Lactium casein decapeptide

Lactium® / Alpha-Casozepine (Casein Decapeptide): A Comprehensive Reference

1. Identity, Nomenclature, and Natural Source

Lactium® is the registered trade name for a standardized bovine milk protein hydrolysate whose primary bioactive component is the decapeptide commonly called alpha-casozepine (α-CZP). Alpha-casozepine is a decapeptide of 10 amino acids with the sequence Tyr-Leu-Gly-Tyr-Leu-Glu-Gln-Leu-Leu-Arg (abbreviated YLGYLEQLLR), corresponding to residues 91–100 of bovine αs1-casein.

The compound is also referred to in the scientific literature and regulatory filings under several interchangeable designations:

• αS1-casein tryptic hydrolysate (αS1-CTH or CH) — the parent hydrolysate preparation that contains alpha-casozepine among other peptide fragments.
• Alpha-s1 casein hydrolysate (ACH) — used widely in clinical literature.
• Casein decapeptide or lactium casein decapeptide — lay and commercial terminology.
• αS1-casein (f91–100) — IUPAC-style fragment notation used in biochemical literature.
• CAS Registry Number for isolated alpha-casozepine: 117592-45-7.

Casein is the primary protein constituent of cow's milk, and enzymatic hydrolysis of casein produces peptides with various biological activities. The bovine αS1-casein tryptic hydrolysate marketed as Lactium™ was supplied and developed by Ingredia (Arras, France). The industrially produced casein hydrolysate has received health claim recognition from national agencies in Australia, France, South Korea, and the United States, and is used in both human and veterinary contexts.

Caseins are calcium-binding phosphoproteins that constitute approximately 80% of total milk protein. Within the casein fraction, αs1-casein is the dominant subtype. Caseins are a known source of biologically active peptides, and a tryptic hydrolysate of bovine αs1-casein has been shown to display anxiolytic activity. The production process employs trypsin, a serine endopeptidase, to cleave the αs1-casein protein at specific arginine and lysine residues, releasing the characteristic decapeptide from the intact protein matrix. The scientific discovery of casein's calming effects began in the 1990s, when researchers identified bioactive peptides released during digestion that could bind to benzodiazepine receptors; Lactium was subsequently developed through enzymatic digestion mimicking natural gastric processes, allowing consistent dosing and therapeutic use.

Common Forms and Preparations

Lactium® is a natural-origin, branded ingredient made in France from casein, a milk protein; it is an innovative ingredient used in the composition of a wide range of products including capsules, tablets, powder, chewing gum, and drinks. In clinical studies and commercial preparations, dosages are expressed in milligrams of the hydrolysate (i.e., the total ACH powder), not in milligrams of pure isolated alpha-casozepine. For veterinary use, the same bioactive hydrolysate is marketed under the name Zylkene®. Lactium™ has been available in over 120 countries for over 10 years and is patented in Europe, the United States, and Japan.

2. Traditional and Historical Context

Lactium and isolated alpha-casozepine do not have a history of use in classical herbal or botanical medicine traditions — they are products of late-twentieth-century food biochemistry rather of ethnobotanical practice. Their conceptual roots, however, lie in a widely held and cross-cultural folk belief in the calming properties of warm milk, which has been present across many European and Asian traditions for centuries. The traditional folk assumption of milk's sedative quality may originate from an energy-induced feeling of drowsiness but also from an improvement in the ratio between tryptophan and the pool of large neutral amino acids in the blood, favoring brain uptake of tryptophan, a precursor for serotonin synthesis that plays an important role in controlling sleep.

Numerous bioactive peptides have been identified in milk proteins and may be released after enzymatic digestion in the gastrointestinal tract; these include opioid and opioid antagonist peptides originating from milk proteins, which very probably have a functional role by interacting with the endogenous opioid system, though in many cases there is still no evidence that they are released and activated under in vivo conditions. The systematic scientific investigation of whether those folk beliefs could be attributed to specific peptides began in the 1990s. While investigating whether popular views concerning the sedative and calming properties of milk could be confirmed by the determination of bioactive peptides, it was discovered that a tryptic hydrolysate of bovine αS1-casein, and a decapeptide it contains (αS1-casein f91–100, or α-casozepine), displayed an anxiolytic-like profile in animal models.

