Ingredientsβ-Guanidinopropionic acid — also written as beta-guanidinopropionic acid, abbreviated β-GPA or simply GPA, and systematically named 3-guanidinopropanoic acid — is an amino acid derivative belonging to the guanidine compound family. Guanidinopropionic acid is a kind of amino acid derivative. Its IUPAC name is 3-(diaminomethylideneamino)propanoic acid; alternative systematic designations include N-(aminoiminomethyl)-β-alanine and β-alanine, N-(aminoiminomethyl)-. Known synonyms include β-GPA and PNU-10483. The compound has also been assigned the pharmaceutical development code RGX-202 and the INN ompenaclid in the oncology context (see §8 below).
The molecular formula is C₄H₉N₃O₂ with a molecular weight of 131.1 Da and CAS Number 353-09-3. The melting point is 217–218 °C. β-Guanidinopropionic acid is a white crystalline powder soluble in water (50 mg/ml, yielding a clear, colorless solution). The Sigma-Aldrich reagent specification notes solubility up to 100 mg/ml in water under standard conditions. Its canonical SMILES representation is C(CN=C(N)N)C(=O)O, with a molecular mass of 131.069477 daltons and PubChem CID 67701.
3-Guanidinopropionic acid is classified as a creatine analog. Structurally, GPA differs from creatine (N-methylguanidinoacetic acid) by substituting the N-methyl group with a hydrogen atom and by extending the carbon backbone by one methylene unit. This makes GPA the propanoic-acid homolog of guanidinoacetic acid, the direct biosynthetic precursor of creatine.
GPA is a physiological constituent of mammalian blood plasma, erythrocytes, brain, liver, kidney, aorta, and urine. It is therefore not a purely synthetic or exogenous molecule; its presence across diverse mammalian tissues underscores its integration into normal physiology. GPA may be formed by L-arginine:glycine amidinotransferase through transamidination between arginine and β-alanine. This enzyme-catalyzed reaction — the same class of reaction that initiates creatine biosynthesis — places GPA at the intersection of arginine metabolism and the β-amino acid pathway.
Beta-guanidinopropionic acid (GPA) is a naturally occurring metabolite structurally similar to creatine. Because GPA is an endogenous mammalian metabolite, it has no dedicated botanical source, traditional herbal origin, or plant-derived form. It does not occur in characteristic concentrations in any particular food crop or medicinal plant. As a dietary supplement, β-guanidinopropionic acid is sold as a dietary supplement in synthetic form — produced by organic chemical synthesis and offered as a white powder or encapsulated preparation. Despite the lack of human data on efficacy and side effects, GPA is available as a food supplement, usually in doses of 500 mg, and is used by sportspersons to induce endurance capacity and promote weight loss.
GPA has no documented traditional or ethnobotanical history of use. As an isolated, endogenous mammalian guanidino compound, it was unknown as a discrete dietary agent before the advent of modern biochemistry. Its existence was established through analytical characterization of mammalian tissue extracts in the mid-twentieth century, and its pharmacological potential was first systematically explored in animal studies beginning primarily in the 1970s and 1980s. There are no records of its use in Ayurvedic, Traditional Chinese, Unani, or any other historical medicinal tradition, and no WHO, ESCOP, or German Commission E monograph exists for GPA as a herbal or traditional substance.
Its emergence as a dietary supplement is entirely a product of modern sports nutrition and metabolic research. Beta-guanidinopropionic acid (GPA) is a creatine analog that has been proposed as a therapeutic intervention for cardiometabolic diseases including type 2 diabetes and hypertension. GPA is also an additive in some commercially available, over-the-counter dietary supplements where it is touted to have beneficial metabolic and exercise-mimetic effects. This commercial application arose from laboratory research on its ability to modulate the creatine–phosphocreatine energy system, not from any folk or traditional knowledge base.
Because GPA is itself the sole active agent in preparations bearing its name, there are no secondary phytochemical constituents to identify. All described biological activities are attributed directly to the β-GPA molecule through its interactions with the creatine–phosphocreatine (PCr) energy system. Several distinct mechanistic pathways have been characterized primarily in animal and cell-culture models.
Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. GPA is one of the more commonly used creatine analogs. It has been shown to competitively inhibit creatine transport across the plasmalemma. The relevant transporter is the creatine transporter (CRT; also designated SLC6A8), a sodium-dependent plasma membrane carrier expressed in skeletal muscle, heart, brain, kidney, and other tissues. The creatine transporter (CRT; SLC6A8) mediates creatine uptake into several cell types, including kidney epithelial cells, where it has been proposed that CRT is important for reclamation of filtered creatine, a process critical for total body creatine homeostasis. By occupying SLC6A8 competitively, GPA reduces the net cellular import of creatine over time, gradually depleting intracellular creatine and its phosphorylated form, phosphocreatine.
βGPA is a creatine analog that gradually depletes cellular phosphocreatine (PCr) levels, resulting in increased AMP/ATP, which is analogous in many ways to chronic exercise. The phosphocreatine system is central to cellular bioenergetics: creatine and phosphocreatine provide an intracellular, high-energy phosphate-buffering system essential for maintaining ATP supply in tissues with high energy demands. Creatine kinase (CK) plays a key role in cellular energy transport. The enzyme transfers high-energy phosphoryl groups from mitochondria to subcellular sites of ATP hydrolysis, where it buffers ADP concentration by catalyzing the reversible transfer of the high-energy phosphate moiety between creatine and ADP. In animal feeding experiments, when fed to rats and mice, GPA was shown to cause the concentrations of creatine and phosphocreatine in heart and skeletal muscle to progressively decrease over time. One rodent study reported that this manipulation produced a 90% decrease in phosphocreatine in skeletal and cardiac muscle and a 50% decrease in ATP in skeletal muscle only.
The rise in the cellular AMP:ATP ratio consequent to PCr depletion activates AMP-activated protein kinase (AMPK), a master metabolic sensor. AMPK responds to cellular energy deficits, manifested as an increased AMP/ATP ratio, and elevated intracellular Ca²⁺ concentration, by activating catabolic pathways to increase energy production while simultaneously inhibiting anabolic pathways to reduce energy expenditure. β-Guanidinopropionic acid (βGPA) is a commercially available dietary supplement that has been shown to promote an AMPK-dependent increase in fatty acid utilization and aerobic capacity in mammals by compromising creatine kinase function.
Activation of AMPK is thought to defend against energy deficiency in skeletal muscle by stimulating mitochondrial biogenesis and alternative oxidative ATP-generating pathways, with increased glucose transport and fatty acid oxidation. AMPK also activates the transcriptional coactivator PGC-1α: creatine analogs induce a mild ATP deficiency in cells, thereby activating adenosine monophosphate–activated protein kinase (AMPK), which, in its turn, activates PGC-1α, as has been convincingly demonstrated in skeletal muscles.
The orally administered creatine analogue beta-guanidinopropionic acid (beta-GPA) decreases plasma glucose levels by increasing the sensitivity to insulin. This effect is based on a beta-GPA-induced expression of mRNA and total protein content of the insulin-responsive glucose transporter GLUT4. Decreasing muscle phosphagen content through dietary administration of the creatine analog beta-GPA improves skeletal muscle oxidative capacity and resistance to fatigue during aerobic exercise in rodents, similar to that observed with endurance training.
In brain tissue, GPA activates a mitochondrial biogenesis pathway distinct from the PGC-1α route observed in muscle. The Nrf2/ARE cascade facilitates adaptation to stress induced by changes in the energy metabolism resulting from the ATP deficit caused by creatine kinase inhibition, via stimulating mitochondrial biogenesis and activating the expression of cytoprotective, antioxidant, and anti-inflammatory enzymes. In an animal study, even short-term 3-week-long β-GPA treatment increased the mitochondrial DNA (mtDNA) copy number in the cortex and ventral midbrain, as well as the expression of several key antioxidant and metabolic enzymes — indicators of mitochondria proliferation and the activation of the Nrf2/ARE signaling cascade.
