VetPlus Calmex Syrup 60ml for Cats

FOR ANIMAL USE ONLY — Administer as directed by a veterinarian or as per VetPlus label instructions. VetPlus Calmex Syrup is a veterinary nutraceutical calming and anxiety support supplement — not a veterinary sedative or anxiolytic medicine. Calmex is non-sedating and does not cause drowsiness or motor impairment at the recommended dose. Calmex is not a substitute for veterinary behavioural assessment and management of anxiety disorders in cats. Cats with severe, persistent, or progressive anxiety, fear, or aggression require a full veterinary behavioural assessment — Calmex is indicated as nutritional support alongside environmental management, behavioural modification, and, where appropriate, veterinary-prescribed pharmacotherapy. Do not use in cats with known hypersensitivity to any ingredient. Use with caution in cats with pre-existing hepatic disease (Piper methysticum [kava] extracts have been associated with hepatotoxicity at high doses in humans; use at the recommended veterinary dose only). Keep out of reach of children. Store in a cool, dry place; refrigerate after opening if specified on the label and use within the stated period.

VetPlus Calmex Syrup 60ml for Cats | L-Theanine, Alpha-Casozepine, Piper methysticum & B-Vitamins | Anxiety, Stress, Noise Fear, Travel & Separation Anxiety Relief

VetPlus Calmex Syrup 60ml is a veterinary nutraceutical calming and anxiety support supplement manufactured by VetPlus Ltd (UK), formulated specifically for cats in a palatable liquid syrup format for easy administration. Calmex Syrup contains a clinically designed combination of L-theanine (the glutamate analogue anxiolytic from Camellia sinensis green tea), alpha-casozepine (the GABA-A receptor partial agonist tryptic decapeptide from bovine whey protein hydrolysate), Piper methysticum (kava) root extract (kavalactone-containing anxiolytic botanical), and B-vitamins (thiamine B1, niacin B3, and pyridoxine B6 — the neurologically active B-vitamins essential for neurotransmitter synthesis). Calmex Syrup is indicated for situational and chronic anxiety in cats: noise fear (thunderstorms, fireworks, construction), travel and transport stress, separation anxiety, new environment stress, and inter-cat or multi-pet household tension. The liquid syrup format enables precise weight-based dosing and easy administration to cats who resist tablet or capsule dosing. 60ml bottle.

Feline Anxiety: Neurobiology and the Multi-Target Approach of Calmex

• The neurobiology of feline anxiety and fear — why cats are uniquely vulnerable: cats are solitary, territorial, and highly neophobic by nature: their social structure (unlike dogs, which are obligate social animals with canine pack hierarchy) means that cats are not innately adapted to sharing territory with other cats, to frequent environmental change, or to close human contact with strangers; the feline hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenomedullary (SAM) axis are the two primary stress-response systems: (a) the HPA axis: amygdala (specifically the basolateral amygdala [BLA] — the fear-learning and fear-memory centre; the BLA receives sensory input from the thalamus and cortex, processes threat-related stimuli, and projects to the central nucleus of the amygdala [CeA]) → CeA → paraventricular nucleus (PVN) of the hypothalamus → CRH (corticotropin-releasing hormone) → anterior pituitary → ACTH (adrenocorticotropic hormone) → adrenal cortex → cortisol (the primary glucocorticoid stress hormone in cats); chronic cortisol elevation → hippocampal CA3 pyramidal neuron dendritic atrophy (glucocorticoid receptor [GR]-mediated downregulation of BDNF [brain-derived neurotrophic factor] → reduced synaptic plasticity in the hippocampus → impaired contextual fear extinction [the cognitive process by which the cat learns that a previously threatening stimulus is now safe]); (b) the SAM axis: locus coeruleus (LC) − the pontine noradrenaline nucleus [the primary source of central noradrenergic projections] → noradrenaline (NA) release → amygdala β1-AR stimulation → fear memory consolidation; LC → sympathetic preganglionic neurons → adrenal medulla → adrenaline/noradrenaline release → the ‘fight-or-flight’ response: tachycardia, mydriasis (pupil dilation), piloerection, increased skeletal muscle blood flow, and in cats: the characteristic signs of fear: hiding, hissing, scratching, aggression, periuria (urination outside the litter box), and hypersalivation; (c) GABA-A receptor hypofunction in anxiety: GABA (γ-aminobutyric acid — the primary inhibitory neurotransmitter in the mammalian CNS) acts via ionotropic GABA-A receptors (pentameric ligand-gated Cl− ion channels; composed of α, β, γ/δ/ε subunits in various combinations; the benzodiazepine-binding site is located at the α/γ subunit interface, distinct from the GABA-binding site at the β/α interface); GABA binding → GABA-A receptor Cl− channel opening → Cl− influx → membrane hyperpolarisation → reduced neuronal excitability; in anxiety states, GABAergic tone in the amygdala and prefrontal cortex (PFC) is reduced → amygdala hyperexcitability → exaggerated fear responses to sub-threshold stimuli; benzodiazepines (diazepam, alprazolam — used as anxiolytic drugs in cats) act as positive allosteric modulators at the α/γ benzodiazepine site → increase GABA-A receptor Cl− channel open frequency → enhanced GABAergic inhibition − but with sedation, motor incoordination, and hepatotoxicity risk in cats (benzodiazepines are associated with acute hepatic necrosis in some cats); Calmex’s alpha-casozepine targets the same GABA-A benzodiazepine site but as a partial agonist → anxiolytic effect without sedation

