Limited · human
This case report tracked a single 25-year-old recreationally active male who self-administered LGD-4033 (a selective androgen receptor modulator) and MK-677 (a growth hormone secretagogue) daily for five weeks. Blood work and body composition (via DXA) were collected before, during, and after the cycle, while muscular strength and skeletal muscle androgen-related biomarkers were assessed during the cycle and compared cross-sectionally against data from non-using trained males. The study observed increases in total body mass, lean mass, and fat mass during the cycle, alongside adverse changes in bone mineral content and density, serum lipids (notably a 40% rise in LDL and a 36% drop in HDL), and liver enzymes (ALT rose over 200%). Total and free testosterone and sex hormone-binding globulin fell markedly during the cycle. Most biomarkers returned toward baseline post-cycle, though total cholesterol, LDL, total fat mass, and bone area did not fully recover. Follicle-stimulating hormone remained below clinical reference ranges even post-cycle. Compared with non-users, the subject showed higher intramuscular testosterone and dihydrotestosterone but lower androgen receptor content, alongside greater strength. Key limitations include the single-subject design, lack of a control group, and reliance on cross-sectional comparisons for intramuscular and strength data, making causal inferences unreliable.
Experimental physiology · Nov 2022DOI ↗ Review
This paper is a narrative review evaluating bremelanotide (Vyleesi), a melanocortin receptor agonist delivered by injection, for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The authors conducted a PubMed literature search of peer-reviewed publications and synthesized available evidence on the drug's proposed mechanism of action, pharmacokinetics, efficacy, and safety profile. The review notes that bremelanotide is thought to work by activating central melanocortin signaling pathways that may enhance sexual desire. Based on clinical trial data, the authors report that bremelanotide produced statistically significant improvements on validated questionnaires measuring sexual desire and distress; however, they characterize the overall clinical benefit as modest. The most commonly reported adverse event across trials was nausea, occurring in approximately 40% of participants. The authors caution that interpreting trial results is complicated by methodological challenges inherent to female sexual dysfunction research, including a pronounced placebo effect, long recall periods, and outcome measures susceptible to expectation bias. This paper does not present original trial data and relies on synthesis of existing literature, limiting its ability to independently confirm efficacy or safety claims.
Expert opinion on pharmacotherapy · Oct 2022DOI ↗ Animal onlyPreprint
This study investigated whether a synthetic small-molecule agonist of the orphan nuclear receptor ERRα (estrogen receptor-related receptor alpha), called SLU-PP-332, could mimic the genetic and physiological effects of aerobic exercise in skeletal muscle. Researchers first used cell-based assays to confirm that SLU-PP-332 activates ERRα and found it triggered an acute aerobic exercise-associated gene expression program in skeletal muscle cells in an ERRα-dependent manner. In cell culture experiments, the compound increased mitochondrial function and cellular respiration. When administered to mice, SLU-PP-332 was reported to increase the proportion of type IIa oxidative skeletal muscle fibers and improve exercise endurance capacity. The authors propose that ERRα is a viable pharmacological target for developing "exercise mimetic" compounds, which could potentially help treat metabolic disorders and age-related muscle decline. Key limitations include the preclinical (mouse and cell-based) nature of all findings, the absence of human data, and the preprint status of the paper, meaning it had not yet undergone formal peer review at the time of reporting. No conclusions about human efficacy or safety can be drawn from this work alone.
Unknown journal · Oct 2022DOI ↗ Review
This review paper traces more than a century of melanocortin research, from the initial discovery of melanocortins in 1916 to contemporary therapeutic applications. It describes the five known melanocortin receptors (MC1R–MC5R), with particular attention to the two neural receptors—MC3R and MC4R—which are predominantly expressed in the central nervous system and play key roles in regulating energy homeostasis. The authors systematically categorize ligands for these receptors into three groups: classical ligands (endogenous melanocyte-stimulating hormones and agouti-related peptide), nonclassical ligands (lipocalin 2, β-defensins, small molecules, and pharmacoperones), and clinically approved or repurposed agents (ACTH, setmelanotide, bremelanotide, and certain repurposed drugs). The review highlights how early medicinal chemistry efforts modifying endogenous peptides yielded potent and selective tool compounds, and how targeting neural MCRs has emerged as a viable strategy for metabolic conditions such as obesity and cachexia. Limitations inherent to this paper include its review design—it synthesizes existing literature rather than generating new experimental data—and therefore cannot independently establish clinical efficacy or safety for any specific ligand.
