Settle

• Owner-problem phase: rabbit owner forums, retailer listings and reviews in the US, UK and EU. Owners feared a stressed animal going off its food more than the stress itself. Two of three category leaders contained comfrey and one contained kava, both linked to liver harm.
• Literature pass: our AI-powered research system ran 65 searches and cross-checked 54 PubMed-indexed papers; our team reviewed each one. No study of alpha-casozepine exists in any rabbit, guinea pig or chinchilla, so the dose is scaled by body weight from rat studies.
• A second, stricter pass removed every herb. Chamomile and a valerian species relaxed isolated rabbit gut tissue, and lemon balm depressed gut contractions in sheep tissue. Slowing the hindgut is exactly what a rabbit should avoid.
• A second, independent research run flagged that digesting milk protein can release opioid-like peptides that slow gut transit in lab models. It is a class risk, not shown at our dose, so our research calls for a gut-tolerance study before launch.

Alpha-casozepine (milk protein hydrolysate)

Milk-derived calming peptide; in rodents it calmed without impairing movement, which matters for a prey animal.

L-tryptophan

Amino acid the body uses to make serotonin, which also supports normal gut movement in rabbits.

Timothy or meadow hay flour

Familiar, high-fibre carrier the animal already eats, ground coarse enough to resist sorting.

Lucerne meal and apple pomace

Natural flavour so the granules taste like food, not medicine.

Acacia gum

Light coating that helps granules cling to damp greens so they are not picked out.

• In rats given oral doses from 5 to 50 mg/kg, 15 mg/kg was the lowest effective dose of the casein hydrolysate, with effects in standard behaviour tests similar to diazepam but without the disinhibition diazepam caused. Rats; ingredient only. [1]
• In rats, the hydrolysate at 15 mg/kg had calming effects like diazepam and still worked after 7 days of twice-daily dosing when diazepam did not; memory retention was better than with diazepam and no place preference developed. Rats; ingredient only. [2]
• In mice given 75 to 500 mg/kg by mouth, the hydrolysate did not significantly change locomotor activity or motor function in open-field and rota-rod tests. Mice; ingredient only. [3]
• Why Settle is herb-free: in isolated rabbit jejunum, chamomile extract at 0.003 to 0.013 mg/mL reduced spontaneous gut muscle contractions in a concentration-dependent way, similar to the drug verapamil. Rabbit tissue in the lab, not live rabbits. [4]

• No study has tested alpha-casozepine in rabbits, guinea pigs or chinchillas, and controlled trials in cats at the vet and in foals found little or no effect. Settle's case is extrapolated from rodents.
• Settle has not yet been tested in animals. Our research calls for gut-tolerance and acceptance studies before launch.
• It is a calming support, not a treatment. A rabbit that has not eaten for 12 hours needs a vet.

1. [1]Violle N, Messaoudi M, et al. 2006. Ethological comparison of the effects of a bovine alpha s1-casein tryptic hydrolysate and diazepam on the behaviour of rats in two models of anxiety.Pharmacology, biochemistry, and behavior · PubMed 16899284
2. [2]Messaoudi M, Lalonde R, et al. 2009. Anxiolytic-like effects and safety profile of a tryptic hydrolysate from bovine alpha s1-casein in rats.Fundamental & clinical pharmacology · PubMed 19453759
3. [3]Dela Peña IJI, Kim HJ, et al. 2016. A tryptic hydrolysate from bovine milk αs1-casein enhances pentobarbital-induced sleep in mice via the GABAA receptor.Behavioural brain research · PubMed 27401107
4. [4]Yazdi H, Seifi A, et al. 2017. Hydro-alcoholic extract of Matricaria recutita exhibited dual anti-spasmodic effect via modulation of Ca(2+) channels, NO and PKA(2)-kinase pathway in rabbit jejunum.Avicenna journal of phytomedicine · PubMed 28884083 · Free full text

These studies tested ingredients or similar products, often in other species, not this finished product.