Melatonin in the Calming Formula
Why the November 2025 AHA findings do not describe what AlchemyPet delivers, and the evidence behind the formula.
In November 2025, a preliminary study presented at the American Heart Association Scientific Sessions found an association between long-term melatonin use and increased heart failure risk in adults with chronic insomnia. The study has not been peer-reviewed.
We welcome the question. It is the kind of scrutiny that serious supplement brands should be prepared to answer.
AlchemyPet's Calming formula is not what that study was looking at. Here is why.
The Dose Is Physiological
AlchemyPet delivers 0.67mg of melatonin per serving. The human body naturally produces 0.1 to 0.9mg per day. Dogs clear it faster still, with a half-life of just 18.6 minutes. Most OTC melatonin products deliver 3 to 10mg or more, placing 3 to 15 times the physiological load on the system.
The AHA study captured patients using unregulated OTC products at unknown, likely high, doses. Our dose is deliberate and physiologically grounded.
Encapsulation Changes the Risk Profile
Conventional melatonin is immediate-release. It spikes concentration fast and high, then clears rapidly. That peak concentration (Cmax) is the likely mechanism behind receptor saturation concerns.
AlchemyPet encapsulates melatonin in alginate microspheres. Alginate-based controlled release for melatonin has peer-reviewed precedent (Lee & Min, International Journal of Pharmaceutics, 1996), designed precisely to deliver melatonin in a circadian-aligned, sustained pattern.
2024 randomized crossover PK study (Pharmaceutics): sustained-release vs. immediate-release at the same dose
- Cmax reduced by nearly 50% with sustained release (11,447 pg/mL vs. 22,786 pg/mL)
- Half-life extended 5-fold (5.1 hours vs. 1.0 hour), mimicking the natural nocturnal curve
- One adverse event (vomiting) occurred with immediate release. Zero with sustained release.
Sustained release is not a marketing claim. It is the pharmacokinetic profile that mirrors how the body actually produces melatonin.
Five Co-Ingredients With Cardiovascular Support Evidence
The Calming formula was designed as a system, not a single-ingredient product. Five co-ingredients have independent published evidence for cardiovascular support.
| Ingredient | Cardiovascular Evidence |
|---|---|
| L-Theanine (100mg) | 2026 peer-reviewed review (ScienceDirect): attenuation of myocardial ischemia and heart failure, blood pressure reduction, lipid profile improvement, atherosclerotic plaque inhibition. |
| Carniking L-Carnitine (20mg) | Studied directly in dogs for cardiac ischemia; used clinically in canine dilated cardiomyopathy (DCM). Combined with grape seed extract in 2024 cardioprotection study. |
| MEGANATURAL GOLD Grape Seed Extract (8mg) | Meta-analysis of 9 RCTs: significant reduction in systolic blood pressure and heart rate. Proanthocyanidins show 20 to 50x antioxidant activity vs. Vitamins E and C. |
| Ashwagandha (15mg) | PubMed-indexed review (2024): cardioprotective effects via antioxidant properties, reduction of ischemia/reperfusion-induced apoptosis, pro-inflammatory cytokine suppression. |
| Vitamin K2 (1.64mg) | Multiple high-impact 2025 studies: cardiovascular health via calcium homeostasis and matrix Gla protein activation; reduced arterial calcification and vascular stiffness. |
| PrimaVie Shilajit (31.25mg) | Cardiovascular Toxicology study: reduced cardiac damage in myocardial injury models. Associated with reduced cholesterol and triglyceride levels. |
The Bottom Line
The AHA study captured humans with chronic insomnia taking unregulated OTC melatonin at high doses in immediate-release form. AlchemyPet delivers 0.67mg via alginate encapsulation, producing a lower Cmax, an extended half-life that mirrors natural circadian release, alongside five co-ingredients with independent cardiovascular support evidence, including L-carnitine studied directly in dogs for cardiac function.
Supporting References
All references cited in the Calming Formula Melatonin Brief. Full PDFs available on request.
A. Melatonin Delivery, Safety, and Encapsulation
- Lee BJ, Min GH. Oral controlled release of melatonin using polymer-reinforced and coated alginate beads. Int J Pharm. 1996;130(2):43-53.Foundational alginate-bead encapsulation study for melatonin, demonstrating sustained circadian-aligned release over 8 hours.