Active Ingredients & Mechanisms of Action

• L-Theanine — the glutamate antagonist and GABA/dopamine modulator from Camellia sinensis: L-theanine (L-γ-glutamylethylamide; the N-ethyl amide of L-glutamic acid; MW 174.20 g/mol; the predominant free amino acid in green tea [Camellia sinensis] leaf, concentrated in the young bud and first flush leaves; synthesised in tea roots by the enzyme theanine synthase [an unusual enzyme catalysing the condensation of ethylamine with L-glutamate]; tea leaves contain 1–3% L-theanine by dry weight; L-theanine crosses the blood-brain barrier [BBB] via the large neutral amino acid transporter LAT1 [SLC7A5], which transports neutral amino acids with large aliphatic or aromatic side chains: leucine, phenylalanine, tyrosine, tryptophan, and structurally similar L-theanine; LAT1 is highly expressed at the BBB endothelium and mediates active brain uptake of L-theanine against its concentration gradient); CNS mechanisms: (a) AMPA/NMDA glutamate receptor antagonism: L-theanine’s structural similarity to L-glutamate (the primary excitatory neurotransmitter) allows it to bind glutamate receptors as a partial antagonist: L-theanine antagonises AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors — the fast-gating ionotropic glutamate receptors responsible for rapid excitatory synaptic transmission; AMPA receptor subunits GluA1–GluA4 form heterotetrameric ion channels; L-theanine acts as a low-affinity competitive antagonist at the GluA1/GluA2 glutamate-binding site) and NMDA receptors (N-methyl-D-aspartate receptors — the voltage-gated, Mg2+-blocked, Ca2+-permeable coincidence detectors; L-theanine is a weak partial agonist at the GluN1 glycine co-agonist site and a weak antagonist at the GluN2B glutamate site); in the amygdala, reduced AMPA/NMDA-mediated excitatory drive → reduced BLA neuronal firing → attenuated fear responses and reduced fear memory consolidation; (b) GABA elevation: L-theanine increases brain GABA concentrations (the mechanism is indirect: reduced glutamate receptor activation → reduced glutamate-driven neuronal depolarisation → reduced glutamate decarboxylase [GAD65/67] substrate availability in inhibitory interneurons? — the exact mechanism of L-theanine’s GABA-elevating effect is not fully characterised at the molecular level; EEG studies in humans and cats show increased alpha-wave activity [8–12 Hz — the ‘alert relaxation’ frequency band] and increased GABA within 30–60 minutes of oral L-theanine administration); (c) dopamine and serotonin modulation: L-theanine increases striatal and hippocampal dopamine concentrations (possibly via reduced dopamine reuptake from the dopamine transporter [DAT/SLC6A3] or via inhibition of glutamate-mediated inhibitory interneuron activity on dopaminergic neurons) and increases serotonin (5-HT) in the brainstem (the raphe nuclei 5-HT neurons project to the forebrain and regulate mood, fear, and anxiety via 5-HT1A, 5-HT2A, and 5-HT3 receptors); (d) cortisol attenuation: L-theanine attenuates cortisol secretion in response to acute psychological stressors (via hypothalamic glutamate receptor antagonism reducing CRH release from PVN neurons → reduced HPA axis activation); EEG evidence in cats: Dramard et al. (2007, JVIM) demonstrated that L-theanine (Zylkene’s active ingredient − alpha-casein hydrolysate − is separate; but theanine-specific EEG studies in cats confirm alpha-wave induction); the ‘alert relaxation’ state (increased alpha-waves without drowsiness or impaired locomotion) is the key clinical outcome distinguishing L-theanine from sedative anxiolytics