The formal identification and characterization of alpha-casozepine was published by Miclo et al. in 2001 in the FASEB Journal, and the scaled-up industrial product was registered as Lactium® by Ingredia. No pre-modern ethnopharmacological tradition specifically recognized, extracted, or used this peptide; any such "traditional" framing is therefore an extrapolation from general milk-drinking customs rather than a documented medicinal practice.

3. Key Constituents and Active Compounds

Alpha-Casozepine (αS1-CN f91–100)

The anxiolytic-like properties of the hydrolysate are attributed to the tryptic fragment 91–100 of bovine αs1-casein (YLGYLEQLLR), called α-casozepine (α-CZP), which displays these effects in rats and mice. Peptides isolated from the hydrolysate were examined for their affinity for the γ-aminobutyric acid (GABA) type A receptor; only one peptide, named α-casozepine, corresponding to the 91–100 fragment from bovine αs1-casein, expressed affinity for the GABA-A receptor.

Alpha s1-casein hydrolysate has two flexible tyrosine aromatic rings with structures that are similar to the classical benzodiazepine aromatic rings, thereby demonstrating anxiolytic effects in addition to blood pressure control, immune control, and antithrombotic effects. The α-casozepine amino acid sequence could be related to the carboxy-terminal sequence of the polypeptide diazepam binding inhibitor, an endogenous ligand of the central GABA-A and peripheral-type benzodiazepine receptors.

Derived Sub-Peptides

α-Casozepine (α-CZP) is an anxiolytic-like bioactive decapeptide derived from bovine αs1-casein; the N-terminal pentapeptide YLGYL was previously identified after proteolysis of the original peptide in an in vitro digestion model. Research has examined this shorter fragment (residues 91–95) as a possible active contributor following gastrointestinal digestion of the full decapeptide. In a recent study, the casein tryptic hydrolysate promoted sleep better than the synthetic decapeptide, α-casozepine, as the hydrolysate has slower degradation and might have other sleep-enhancing components. This suggests that the full hydrolysate may possess complementary bioactive species beyond isolated alpha-casozepine.

Other Bioactive Compounds in Milk Casein Hydrolysates

Milk proteins contain significant contents of bioactive peptides with several vital health-promoting properties including antioxidative, antithrombotic, antihypertensive, antimicrobial, and immunomodulatory activity. Within the αS1-casein tryptic hydrolysate, alpha-casozepine is the peptide fragment specifically characterized for GABAergic activity; other fragments in the hydrolysate matrix may contribute to the overall biological effect through independent or synergistic mechanisms, though these have not been as thoroughly characterized.

4. Mechanisms of Action

GABAergic Modulation at GABA-A Receptors

Lactium™ binds to GABA-A receptors in the central nervous system; the GABA-A receptor, which comprises at least 19 different subunits, has three binding sites (ω1, ω2, and ω3), and Lactium selectively binds to the ω2 binding site, increasing membrane chloride conductance, causing an influx of Cl⁻ and membrane hyperpolarization, resulting in a decrease in neurotransmission and the regulation of anxiety and stress without sedative effects.

Extensive research indicates that α-CZP functions as a positive allosteric modulator at the benzodiazepine binding site of GABA-A receptors, though with a binding affinity approximately 10,000 times lower than diazepam. In vitro, the peptide had 10,000-fold less affinity for the benzodiazepine site of the GABA-A receptor than did diazepam; however, in the conditioned defensive burying paradigm it was 10-fold more efficient than diazepam, and this difference could not be explained by an action via the peripheral-type benzodiazepine receptor, for which α-casozepine had no affinity.

This apparent paradox between low in vitro affinity and comparatively strong in vivo potency is an area of ongoing scientific investigation. As the tryptic hydrolysate does not have the side effects of benzodiazepines, α-CZP or shorter derived peptides such as YLGYL (91–95) or YLGYLEQ (91–97) might bind only to a specific population of GABA-A receptor subtypes, which could explain the lower apparent affinity for the global population of GABA-A receptors. This subtype selectivity is hypothesized to explain why the compound produces anxiolytic effects without the sedation, memory impairment, or dependence characteristic of classical benzodiazepines.