Biomolecules · Oct 2022DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (recruiting). The objective of this study is to compare the safety and efficacy of RGN-259 to placebo for the treatment of Neurotrophic Keratopathy (NK)
ClinicalTrials.gov · Sep 2022View trial ↗ Animal only
This study investigated the role of melanocortin signaling in the nucleus accumbens (NAcc) on food intake and motivation to eat in mice. Male C57BL/6J mice received bilateral microinjections of melanotan-II (MT-II), a melanocortin receptor 3/4 agonist, directly into the NAcc, and researchers measured effects on food consumption and operant responding for food. The study found that MT-II microinjected into the NAcc significantly reduced both the amount of food consumed (measured in home cage settings) and appetitive responding (measured by operant self-administration tasks requiring effort to obtain food). Importantly, these effects appeared to occur without inducing conditioned taste avoidance—suggesting the reductions were not due to nausea or aversion—and without measurable changes in metabolic rate. The authors concluded that melanocortin signaling in the NAcc may selectively regulate appetite and satiety independent of metabolism or aversive side effects. Key limitations include that this was an animal-only study conducted exclusively in male mice of a single inbred strain, limiting generalizability to other sexes, species, or humans. The microinjection approach is also not clinically translatable in its current form.
Neuropeptides · Sep 2022DOI ↗ Animal only
This study investigated the metabolic profile of ibutamoren (MK-0677) — an orally active, non-peptide growth hormone secretagogue — in thoroughbred horses, with the goal of supporting anti-doping detection efforts. Researchers administered ibutamoren orally to horses and collected biological samples, which were analyzed using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) to identify and characterize the parent compound and its metabolites. The study identified 22 metabolites in total: 17 Phase I metabolites (including mono- and di-hydroxylated forms, dissociated side chain products such as a benzyl group and 2-amino-2-methylpropanamide, and hydrogenated metabolites) and 5 Phase II metabolites (glucuronic acid conjugates; no sulfate conjugates were detected). The study reported that major metabolites were detectable up to 96 hours post-administration, while the parent compound ibutamoren itself persisted for up to 72 hours. The authors conclude that these findings provide a useful metabolic reference framework to help detect illicit use of ibutamoren in competitive equine sports. Key limitations include the use of an animal model (horses only), meaning findings may not directly translate to human metabolism or human anti-doping contexts.
Rapid communications in mass spectrometry : RCM · Sep 2022DOI ↗ Limited · human
This study investigated a method for detecting a broad range of peptide-based doping agents (molecular mass 2–10 kDa) in blood samples collected for anti-doping control purposes. Researchers developed a simplified, generic sample preparation workflow using mixed-mode solid-phase extraction (SPE), coupled with liquid chromatography and high-resolution mass spectrometry (HRMS; resolution >100,000 FWHM) as an initial testing procedure. The target analytes included multiple insulin variants (human and synthetic analogues such as lispro, aspart, glulisine, detemir, glargine, and others), growth hormone–releasing hormones (sermorelin, CJC-1295, tesamorelin), insulin-like growth factors (Long-R3-IGF-I, R3-IGF-I, Des1-3-IGF-I), and mechano growth factors. The study demonstrated that the method met WADA's Technical Document 2022 (TD2022 MRPL) requirements for minimum required performance levels. Proof-of-principle was shown using real post-administration blood samples from subjects treated with synthetic insulin analogues. A key advantage noted was that blood, unlike urine, contains intact peptide hormones at relatively higher concentrations, simplifying detection. Limitations include the study's primarily analytical/methodological scope and the small number of post-administration samples used for validation.