Although the oral availability of beta-GPA is well established, the underlying uptake mechanism has not yet been fully characterized. Investigations have examined whether the H⁺-coupled amino acid transporter PAT1, which is expressed in the apical membrane of intestinal cells, accepts guanidine derivatives as substrates. This represents an important distinction from the creatine absorption pathway and may have implications for pharmacokinetic interactions with other amino acid derivatives sharing the PAT1 transporter.
AMP-activated protein kinase (AMPK) controls autophagy through the mammalian target of rapamycin (mTOR) and Unc-51 like kinase 1 (ULK1/Atg1) signaling, which augments the quality of cellular housekeeping, and β-guanidinopropionic acid (β-GPA), a creatine analog, leads to a chronic activation of AMPK. β-GPA treatment enhanced AMPK signaling and expression of autophagy-related proteins in developing muscle cell models, indicating an effect on cellular quality-control mechanisms analogous to the autophagic responses observed in caloric restriction and exercise.
The 2013 systematic review by Oudman, Clark, and Brewster (published in PLoS ONE) represents the most comprehensive synthesis of the preclinical evidence base. The authors performed a systematic review and searched the electronic databases PubMed, EMBASE, the Cochrane Library, and LILACS from their inception through March 2011. They also searched the internet and explored references from textbooks and reviews. After applying inclusion criteria, they retrieved 131 publications, mainly considering the effect of chronic oral administration of beta-guanidinopropionic acid (0.5 to 3.5%) on skeletal muscle, the cardiovascular system, and brain tissue in animals. The review found no controlled human data on efficacy at that time. The following subsections describe findings by organ system and therapeutic area.
Preclinical evidence (animal/cell studies): This is the most extensively characterized area of GPA biology. Beta-guanidinopropionic acid decreased intracellular creatine and phosphocreatine in all tissues studied. In skeletal muscle, this effect induced a shift from glycolytic to oxidative metabolism, increased cellular glucose uptake, and increased fatigue tolerance. The shift in fiber-type metabolism — from fast-twitch glycolytic fibers toward the metabolic phenotype of slow-twitch oxidative fibers — is one of the most replicated findings in GPA animal literature. Chronic beta-guanidinopropionic acid increases fatigue tolerance of skeletal muscle and survival during ischaemia in animal studies, with modestly reduced myocardial contractility.
Dietary supplementation of the creatine analogue β-guanidinopropionic acid (β-GPA) decreases in vitro skeletal muscle AMP deaminase (AMP-D) activity in rats. Downregulation of AMP-D activity was progressive and greater in fast-twitch muscles (70–80%) than in the slow-twitch soleus muscle (approximately 50%).
Human/clinical evidence: There are currently no published controlled human trials specifically evaluating β-GPA for exercise performance or fatigue tolerance. The existing evidence is entirely derived from rodent models; translation to humans has not been demonstrated.
Evidence strength: Consistent across a large body of animal studies. Evidence in humans is absent for this indication.
Preclinical evidence (animal studies): Multiple animal models of non-insulin-dependent (type 2) diabetes have shown pronounced antihyperglycemic effects of GPA. In KKAy mice, a model of noninsulin-dependent diabetes, two acidic guanidines — 3-guanidinopropionic acid (3-GPA) and guanidinoacetic acid — decreased the plasma glucose level; other compounds were ineffective. 3-GPA was more potent than even metformin. Insulin suppression tests in KKAy mice indicated that improved insulin sensitivity was the mode of action for 3-GPA. Glycemic effects in KKAy mice resulted from increased glucose disposal whereas gluconeogenesis, hepatic glycogen content, and intestinal glucose absorption were unchanged.
3-GPA's glycemic effect was corroborated in two other models of noninsulin-dependent diabetes. In ob/ob mice, the compound reduced hyperglycemia, polyuria, glycosuria, and hyperinsulinemia. In insulin-resistant rhesus monkeys, it increased the disappearance of intravenously administered glucose. The glycemic action of 3-GPA required the presence of some circulating insulin as well as hyperglycemia, because the compound was ineffective in normoglycemic mice, insulinopenic Chinese hamsters, and streptozotocin-diabetic rats. These data indicate that acidic guanidine derivatives can ameliorate hyperglycemia in animal models of noninsulin-dependent diabetes. Because acidic derivatives uniquely lack the propensity of guanidine compounds for inducing lactic acidosis, these findings suggest a new approach for developing improved antidiabetes compounds from this chemical class.