• Alpha-casozepine (from bovine whey protein hydrolysate) — the GABA-A benzodiazepine site partial agonist decapeptide: alpha-casozepine (Tyr-Pro-Phe-Pro-Gly-Pro-Ile-His-Asn-Ser — the tryptic decapeptide from the f91–100 region of bovine αs1-casein; first identified and characterised by Miclo et al., FASEB J 2001) is produced by: tryptic hydrolysis of bovine αs1-casein (the primary caseins in cow’s milk: αs1-casein [~38% of total casein], αs2-casein [~10%], β-casein [~35%], κ-casein [~12%]; αs1-casein is a 214-amino acid phosphoprotein; trypsin cleaves at Arg/Lys residues → the f91–100 fragment [between Lys90 and Ser101] is alpha-casozepine); mechanism: alpha-casozepine is a partial agonist at the benzodiazepine-binding site of the GABA-A receptor (the α/γ subunit interface site; distinct from the GABA orthosteric site at the β/α interface); partial agonism → submaximal positive allosteric modulation of GABA-A receptor Cl− channel opening frequency at the α/γ site (intrinsic efficacy approximately 30–40% of full benzodiazepine agonists such as diazepam) → enhanced GABAergic inhibitory tone in the amygdala and PFC → anxiolytic effect WITHOUT sedation or motor impairment (the ceiling of partial agonism prevents the full GABA-A potentiation that produces sedation with full benzodiazepine agonists); alpha-casozepine’s partial agonism also confers a reduced risk of GABA-A receptor downregulation (the receptor desensitisation/tolerance mechanism seen with chronic full benzodiazepine agonist use); milk-derived peptide safety in cats: bovine casein tryptic hydrolysate is well-tolerated in cats (Beata et al., JVIM 2007 — the key clinical trial demonstrating alpha-casein hydrolysate efficacy in reducing anxiety scores in cats over 56 days, with a significant reduction in the validated anxiety score vs placebo); alpha-casozepine is a food-derived peptide — classified as a nutraceutical rather than a drug, hence no prescription requirement and no sedation risk
• Piper methysticum (kava) root extract — kavalactone GABA-A modulation and limbic system anxiolytic activity: Piper methysticum (kava; Piperaceae family; the ceremonial beverage plant of Pacific Island cultures) contains kavalactones (kavapyrones) as the primary bioactive constituents: kavain (the most abundant and most bioavailable kavalactone: (±)-kavain, also termed kawain; MW 230.26 g/mol), dihydrokavain (DHK), methysticin, dihydromethysticin (DHM), yangonin, and desmethoxyyangonin; in the Calmex feline formulation, the specific extract and kavalactone content is standardised by VetPlus (the exact standardisation not publicly declared on the label but consistent with Calmex’s established VetPlus formulation); mechanisms of kavalactone anxiolytic activity: (a) GABA-A receptor positive allosteric modulation: kavalactones (particularly kavain and dihydrokavain) modulate GABA-A receptors via a binding site distinct from both the GABA orthosteric site and the benzodiazepine site (the kavalactone site is proposed to be within the transmembrane domain of the GABA-A receptor — possibly at the β/α TM2 helical interface, in the hydrophobic pocket also occupied by neurosteroids and volatile anaesthetics; this is structurally analogous to the binding of propofol [2,6-diisopropylphenol] in the transmembrane domain of GABA-A receptors); kavalactone GABA-A modulation → increased Cl− channel open frequency and open duration → enhanced GABAergic inhibitory tone; (b) GABA transporter (GAT1/SLC6A1) inhibition: kavain inhibits neuronal and glial GABA reuptake via GAT1 (the dominant neuronal GABA transporter in the forebrain; the same transporter inhibited by tiagabine [an anticonvulsant]) → increased synaptic GABA concentration → prolonged GABA-A receptor activation; (c) limbic system GABA-B receptor interaction: dihydromethysticin has GABA-B receptor agonist properties (GABA-B receptors are metabotropic [Gi/Go-coupled GPCRs; GABA-B1/GABA-B2 heterodimer] inhibitory receptors predominantly on presynaptic terminals [autoreceptors and heteroreceptors]; GABA-B activation → reduced presynaptic Ca2+ influx via inhibition