Analytical science advances · Aug 2022DOI ↗ 🧪 TrialInsufficient
Registered observational trial (enrolling by invitation). This is an observational, retrospective, cohort study using administrative insurance claims data. The aim of this non-interventional study (NIS) is to compare maternal, fetal and infant outcomes of women exposed to Wegovy during pregnancy to a reference population not exposed to Wegovy, so that participants and healthcare providers can make informed treatment decisions.
ClinicalTrials.gov · Aug 2022View trial ↗ 🧪 TrialInsufficient
Registered Phase 2 interventional trial (completed). A multicenter randomized double-blind placebo parallel control design was used in this study.60 subjects eligible for inclusion will be randomly assigned to either a low-dose (0.25ug/kg) medium-dose (0.5ug/kg) high-dose (2.0ug/kg) experimental drug group or a control group (placebo) at a ratio of 1:1:1:1.After randomization, subjects received the experimental drug or placebo once a day, intravenously, on day 2 to 7, 12 hours and 4 hours after PCI.Ninety days after PCI were observed.
ClinicalTrials.gov · Aug 2022View trial ↗ Preclinical
This study investigated how synthetic and endogenous ligands bind to and activate the growth hormone secretagogue receptor (GHS-R), a G-protein coupled receptor involved in growth hormone (GH) release and appetite regulation. Using radiolabeled ligand-binding assays, calcium-response (aequorin-based) assays, GH release assays in mice, receptor chimeras (human/puffer fish domain swaps), and site-directed mutagenesis, researchers characterized the structural basis of ligand-receptor interactions. The study found that synthetic agonists MK-0677 and GHS-25 displayed high binding affinity and, notably, greater in vivo GH secretagogue activity compared to the endogenous peptide ghrelin. GHS-R knockout mice showed complete abolition of activity, confirming receptor specificity. Chimera analysis identified the C-terminal region, particularly transmembrane domain 6 (TM6), as critical for ligand-dependent activation. Site-directed mutagenesis pinpointed residues D99 and W276 as essential for ligand binding, while E124 was selectively important for MK-0677, and F279 was preferentially involved in ghrelin and GHS-25 interactions. The study is primarily mechanistic and largely preclinical (in vitro and animal models), limiting direct translation to human therapeutic contexts. Its findings advance structural understanding of GHS-R and may inform future drug design efforts.
Journal of translational internal medicine · Jun 2022DOI ↗ Limited · human
This paper presents a case report of a 27-year-old male with no relevant medical history who attended an emergency department two hours after self-administering Melanotan II (also marketed as a "Barbie drug") subcutaneously. Melanotan II is a synthetic analogue of alpha-melanocyte-stimulating hormone (α-MSH) that stimulates eumelanin production to induce skin pigmentation without sun exposure. It is readily available for purchase online and in gyms, despite not being approved for clinical use. Following self-administration, the patient developed sympathomimetic symptoms requiring treatment with lorazepam, supplemental potassium, and intravenous fluid resuscitation. The authors also note that prior research has associated Melanotan II use with the development of new pigmented and dysplastic naevi, raising additional dermatological safety concerns. The paper concludes that despite its easy accessibility, Melanotan II carries real and potentially serious risks. Key limitations include its single-patient case design, which precludes generalization about incidence or severity of adverse effects across the broader population of users.
Nederlands tijdschrift voor geneeskunde · May 2022Source ↗ Limited · human
This study compared the growth hormone (GH) response elicited by a single oral dose of LUM-201 (ibutamoren/MK-0677), a GH secretagogue receptor agonist, to responses from standard diagnostic GH stimulation tests (arginine, glucagon, clonidine, L-dopa, and insulin-induced hypoglycemia) in 68 pediatric subjects enrolled in a pediatric growth hormone deficiency (PGHD) clinical trial. The study found that LUM-201 produced significantly greater GH responses than the conventional secretagogues, with median peak GH of 15.0 ng/mL versus 5.5 ng/mL for standard tests (p-value not fully captured in abstract but reported as statistically significant). Notably, the larger GH responses to LUM-201 were most pronounced in subjects who also showed higher peak GH responses to conventional testing, suggesting a functional somatotroph reserve may be required. The authors concluded that LUM-201 may represent a potential oral treatment alternative to injectable recombinant human GH (rhGH) in a subset of PGHD patients who demonstrate adequate acute GH responses to LUM-201. Limitations include the lack of a placebo-controlled design, relatively small sample size, and the single-dose comparison design which does not assess long-term growth outcomes.