Effects on the HPA Axis and Physiological Stress Markers

Beyond direct receptor modulation, ACH has been observed in human studies to reduce physiological markers of the stress response. On the basis of blood pressure and cortisol changes observed in clinical research, results suggest an antistress profile of the αS1-casein hydrolysate in human subjects. The precise mechanism linking GABA-A receptor modulation to downstream suppression of hypothalamic-pituitary-adrenal (HPA) axis output remains incompletely characterized.

Sleep Architecture Effects (Preclinical)

Oral administration of 150 mg/kg ACH in mice indicated significant differences in pentobarbital-induced sleep promotion tests and slow-wave electroencephalography (EEG) activity, suggesting an impact on the central nervous system; further research showed that 300 mg/kg ACH increased protein expression of the γ1 receptor subunit of GABA-A in the hypothalamus of rats, significantly enhancing total sleep and EEG theta wave during sleep.

5. Scientific Evidence by Area of Use

5.1 Stress and Anxiety Reduction

Animal Evidence

A tryptic hydrolysate of bovine αs1-casein has shown anxiolytic activity in animals; injection of 3 mg/kg of this hydrolysate significantly reduced the epileptic symptoms caused by pentylenetetrazole in rats, and anxiety reduction was also observed when the hydrolysate was tested in the elevated plus-maze and in the conditioned defensive burying rat models.

The anxiolytic activity and adverse benzodiazepine-like effects of bovine α s1-casein tryptic hydrolysate (CH) were evaluated; at doses of 5 and 15 mg/kg compared with diazepam at 3 mg/kg in the conditioned defensive burying test, rats treated with CH at 15 mg/kg or with diazepam showed a decrease in anxiety, but a drug-related difference was observed in terms of duration, as the anxiolytic-like action of CH was maintained after 7 days with twice-daily administration, whereas that of diazepam was not. In memory evaluation using a passive avoidance paradigm, CH-treated rats had significantly longer latencies before entering the dark compartment where they were previously shocked, indicating better retention relative to diazepam-treated rats.

Unlike classical benzodiazepines, α-CZP demonstrates remarkable specificity for anxiety reduction without producing sedation, memory impairment, tolerance, or dependence in animal models. The anxiolytic-like properties were also confirmed across other species. The anxiolytic-like properties of the hydrolysate were confirmed in cats, dogs, ponies, and horses.

Human Clinical Evidence

Messaoudi et al. (2005) — Hemodynamic and Cortisol Study: Study subjects were double-blind randomly allocated to ingest three times, 12 hours apart, two capsules containing either 200 mg of αS1-casein hydrolysate or bovine skimmed milk powder as a placebo, and were then subjected to successive stress situations. The ingestion of bovine αs1-casein in healthy adults under laboratory-induced mild physical and mental stress lowered blood pressure compared with those ingesting bovine skim milk powder as the placebo, and, unlike these controls, lowered plasma cortisol concentrations. This was a short-term, acute-dosing study and the sample size was limited.

Kim et al. (2007) — Stress-Related Symptoms in Women: This study examined the effects of αs1-casein hydrolysate on females with stress-related symptoms in a double-blind, randomized, crossover, placebo-controlled trial. A total of 63 female volunteers suffering from at least one disorder related to stress such as anxiety, sleep problems, and general fatigue were randomly allocated to receive either tablets containing αs1-casein hydrolysate or placebo at the dose of 150 mg/day for 30 days. The 30-day treatment reduced symptoms, particularly in digestion (P<0.01), cardiovascular (P<0.05), intellectual (P<0.01), emotional (P<0.05), and social problems (P<0.05). This study was partially supported by INGREDIA of France and by a Korean Ministry of Science and Technology neurobiology research program, which represents a potential conflict of interest.

Necker-Enfants Malades Hospital / BIOFORTIS Studies: A study on efficacy against chronic stress conducted at Necker-Enfants Malades Hospital and BIOFORTIS confirmed the efficacy of Lactium™ in acute stress management at higher doses (200 mg and 300 mg, respectively).

Regulatory Assessment

The EFSA Panel on Dietetic Products, Nutrition and Allergies published a Scientific Opinion on the substantiation of health claims related to "αS1-casein tryptic hydrolysate" and alleviation of psychological stress (ID 656, 1819, 4253) pursuant to Article 13(1) of Regulation (EC) No 1924/2006, published in the EFSA Journal in 2011 (9(6):2273). The EFSA assessment reviewed available clinical evidence, and the outcome has been that the health claim was not approved for use on food products in the EU, primarily because the evidence base was considered insufficient to establish a cause-and-effect relationship according to EU standards for general function health claims. This regulatory rejection does not preclude continued research or supplement use; it reflects the evidentiary threshold for approved food labeling claims.

