanfacine group were somnolence (38.6%), headaches (20.5%), and fatigue (15.2%). Conclusions Guanfacine is safe and effective for treating ADHD, with no serious adverse events. Guanfacine should be considered as an effective treatment option where effectiveness or tolerability of the central nervous system stimulant is of concern. There is stronger evidence of efficacy for children; more clinical studies are needed for adults.