Hormone research in paediatrics · Mar 2022DOI ↗ Animal only
This study investigated the metabolism of MK-0677 (ibutamoren mesylate), an orally active non-peptide growth hormone secretagogue, in horses to support equine doping control efforts. Researchers conducted both in vitro incubations and in vivo oral administration to two Thoroughbred racehorses, then used liquid chromatography high-resolution mass spectrometry (LC-HRMS) and LC-tandem mass spectrometry to identify and profile metabolites in urine and plasma. Fourteen phase I metabolites were identified in vitro; 13 were subsequently detected in post-administration urine and nine in plasma, along with the parent compound in both matrices. The study found that an O-dealkylated metabolite of MK-0677 showed the longest detection window in both urine and plasma, making it the recommended analytical target for doping control laboratories. Both MK-0677 and this key metabolite were found to be excreted predominantly in unconjugated form. Limitations include the very small sample size (n=2 horses) and the fact that findings are restricted to equine species, meaning results cannot be directly extrapolated to human metabolism or doping detection in human sport.
Drug testing and analysis · Mar 2022DOI ↗ Insufficient
This study developed and validated an antibody-free analytical method for detecting prohibited growth hormone-releasing hormone (GHRH) analogues — specifically sermorelin, CJC-1293, a sermorelin metabolite, CJC-1295, and tesamorelin — in human urine samples. Instead of the conventional, labor-intensive immunoaffinity purification approach, the researchers used ultrafiltration alone to preconcentrate urine samples before analysis by nano liquid chromatography coupled with high-resolution tandem mass spectrometry (nanoLC-HRMS/MS). The method achieved limits of detection between 5 and 25 pg/mL and limits of identification between 25 and 50 pg/mL, with analyte recoveries of 59–115%. Robustness was demonstrated across over 200 injections. When compared directly to immunoaffinity purification, the ultrafiltration approach yielded similar sensitivity at lower cost and without requiring specialized antibodies. Stability experiments revealed that sermorelin and its metabolite degrade rapidly at temperatures above 4°C and at pH below 7, highlighting the critical importance of proper sample handling. The authors note the method could be extended to other emerging peptide drugs (≥ ~3 kDa) and their metabolites. A key limitation is that the study is an analytical methods validation paper rather than a clinical or pharmacological study; it does not assess biological effects or pharmacokinetics in human subjects.
Journal of pharmaceutical and biomedical analysis · Mar 2022DOI ↗ 🧪 TrialLimited · human
Registered Phase 3 interventional trial (completed), with sponsor-posted results. This study will compare the new medicine IcoSema, which is a combination of insulin icodec and semaglutide, taken once a week, to semaglutide taken once a week in people with type 2 diabetes. The study will look at how well IcoSema controls blood sugar level in people with type 2 diabetes compared to semaglutide. Participants will either get IcoSema or semaglutide. Which treatment participants get is decided by chance. IcoSema is a new medicine that doctors cannot prescribe. Doctors can already prescribe semaglut
ClinicalTrials.gov · Feb 2022View trial ↗ Animal onlyPreprint
This study investigated whether pharmacological activation of estrogen-related receptors (ERRα and ERRγ) could serve as a therapeutic strategy for heart failure. Using structure-based drug design, researchers developed two novel synthetic pan-ERR agonists — SLU-PP-332 and SLU-PP-915 — and tested them in a mouse model of pressure overload-induced heart failure. Both compounds significantly improved cardiac ejection fraction and reduced fibrosis without affecting cardiac hypertrophy. Mechanistic analyses revealed that ERR agonists broadly activated metabolic gene programs, particularly those governing fatty acid oxidation and mitochondrial function, with ERRγ identified as the primary mediator. Metabolomics profiling showed that SLU-PP-915 normalized disrupted fatty acid/lipid and TCA cycle/oxidative phosphorylation metabolite profiles in failing mouse hearts. The agonists also induced autophagy in cardiomyocytes and downregulated cell cycle and developmental pathways, partly via suppression of the transcription factor E2F1. The study is limited to preclinical mouse models with no human data, and the long-term safety profile of these compounds remains uncharacterized. The authors conclude that these findings provide direct pharmacological evidence supporting further development of ERR agonists as heart failure therapeutics.