Studies on animals (rats, monkeys, hamsters) show that acidic guanidine derivatives such as β-GPA can ameliorate hyperglycemia in animal models of noninsulin-dependent diabetes.
Human/clinical evidence: No published controlled clinical trials evaluating β-GPA for type 2 diabetes or insulin sensitivity in humans have been identified. Animal data — including primate data — are encouraging but unconfirmed in human subjects.
Evidence strength: Consistently positive preclinical evidence across multiple animal models including non-human primates. No human data. Evidence is preliminary.
Mechanistic and preclinical context: The hypothesis linking GPA to blood pressure reduction is based on the role of creatine kinase in vascular contractility and sodium retention. Investigators proposed that high intracellular activity of the ATP-regenerating enzyme creatine kinase (CK) increases pressor responses and hypertension risk. In line with this, plasma CK activity after rest, a surrogate measure of tissue activity, is the main predictor of blood pressure levels and failure of antihypertensive therapy in the general population. It was shown that beta-guanidinopropionic acid (GPA), a kidney-synthesized creatine analogue and competitive CK inhibitor, reduced blood pressure in spontaneously hypertensive rats.
Regarding cardiac effects, the systematic review found: in heart tissue the shift to mitochondrial metabolism was less pronounced. Myocardial contractility was modestly reduced, including a decreased ventricular developed pressure, albeit with unchanged cardiac output.
Human/clinical evidence — the ABC Trial: The first-in-human study of GPA for blood pressure was the ABC Trial (Acute effect of Beta-guanidinopropionic acid vs. Creatine), published in British Journal of Clinical Pharmacology (2017). In this active and placebo-controlled, triple-blind, single-centre trial, 24 healthy men (18–50 years old, BMI 18.5–29.9 kg/m²) were recruited in the Netherlands. Participants were randomized (1:1:1) to one week of daily oral administration of GPA 100 mg, creatine 5 g, or matching placebo. The primary outcome was the tolerability of GPA, in an intent-to-treat analysis.
This first-in-human study in healthy men, who orally ingested a daily dose of 100 mg GPA for 1 week, raised no safety or tolerability concerns, including no adverse effects reported and no significant differences detected compared to baseline. In subsequent intervention studies, the oral competitive CK inhibitor beta-guanidinopropionic acid (GPA) reduced blood pressure in spontaneously hypertensive rats (SHRs), and a 1-week trial of sub-therapeutic dose GPA in healthy men was uneventful.
This study was designed to increase knowledge on the effect of moderate reversible cytoplasmic creatine kinase inhibition on the human cardiovascular system and provide data on tolerability and hemodynamic parameters. Beta-guanidinopropionic acid doses were low, aimed at preventing toxicity in this first-in-men study. This limits the study of the efficacy of the drug.
Evidence strength: Strong and consistent preclinical evidence in rodent models. One small human tolerability trial (n = 24) using a sub-therapeutic dose, with no efficacy outcomes assessed. No human antihypertensive efficacy data exists. Evidence is early-stage for the human context.
Preclinical evidence (animal studies): In brain tissue, adaptations in energy metabolism resulting from GPA supplementation resulted in enhanced ATP stability and survival during hypoxia. β-Guanidinopropionic acid (β-GPA) has been used as a nutritional supplement for increasing physical strength and endurance with positive and predictable results. In muscles, it works as a nonadaptive stimulator of mitochondria biogenesis; it also increases lipid metabolism. There are data indicating that β-GPA can be also neuroprotective, but its mechanisms of action in the brain are less understood.