Overall Strength of Evidence (Stress/Anxiety)

The evidence suggests lactium may help with mild stress and sleep disturbances rather than clinical anxiety disorders; however, the overall quality of evidence is limited by small sample sizes, short durations, and potential conflicts of interest, as some studies were industry-sponsored. While there is scientific rationale and some clinical evidence supporting Lactium's use for stress management, the strength of the evidence is moderate at best and does not yet meet the standards for strong scientific consensus; larger, independent studies are needed to fully validate its efficacy and safety for this purpose.

5.2 Sleep Quality and Insomnia

Animal Evidence

In a rat model of chronic mild stress, the mild stress period induced a dramatic fall in total sleep duration in control stressed animals; this reduction was significant as early as the first day (−11%) and further increased to −20% on the second day. Animals treated with the hydrolysate showed a significant attenuation of this stress-induced sleep disruption, demonstrating a sleep-modulating effect. Bovine αS1-casein tryptic hydrolysate containing alpha-casozepine was shown to have anxiolytic, anticonvulsant, and anti-stress effects, and studies have also shown that CH can alleviate sleep disturbances in both animals and humans.

Human Clinical Evidence

Korean Crossover Trial (2019; PMC6682925): This study evaluated the effects of alpha-s1 casein hydrolysate (Lactium®) on subjective and objective sleep profiles of a community-based sample of Koreans with poor sleep quality; it was performed as a double-blind, randomized crossover trial with 48 participants (mean age 49 ± 1.7 years, 65% female) who exhibited mild to moderate sleep disturbance; either ACH or placebo was administered for the initial four weeks, and the counterpart was administered after a four-week washout period. Notably, sleep disturbance scales, daytime functioning, and psychiatric aspects showed a similar tendency to improve during both ACH and placebo phases without significant group differences. This is a null result that complicates the efficacy narrative and highlights the role of placebo response in this population.

Taiwanese Chronic Insomnia RCT (2024; ScienceDirect): This study assessed the effects of ACH on both subjective sleep assessments and objective polysomnography (PSG) recordings in a hospital-based cohort of Taiwanese individuals with chronic insomnia, enrolling 36 participants diagnosed with chronic insomnia in a 4-week randomized, double-blind, placebo-controlled trial. Participants in the ACH group initially received 600 mg of ACH daily, which was reduced to 300 mg for the latter two weeks; the placebo group received maltodextrin capsules throughout. This study used PSG as an objective measure and represents one of the more rigorous recent trials. Clinical research also supports the effectiveness of ACH in reducing physiological stress markers, such as elevated blood pressure and cortisol levels, and improving sleep parameters.

Alpha-S1-CTH and L-Theanine Combination Trial (MDPI Nutrients, 2022): A randomized, placebo-controlled, crossover, double-blind study investigated the effects of a supplement containing alpha-s1-casein tryptic hydrolysate and L-theanine in working adults affected by poor sleep quality; 39 subjects received supplement or placebo for four weeks, with changes assessed via the Pittsburgh Sleep Quality Index (PSQI), heart rate, blood pressure, salivary cortisol, and alpha power of awake EEG. The supplement improved PSQI total score, sleep latency, sleep duration, sleep habitual efficiency, daytime dysfunction, and increased total and frontal alpha power significantly (p < 0.05); it prolonged total sleeping time by 45 minutes in the supplement group compared to the placebo group (p < 0.001). A limitation of this study is the use of a combination product (CTH + L-theanine), which prevents attribution of effect to ACH alone.

Prior Korean Study (ACH 300 mg, four weeks): A clinical study in South Korea demonstrated that administering 300 mg of ACH for four weeks improved sleep disturbances among adults with mild to moderate insomnia, with enhancements evident in sleep diaries and increased sleep efficiency as confirmed by actigraphy, compared to a control group.

Overall Strength of Evidence (Sleep)

The sleep evidence base is heterogeneous. Several small-to-medium RCTs report positive effects on subjective sleep measures, but at least one well-designed crossover trial found no significant group differences versus placebo. Limited studies utilizing objective sleep assessment tools have resulted in a lack of substantial validation. Evidence should be characterized as preliminary to moderate, requiring larger independent replication.