Unknown journal · Feb 2022DOI ↗ Animal only
This animal study investigated whether treatment with a nicotinamide N-methyltransferase inhibitor (NNMTi; 5-amino-1-methylquinolinium) combined with a low-fat diet (LD) switch produced distinct gut microbiome changes in diet-induced obese (DIO) mice, compared to mice maintained on a high-fat Western diet, switched to LD alone, or kept as lean controls. Researchers analyzed cecal microbiome profiles using amplicon sequence variant (ASV) sequencing across these groups. The study found that diet switch (regardless of NNMTi treatment) drove several microbiome differences at the genus and phylum levels relative to controls, while differences between lean and obese controls were minimal, suggesting adiposity alone had limited microbiome impact in this model. Alpha diversity did not significantly differ between groups, but beta diversity analyses indicated within-group similarity. K-means clustering revealed that NNMTi-treated LD-switched mice had a distinct microbiome pattern, characterized by decreased Erysipelatoclostridium and increased Lactobacillus—genera associated with metabolic regulation and body weight. Parasutterella abundance, elevated in both LD-switched groups, significantly correlated with several adipose tissue metabolites. The authors acknowledge this is a foundational, exploratory study in mice, limiting direct translation to human metabolic disease.
Scientific reports · Jan 2022DOI ↗ Animal only
This study investigated whether hexarelin, a synthetic growth hormone-releasing peptide, could reduce the development of abdominal aortic aneurysm (AAA) using an elastase-induced mouse model. Mice received hexarelin injections twice daily, and outcomes were assessed via echocardiography, in situ imaging, histology, and molecular analyses. The study found that hexarelin-treated mice showed reduced infrarenal aortic diameter and improved elastin integrity compared to untreated controls. At the cellular level, hexarelin appeared to preserve smooth muscle cell (SMC) contractile phenotype, evidenced by increased α-SMA expression and decreased MMP2. Additionally, hexarelin was associated with reduced inflammatory cell infiltration, suppression of NLRP3 inflammasome activation, lower IL-18 production, and inhibition of the NF-κB signaling pathway. The authors concluded that hexarelin attenuates AAA development by targeting SMC phenotype switching and NF-κB-mediated inflammation. Key limitations include the exclusive use of an animal model, meaning findings have not been validated in humans, and the mechanistic conclusions are based on a single preclinical model that may not fully replicate human AAA pathophysiology.
Microvascular research · Nov 2021DOI ↗ In vitro
This study, motivated by anti-doping enforcement, investigated the in vitro metabolism and urinary detection of four synthetic growth hormone releasing hormone (GHRH) analogs: sermorelin, tesamorelin, CJC-1295, and CJC-1295 with drug affinity complex (DAC). Because these compounds are banned by the World Anti-Doping Agency (WADA) yet rarely detected in accredited laboratory samples—likely due to low urinary concentrations and poorly understood metabolism—researchers used in vitro methods to identify 19 major metabolites. These metabolites were synthesized, purified, and characterized in-house to serve as reference materials. Using these standards alongside commercially available parent compounds and one known sermorelin metabolite (sermorelin(3-29)-NH₂), the team developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method applied to fortified (spiked) urine samples. Limits of detection were generally at or below 1 ng/mL, meeting WADA's required performance threshold. Key limitations include the in vitro nature of the metabolism work, meaning real-world in vivo metabolite profiles in humans may differ, and no actual athlete or clinical urine specimens were analyzed. The study advances analytical capability for anti-doping testing but does not evaluate physiological or clinical effects of these peptides.
Drug testing and analysis · Nov 2021DOI ↗