A 2018 study published in the Journal of Experimental Neuroscience examined β-GPA's effects on brain mitochondria and behavior in mid-age mice. The study examined the effects of β-GPA on animal behavior and mitochondrial biogenesis in the cortex and midbrain of mid-age healthy mice. Short-term 3-week β-GPA treatment increased the mitochondrial DNA (mtDNA) copy number in the cortex and ventral midbrain, as well as the expression of several key antioxidant and metabolic enzymes — indicators of mitochondria proliferation and the activation of the Nrf2/ARE signaling cascade. At the same time, β-GPA downregulated the expression of β-oxidation genes.
These biochemical changes are reflected not only in changes in muscle strength and endurance, but also in the cognitive behavioral patterns — for example, the apparent anxiolytic action of β-GPA. However, as the same research group noted, in the brain they found no expression upregulation for Pgc-1α, Pparα, and a number of genes involved in fatty acid oxidation, indicating that the brain biogenesis pathway operates through the Nrf2/ARE cascade rather than exclusively through the AMPK/PGC-1α axis.
Additionally, this product has been shown to protect neurons from 3-NP toxicity. The neurochemical 3-nitropropionic acid (3-NP) is used to model mitochondrial dysfunction and Huntington's disease-like pathology; GPA's protective effect in this context supports a potential neuroprotective application.
Human/clinical evidence: None identified. All neurological evidence is from animal models.
Evidence strength: Preliminary, based solely on animal studies. Translational relevance to humans is unknown.
Preclinical evidence: Several animal studies have documented effects of GPA on body composition and adipose tissue. GPA feeding of rats causes an increase in the mass of brown adipose tissue as well as in DNA, glycogen, and total protein content in this tissue. At the same time, there is an impairment in thermogenic activity in the brown adipose tissue, leading to hypothermia. The systematic review observed that GPA-fed animals exhibited body weight changes, though the mechanism and direction were not uniform across studies. With limited evidence for unchanged food intake, weight loss may as well be a consequence of reduced intake.
Human/clinical evidence: None identified.
Evidence strength: Preliminary animal data; complex and inconsistent effects on thermogenesis. No human data.
Preclinical evidence: A 2015 study published in Aging reported that dietary administration of β-GPA to adult Drosophila at a concentration higher than 900 mM induced a significant extension of the lifespan of Drosophila melanogaster in repeated experiments, attributed to AMPK-dependent autophagy activation. However, a subsequent report suggested that dietary GPA supplementation in Drosophila may not reliably extend lifespan through its effect on AMPK signaling and regulation of autophagy, indicating that this initial finding has been contested.
Evidence strength: Contradictory results even within invertebrate models. No mammalian lifespan data exist. This area is highly speculative.
Preclinical evidence: GPA has been shown to inhibit replication of several viruses including human and simian cytomegaloviruses and varicella zoster virus, and to reduce tumor size. These are in vitro or early animal findings only.
Human/clinical evidence: None identified for antiviral effects as a dietary supplement. The oncological application via the pharmaceutical agent ompenaclid (RGX-202) is discussed separately in §8.
Evidence strength: Preliminary cell-culture/animal data only.
Preclinical (animal) dosing: The systematic review by Oudman et al. (2013) identified that the retrieved publications mainly considered the effect of chronic oral administration of beta-guanidinopropionic acid at 0.5 to 3.5% of the diet on skeletal muscle, the cardiovascular system, and brain tissue in animals. In one mouse study, three-week-old, post-weanling CD-1 mice were fed a standard rodent chow supplemented with either 2% (w/w) α-cellulose (control) or βGPA. A separate rat aging study noted that rats were treated with GPA for up to 4 months starting at 14 or 30 months of age.
Supplement market dosing: GPA is available as a food supplement, usually in doses of 500 mg, used by sportspersons.
Human clinical trial dosing — ABC Trial: This was a randomized, active and placebo-controlled, triple-blind, double-dummy, single-center clinical intervention trial in 24 healthy male volunteers aged 18–50 years. The intervention consisted of one week of daily oral administration of beta-guanidinopropionic acid 100 mg, creatine 5 grams, or placebo. The primary outcome was tolerability. This 100 mg per day dose was explicitly described as sub-therapeutic and was chosen to minimize safety risk in the first human study. No effective or therapeutic dose in humans has been established.