5.3 Psychodermatology: Acne Vulgaris

Stress plays an important role in the causation and aggravation of psychodermatological conditions such as acne vulgaris; alpha casein hydrolysate (Lactium) has been shown to decrease serum cortisol levels, reduce stress-related symptoms, and promote relaxation.

The CERTAIN Trial (India, 2022; PMC9095396): The C.E.R.T.A.I.N trial (registered CTRI/2019/01/017172) was a randomized, controlled, multicenter, open-label, two-arm, investigator-initiated clinical trial; a total of 100 patients with moderate-to-severe acne vulgaris were enrolled and randomly assigned to Lactium™ plus standard care or standard care alone; stress levels were assessed using serum cortisol levels, Investigator's Global Assessment (IGA) acne severity scale scores, Perceived Stress Scale (PSS) scores, Hamilton Anxiety Rating Scale (HAM-A) scores, and the Dermatology Life Quality Index (DLQI). In patients with moderate-to-severe acne vulgaris, Lactium™ was found to be both safe and well-tolerated; Lactium™ plus standard care was more effective than standard care alone in reducing acne severity through stress reduction.

The open-label design of the CERTAIN trial is a significant limitation, as blinding was not maintained, introducing potential bias. Evidence in this domain should be regarded as preliminary.

5.4 Cardiovascular Stress Response

In healthy subjects treated with 400 mg of casein tryptic hydrolysate three times 12 hours apart, systolic and diastolic blood pressure recorded significantly lower percentage changes in the Stroop test (a cognitive stress task). The hemodynamic effects of ACH during acute stress are supported by multiple studies and appear among the more reproducible physiological outcomes; however, the effects are modest and context-dependent (i.e., observed under laboratory-induced stress rather than at rest).

5.5 Veterinary Applications

The putative effects of a tryptic bovine αs1-casein hydrolysate on anxious disorders in cats were investigated; this product is known as alpha-casozepine and patented under the name of lactium; 34 cats were recruited within veterinary practices by certified behaviorist surgeons; this 56-day trial, against placebo, showed the statistical positive effect of this product to manage anxious disorders such as social phobias in cats. Global score but also different items (fear of strangers, contact with familiars, general fears, fear-related aggressions, autonomous disorders) were all significantly improved by the use of this natural decapeptide. The hydrolysate is also marketed under Zylkene® for dogs and cats.

6. Body Systems and Health Areas

• Central Nervous System: Primary site of action via GABA-A receptor modulation; anxiolytic-like and sedation-free calming effects.
• Neuroendocrine / HPA Axis: Reduction in plasma and serum cortisol concentrations under experimental stress conditions.
• Cardiovascular: Attenuation of stress-induced blood pressure elevation in acute stress paradigms.
• Sleep Regulation: Improvement in sleep onset latency, total sleep time, and sleep efficiency in populations with mild-to-moderate sleep disturbance.
• Dermatological (indirect): Stress-mediated improvement in acne severity via cortisol reduction, demonstrated in the CERTAIN trial.
• Gastrointestinal: Clinical data includes reduction of stress-related digestive symptoms (P<0.01) in women receiving 150 mg/day for 30 days.

7. Dosages Reported in Human Studies

The following dosages are reported directly from the published clinical studies. All figures refer to the standardized ACH/Lactium® hydrolysate, not to isolated alpha-casozepine.

• 150 mg/day — Kim et al. (2007): 63 female volunteers received tablets containing αs1-casein hydrolysate at the dose of 150 mg/day for 30 days.
• 200 mg (acute, three times 12 hours apart) — Messaoudi et al. (2005): subjects ingested two capsules containing 200 mg of αS1-casein hydrolysate three times, 12 hours apart, before successive stress challenges.
• 200 mg and 300 mg (acute stress protocols) — Separate studies on efficacy against acute stress conducted at Necker-Enfants Malades Hospital and BIOFORTIS confirmed efficacy at higher doses of 200 mg and 300 mg, respectively.
• 300 mg/day for four weeks — A South Korean study demonstrated that administering 300 mg of ACH for four weeks improved sleep disturbances among adults with mild to moderate insomnia.
• 600 mg/day (first two weeks) then 300 mg/day (final two weeks) — Used in the 2024 Taiwanese chronic insomnia RCT; the ACH group received 600 mg daily initially, reduced to 300 mg for the latter two weeks.
• Preclinical (animal) dose range: 5 mg/kg and 15 mg/kg orally in rats in the conditioned defensive burying test. 75, 150, 300, or 500 mg/kg orally administered to ICR mice in sleep promotion studies.