of P/Q-type VGCCs → reduced neurotransmitter release; on postsynaptic neurons: GABA-B → Gi/o → GIRK channel opening → K+ efflux → membrane hyperpolarisation → reduced excitability); (d) noradrenaline reuptake inhibition: kavain inhibits the noradrenaline transporter (NET/SLC6A2) → increased synaptic NA → α-2A autoreceptor feedback activation → reduced locus coeruleus firing rate → reduced central sympathetic outflow (a paradoxical anxiolytic mechanism: by activating the inhibitory α-2A autoreceptor on LC neurons, elevated synaptic NA from NET inhibition ultimately reduces LC noradrenergic tone); hepatotoxicity consideration in cats: kava-associated hepatotoxicity (reported in humans at high doses and with prolonged use — mechanisms proposed: reactive intermediate formation from the methylenedioxy group of methysticin via CYP3A4 oxidative metabolism → reactive epoxide intermediate → protein adducts; inhibition of CYP1A2 and CYP2D6 by flavokawains → impaired detoxification of reactive metabolites); in cats: cats are obligate CYP1A2-low metabolisers (cats have very low hepatic CYP1A2 expression vs dogs and humans) and may metabolise kava alkaloids differently; Calmex is formulated at VetPlus-established safe feline doses; do not exceed the recommended dose
• B-vitamins (Thiamine B1, Niacin B3, Pyridoxine B6) — essential cofactors for neurotransmitter synthesis and neurological function: (a) thiamine (B1/TPP) — as previously described (PDH/α-KGDH cofactor for neuronal energy metabolism; cats’ high cerebral glucose oxidation rate makes them uniquely vulnerable to thiamine deficiency); in the context of anxiety: thiamine supports GABAergic interneuron energy metabolism (fast-spiking GABAergic PV+ [parvalbumin-positive] interneurons are highly metabolically active and are acutely sensitive to thiamine-dependent mitochondrial energy supply impairment); (b) niacin (B3/NAD+) — NAD+/NADH cofactor for tryptophan → serotonin (5-HT) biosynthesis: the kynurenine pathway (the primary route of tryptophan catabolism) competes with serotonin synthesis; IDO1/IDO2 (indoleamine 2,3-dioxygenase) and TDO2 (tryptophan 2,3-dioxygenase) divert tryptophan → kynurenine → quinolinate (a NMDA receptor agonist and neurotoxin at high concentrations) OR → NAD+ (via the kynurenine → anthranilic acid → quinolinate → NAMN [nicotinic acid mononucleotide] → NMN → NAD+ pathway — the de novo NAD+ synthesis route from tryptophan); adequate niacin/NAD+ status reduces the metabolic pressure driving tryptophan into the kynurenine→quinolinate branch (neurotoxic) and supports the residual tryptophan flux into serotonin (via tryptophan hydroxylase [TPH1/TPH2] → 5-HTP → AADC → 5-HT); NAD+ is also the substrate for SIRT1-mediated PGC-1α deacetylation → mitochondrial biogenesis in neurons; (c) pyridoxine (B6/PLP) — PLP is the essential cofactor for: (i) GABA synthesis: glutamic acid decarboxylase (GAD65/GAD67) − the enzyme catalysing L-glutamate → GABA (decarboxylation at the α-carboxyl group; PLP forms an aldimine Schiff base with the ε-amino group of the active site Lys residue [Lys396 in GAD67] − the external aldimine with L-glutamate substrate; decarboxylation → GABA-PLP quinonoid intermediate → GABA release); pyridoxine deficiency → reduced GAD65/67 activity → reduced GABA synthesis → reduced GABAergic inhibitory tone → increased anxiety and seizure threshold lowering; (ii) serotonin synthesis: aromatic amino acid decarboxylase (AADC/DDC — DOPA decarboxylase) converts 5-HTP → serotonin (5-HT) (PLP-dependent decarboxylation); (iii) dopamine synthesis: AADC also converts L-DOPA → dopamine (PLP-dependent); the B-vitamins in Calmex collectively ensure adequate neurotransmitter synthetic capacity (GABA, serotonin, and dopamine) for the anti-anxiety mechanisms of L-theanine and alpha-casozepine to act on optimal neurotransmitter substrate pools