Pharmaceutical oncology dosing (ompenaclid/RGX-202): In the Phase 1b/2 oncology trial, ompenaclid was administered as an oral small molecule; specific dose levels used in the escalation cohort have not been reported in accessible public documents. Ompenaclid (RGX-202) is an oral small molecule inhibitor of SLC6A8 that is currently being tested in combination with the standard-of-care regimen FOLFIRI and bevacizumab in a Phase 1b/2 clinical trial for the second-line treatment of patients with advanced colorectal cancer whose tumors express mutations in the RAS gene.
A major development in the translational science of GPA has been the pharmaceutical-grade optimization of its SLC6A8-inhibiting mechanism for oncology. Merck has agreed a deal with Inspirna for ompenaclid (RGX-202), a first-in-class oral inhibitor of the creatine transport channel SLC6A8. Inspirna's lead drug candidate, ompenaclid (RGX-202), is an orally administered small molecule that targets the CKB/SLC6A8 pathway. This pathway becomes activated in the tumors of select patients where it enables the generation of the energy molecule ATP in response to tumor hypoxia.
Phase 1b/2 results presented at the 2023 ESMO Congress showed: as of the September 18, 2023 data cutoff, median progression-free survival was 10.2 months and median overall survival was 19.1 months across all 41 patients with RAS-mutant metastatic colorectal cancer. Of the 30 patients evaluable for response, the objective response rate was 37%, with 11 partial responses. Ompenaclid was well-tolerated, with no dose-limiting toxicities observed in the dose-escalation cohort and combination safety profile comparable to FOLFIRI plus bevacizumab backbone treatment.
Ompenaclid is currently being evaluated in a Phase II study for the second-line treatment of RAS-mutated advanced or metastatic colorectal cancer. Inspirna has initiated a Phase II double-blind randomized controlled trial in second-line RAS-mutant advanced or metastatic colorectal cancer comparing ompenaclid versus placebo plus FOLFIRI and bevacizumab. It is important to note that ompenaclid is a pharmaceutical investigational agent, not the dietary supplement form of GPA. These clinical findings cannot be directly extrapolated to over-the-counter GPA supplementation.
The safety profile of GPA is incompletely characterized, especially in humans, and several preclinical observations raise substantive concerns that deserve factual attention.
Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. This substance is marked as safe for human use, but the effects are unclear. This characterization — present in the systematic review literature — reflects regulatory designation rather than a finding based on extensive human safety studies. The 2013 systematic review concluded that chronic β-GPA increases fatigue tolerance of skeletal muscle and survival during ischaemia in animal studies, with modestly reduced myocardial contractility. Because it is marked as safe for human use, there is a need for human data.
One of the most significant safety signals from animal research is the induction of mitochondrial damage in skeletal muscle with long-term GPA feeding. The long-lasting depletions of creatine phosphate induced by feeding rats with a β-GPA-supplemented diet induce specific mitochondrial alterations in skeletal muscles very similar to those observed in human mitochondrial myopathies. The slow-twitch soleus muscle appears to be affected primarily, while the fast-twitch extensor digitorum longus is affected less severely and only after a longer period of treatment (6 months). Changes in the enzyme activities of glucose metabolism appear to be secondary and differ between the two muscles. Importantly, withdrawal of GPA from the diet after 2 months of treatment shows that both mitochondrial alterations and biochemical modifications are reversible.
A 2023 study published in GeroScience raised a particularly important age-dependent genotoxic concern. Beta-guanidinopropionic acid (GPA) is a creatine analog suggested as a treatment for hypertension, diabetes, and obesity, which manifest primarily in older adults. Beta-guanidinopropionic acid has been proposed for use in age-associated diseases, yet the pharmacodynamics of GPA differ with age and include the detrimental induction of mtDNA deletions, a mitochondrial genotoxic stress that is pronounced in muscles that are most vulnerable to aging. A notable side effect of GPA is the induction of mitochondrial DNA deletion mutations.