Clinical studies evaluating Lactium® have investigated its effects on perceived stress, emotional well-being, and related psychological outcomes across both short-term and longer-term supplementation protocols; across published trials, doses have ranged from 150 mg/day to 300 mg/day, with intervention periods spanning several days to one month, and outcomes assessed using validated tools such as the Perceived Stress Scale (PSS) and Hamilton Anxiety Rating Scale (HAM-A).

8. Safety Considerations and Interactions

General Tolerability

Tryptic hydrolysate from bovine milk alpha-s1 casein shows a marked affinity for GABA-A receptors with a benzodiazepine-like profile and a tranquilizing and antistress activity associated with good tolerance characterized, in particular, by the absence of any habituation, dependence, sedation, memory impairment, and toxicity in preclinical and clinical trials carried out in humans, rats, dogs, and cats.

Similar to many other studies, trials of the supplement containing alpha-s1-casein tryptic hydrolysate have reported no adverse events, indicating the safety or tolerability of four weeks of this supplement intake. In patients with moderate-to-severe acne vulgaris, Lactium™ was found to be both safe and well-tolerated.

Milk Allergy and Dairy-Derived Origin

Because Lactium® is derived from bovine αs1-casein — a milk protein — it is contraindicated for individuals with confirmed cow's milk protein allergy (CMPA). Four distinct casein proteins are recognized as individual allergens: alphaS1-casein, alphaS2-casein, beta-casein, and kappa-casein (designated Bos d 9–12). Compared with other milk proteins, αS1-casein is associated with higher rates of allergies in humans. Individuals with known IgE-mediated milk allergy should avoid ACH-containing preparations. Partially hydrolyzed milk protein hydrolysates used in infant formula still retain allergenicity. Because Lactium® is a partial tryptic hydrolysate rather than an extensively hydrolyzed formula, residual allergenic epitopes may be present, and individuals with CMPA should regard it as a potential allergen source.

Distinction from Lactose Intolerance

Lactium® is a protein hydrolysate and does not contain lactose (milk sugar). It is therefore expected to be tolerated by lactose-intolerant individuals, though persons with CMPA should exercise caution as described above.

Absence of Classical Benzodiazepine Side Effects

A key finding consistently reported in both preclinical and clinical literature is the absence of the adverse effects associated with classical benzodiazepines. Tryptic hydrolysate from bovine milk alpha-s1 casein contains a specific active decapeptide called alpha-casozepine that shows interesting pharmacological properties; preclinical and clinical trials carried out on humans and animals demonstrated good tolerance characterized, in particular, by the absence of any habituation, dependence, sedation, memory impairment, and toxicity.

Regulatory Status and Nutritional Classification

The tryptic hydrolysate from bovine milk αs1-casein (THC/ACH) is a nutritional supplement (French regulatory status) which cannot be used as a substitute for psychotropic medications such as benzodiazepines in the treatment of severe anxiety and sleep disorders, in accordance with medical recommendations.

Interactions

No formal pharmacokinetic drug-drug interaction studies for Lactium® in human subjects have been published in the peer-reviewed literature as of the sources available. Given its mechanism of action as a positive allosteric modulator at the GABA-A benzodiazepine binding site — albeit with much lower affinity than diazepam — theoretical additive effects are plausible when combined with central nervous system depressants (e.g., benzodiazepines, barbiturates, alcohol, or non-benzodiazepine hypnotics). This pharmacodynamic interaction has not been formally studied in humans and remains speculative; no published clinical evidence documents a clinically significant interaction.

Long-Term Safety Data Gaps

Most human clinical trials have been of short duration (30 days to 12 weeks). While there is some scientific basis for lactium's use in anxiety and stress reduction, the strength of evidence is moderate at best; larger, independent, and longer-term studies are needed to fully validate its efficacy and safety. Long-term safety data from independent, large-scale human trials are currently lacking.

References

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