Feline Anxiety Behavioural Signs

The most common behavioural indicators of anxiety and stress in cats include:

• Hiding away and avoiding contact with people or other pets
• Scratching furniture, surfaces, or inappropriate objects (marking behaviour driven by anxiety)
• Aggression — hissing, growling, swiping, biting
• Periuria — urinating outside the litter box (a primary sign of feline stress; must be differentiated from UTI or FLUTD by a veterinarian before attributing to anxiety)
• Reduced appetite or complete food refusal
• Excessive licking or over-grooming (psychogenic alopecia — repetitive self-grooming as a displacement behaviour driven by anxiety; can cause bilateral symmetrical alopecia on the abdomen, flanks, and inner thighs)
• Seeming tense, hypervigilant, or startling easily
• Increased vocalisation (yowling, chirping) in response to noise triggers

Indications

• Noise fear and phobia — thunderstorms, fireworks, construction, Diwali firecrackers
• Travel and transport anxiety — car journeys, carrier stress, veterinary visit stress
• Separation anxiety — distress when left alone
• New environment, rehoming, or moving home stress
• Inter-cat tension in multi-cat households
• New pet or new person introduction stress
• Chronic low-level environmental anxiety in indoor cats

Directions for Use

• Administer as directed by a veterinarian or as per the VetPlus label instructions
• The syrup is administered orally — directly into the mouth or mixed into a small amount of food; the palatable formulation facilitates voluntary acceptance by most cats
• For situational anxiety (travel, fireworks), begin administration 1–2 hours before the anticipated stressor and continue as directed
• For chronic anxiety, administer daily for a minimum of 4–6 weeks to assess full effect (L-theanine’s GABA-elevating and alpha-wave effects are rapid [30–60 minutes], but alpha-casozepine’s effect on anxiety behaviour scores in cats is most significant after 4–8 weeks of daily use per clinical trial data [Beata et al., JVIM 2007])
• 60ml bottle; store in a cool, dry place and refrigerate after opening as directed on the label

Safety Information

• For animal use only — keep out of reach of children
• Non-sedating at the recommended dose — does not cause drowsiness or motor impairment
• Use with caution in cats with pre-existing hepatic disease; do not exceed the recommended dose
• Not a substitute for veterinary assessment of severe, persistent, or progressive anxiety disorders; consult a veterinarian if anxiety signs are severe or worsening
• Periuria (urinating outside the litter box) must be assessed by a veterinarian to rule out UTI, FLUTD, or other medical causes before attributing to anxiety