GPA decreased body and muscle mass and mtDNA copy number while increasing mtDNA deletion frequency. The interactions between age and GPA treatment observed in the quadriceps were not observed in the adductor longus, indicating muscle-type-specific and age-specific vulnerability. This finding is particularly concerning given that the populations most likely to be targeted for GPA's proposed metabolic and cardiovascular benefits — older adults with diabetes or hypertension — may be the very individuals most susceptible to these genotoxic effects.
As noted above, GPA feeding of rats causes an increase in the mass of brown adipose tissue, but at the same time there is an impairment in thermogenic activity in the brown adipose tissue, leading to hypothermia. This is a pharmacologically significant finding in the context of long-term metabolic supplementation.
In growing animals, GPA supplementation impairs normal muscle development. Increased AMP-activated protein kinase (AMPK) activity leads to enhanced fatty acid utilization, while also promoting increased ubiquitin-dependent proteolysis (UDP) in mammalian skeletal muscle. The 2015 study in Molecular and Cellular Biochemistry examined juvenile CD-1 mice supplemented with 2% βGPA and assessed growth outcomes. The study demonstrated reductions in whole-body and skeletal muscle growth, which the authors attributed to the AMPK-driven catabolic shift. In young rodents, GPA treatment has positive and negative effects on skeletal muscle structure, function, and metabolism, as well as myopathic alterations.
The cardiovascular safety concern from the systematic review involves cardiac contractility: myocardial contractility was modestly reduced, including a decreased ventricular developed pressure, albeit with unchanged cardiac output. Although cardiac output was maintained in animal studies, the reduction in contractility warrants attention before GPA is used therapeutically in individuals with pre-existing heart disease.
Beta-guanidinopropionic acid (GPA), a kidney-synthesized creatine analogue and competitive CK inhibitor, reduced blood pressure in spontaneously hypertensive rats. To further develop the substance as a potential blood pressure-lowering agent, researchers assessed the tolerability of a sub-therapeutic GPA dose in healthy men. This first-in-human study in healthy men, who orally ingested a daily dose of 100 mg GPA for 1 week, raised no safety or tolerability concerns, including no adverse effects reported and no significant differences detected compared to baseline. However, this result is limited in scope: the dose was sub-therapeutic, the duration was one week, the population was healthy young adult males only, and the sample size was 24 participants. Long-term human safety data are entirely absent.
Although the oral availability of beta-GPA is well established, the underlying uptake mechanism has not yet been fully characterized. Investigations into whether the H⁺-coupled amino acid transporter PAT1, expressed in the apical membrane of intestinal cells, accepts guanidine derivatives as substrates suggest that GPA may compete with other PAT1 substrates — including GABA, proline, glycine, and certain other amino acid derivatives — for intestinal absorption. No clinical interaction data in humans have been reported.
β-Guanidinopropionic acid occupies a scientifically interesting niche as an endogenously occurring creatine analog with well-characterized metabolic mechanisms in preclinical models. It mimics aspects of endurance exercise training — mitochondrial biogenesis, fiber-type shift, increased GLUT4 expression, AMPK activation, and autophagy induction — through a fundamentally energy-depleting mechanism. Across more than 130 animal studies, it has consistently demonstrated effects on skeletal muscle energetics, antihyperglycemic activity, and potential antihypertensive effects. Its pharmaceutical derivative, ompenaclid, has shown encouraging Phase 1b/2 results in RAS-mutant colorectal cancer.
Despite this substantial preclinical basis, the translation to human evidence is extremely limited. Only one small, short-duration, sub-therapeutic dose human tolerability trial has been published (ABC Trial, 2017; n = 24, 100 mg/day × 7 days). No human efficacy data exist for any indication. The critical safety concerns — mitochondrial myopathy, age-dependent mtDNA genotoxicity, impaired thermogenesis, and reduced myocardial contractility — identified in animal models have not been systematically evaluated in humans. The conclusion of the 2013 systematic review remains accurate as of the available published literature: chronic β-GPA increases fatigue tolerance of skeletal muscle and survival during ischaemia in animal studies, with modestly reduced myocardial contractility. Because it is marked as safe for human use, there is a need for human data.
Health conditions that GPA (guanidinopropionic acid) may help support.
Body systems that GPA (guanidinopropionic acid) may help support.
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