- Comparative pharmacokinetics of sustained-release versus immediate-release melatonin capsules in fasting healthy adults: a randomized, open-label, cross-over study. Pharmaceutics. 2024;16(10):1248. PMID: 39458580. doi:10.3390/pharmaceutics16101248.Demonstrated ~50% lower Cmax and 5x longer half-life with sustained-release vs. immediate-release. Zero adverse events with sustained release.
- Nnadi EO, et al. Long-term use of melatonin supplements for insomnia associated with higher risk of heart failure, hospitalization, and death. Abstract presented at: American Heart Association Scientific Sessions 2025; November 2025; New Orleans, LA. [Not yet peer-reviewed.]Observational study (n=130,828). Did not capture dosage, formulation type, or OTC use. No causal relationship established.
- Nuszkiewicz J, Rzepka W, Markiel J, Porzych M, Wozniak A, Szewczyk-Golec K. Circadian rhythm disruptions and cardiovascular disease risk: the special role of melatonin. Curr Issues Mol Biol. 2025;47(8):664. doi:10.3390/cimb47080664.2025 review distinguishing circadian-aligned melatonin use (cardioprotective) from disruptive supraphysiological dosing patterns.
- Council for Responsible Nutrition. CRN responds to melatonin study presented at AHA Scientific Sessions 2025 [press release]. November 3, 2025. Available at: crnusa.org.Industry response affirming that low-dose, short-term supplementation safety profile is not altered by the preliminary AHA findings.
B. Co-Ingredient Cardiovascular Evidence
- Pharmacological effects and molecular targets of L-theanine in cardiovascular diseases and comorbidities. Eur J Pharmacol. 2026;1019. doi:10.1016/j.ejphar.2026.178715.Comprehensive 2026 review covering L-theanine's role in attenuating heart failure, reducing blood pressure, improving lipid profiles, and inhibiting atherosclerotic plaque formation.
- Li Q, Ding J, Xia B, Liu K, Zheng K, Wu J, Huang C, Yuan X, You Q. L-theanine alleviates myocardial ischemia/reperfusion injury by suppressing oxidative stress and apoptosis through activation of the JAK2/STAT3 pathway in mice. Mol Med. 2024. PMC: 11214244. doi:10.1186/s10020-024-00865-0.Mechanistic study demonstrating L-theanine directly reduces cardiac damage in myocardial ischemia/reperfusion injury models.
- Feringa HH, Laskey DA, Dickson JE, Coleman CI. The effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trials. J Am Diet Assoc. 2011;111(8):1173-1181.Meta-analysis of 9 RCTs (n=390) showing grape seed extract significantly lowers systolic blood pressure and heart rate.
- Aldayel TS, Kilany OE, Gad El-Hak HN, Abdelrazek HMA, Abdallah O, Omar DE. Clinicopathological studies on the impact of grape seed extract and L-carnitine as cardioprotective agents against doxorubicin-induced toxicity in rats. Life. 2024;14(12):1656. doi:10.3390/life14121656.2024 study examining grape seed extract and L-carnitine together as cardioprotective agents, including ECG, cardiac markers, and inflammatory marker outcomes.
- Wicinski M, Fajkiel-Madajczyk A, Kurant Z, Liss S, Szyperski P, Szambelan M, Gromadzki B, Rupniak I, Slupski M, Sadowska-Krawczenko I. Ashwagandha's multifaceted effects on human health: impact on vascular endothelium, inflammation, lipid metabolism, and cardiovascular outcomes. Nutrients. 2024;16(15):2481. PMID: 39125360. doi:10.3390/nu16152481.Peer-reviewed review confirming ashwagandha's cardioprotective effects, anti-inflammatory cytokine reduction, and ischemia/reperfusion protection.
- Hariri E, Kassis N, Iskandar JP, Schurgers LJ, Saad A, Abdelfattah O, Bansal A, Isogai T, Harb SC, Kapadia S. Vitamin K2: a neglected player in cardiovascular health: a narrative review. Open Heart. 2021;8(2):e001715. PMID: 34785587. doi:10.1136/openhrt-2021-001715.Cleveland Clinic-authored review establishing Vitamin K2's cardiovascular role via matrix Gla protein activation and arterial calcification prevention.
- Cardioprotective effect of mumie (shilajit) on experimentally induced myocardial injury. Cardiovasc Toxicol. 2014. [Full author details available on request.]Pre-clinical study demonstrating shilajit reduced cardiac damage in experimental myocardial injury models.