pairings-data.js

/* Auto-generated from data/pairings.json. Do not edit by hand. */
window.SUPP_PAIRINGS = [{"id": "p1", "members": ["Vitamin D3", "Vitamin K2 (MK-7)"], "kind": "mechanism-complementary", "strength": 5, "goal": "Bone density + vascular calcification protection", "rationale": "D3 increases intestinal Ca absorption. K2 activates osteocalcin/MGP, directing Ca into bone rather than arteries.", "dose": "D3 1,000-2,000 IU + MK-7 90-200 mcg, with fat.", "contraindications": ["warfarin"]}, {"id": "p2", "members": ["Vitamin D3", "Calcium", "Vitamin K2 (MK-7)"], "kind": "mechanism-complementary", "strength": 5, "goal": "Post-menopausal bone health (WHI-validated)", "rationale": "Calcium + D3 reduces hip fracture risk; K2 ensures deposition into bone.", "dose": "Calcium 500-600 mg/dose + D3 1,000-2,000 IU + MK-7 90-200 mcg.", "contraindications": ["warfarin (for K2)", "hypercalcemia"]}, {"id": "p3", "members": ["Iron", "Vitamin C (moderate dose)"], "kind": "absorption-enhancer", "strength": 5, "goal": "Maximal non-heme iron absorption", "rationale": "Ascorbate reduces Fe3+ to Fe2+ and chelates it for uptake. Increases absorption 2-3x.", "dose": "25-50 mg elemental Fe (bisglycinate) + 100-250 mg C on empty stomach.", "apart_from": ["Calcium", "Zinc", "tea", "coffee", "dairy"]}, {"id": "p4", "members": ["Collagen peptides", "Vitamin C (moderate dose)"], "kind": "cofactor", "strength": 5, "goal": "Tendon / skin / joint collagen synthesis", "rationale": "Vitamin C is a required cofactor for prolyl and lysyl hydroxylases in collagen cross-linking.", "dose": "10-15 g collagen + 50 mg C. For tendon rehab, 60 min pre-exercise (Shaw protocol)."}, {"id": "p5", "members": ["L-Theanine", "Caffeine (standardised)"], "kind": "synergy", "strength": 5, "goal": "Sustained attention without jitters", "rationale": "Theanine raises alpha-wave activity and blunts caffeine-driven HR/anxiety; RCT-backed 2:1 ratio.", "dose": "200 mg theanine + 100 mg caffeine. Morning. No afternoon caffeine.", "existing_entry": "L-Theanine + caffeine (cognitive stack)"}, {"id": "p6", "members": ["Zinc", "Copper (as glycinate)"], "kind": "depletion-offset", "strength": 4, "goal": "Prevent copper deficiency from long-term zinc use", "rationale": "Zn blocks Cu absorption via metallothionein induction. Long-term Zn >25 mg/day depletes Cu and can cause sideroblastic anemia and myelopathy.", "dose": "Zn 25-30 mg + Cu 1-2 mg, taken at different meals.", "apart_from_each_other_in_time": true}, {"id": "p7", "members": ["Curcumin (bioavailable form)", "Black pepper extract (piperine)"], "kind": "absorption-enhancer", "strength": 4, "goal": "Curcumin bioavailability", "rationale": "Piperine inhibits hepatic glucuronidation, raising serum curcumin up to 20x. Not needed if using phytosomal or liposomal forms.", "dose": "Curcuminoids 250-500 mg + piperine 5 mg with fat."}, {"id": "p8", "members": ["Probiotics", "Fibre (general dietary)"], "kind": "synergy", "strength": 4, "goal": "Gut colonisation and short-chain fatty acid production", "rationale": "Probiotic strains require prebiotic substrate (inulin, acacia, psyllium, resistant starch) to establish and produce SCFAs. Synbiotic concept.", "dose": "1-10B CFU strain-specific + 5-10 g soluble fibre daily."}, {"id": "p9", "members": ["Folate (5-MTHF)", "Vitamin B12"], "kind": "cofactor", "strength": 5, "goal": "Methylation cycle / homocysteine / pregnancy", "rationale": "The two feed the same cycle via methionine synthase. High-dose folate masks B12 deficiency and can accelerate neurologic damage.", "dose": "400-800 mcg 5-MTHF + 500-1,000 mcg methylcobalamin."}, {"id": "p10", "members": ["Myo-inositol", "D-Chiro Inositol"], "kind": "physiological-ratio", "strength": 5, "goal": "PCOS: ovulation, insulin sensitivity, androgen reduction", "rationale": "Ovarian tissue uses a ~40:1 myo:DCI ratio. High-dose DCI alone worsens oocyte quality (DCI paradox).", "dose": "2,000 mg myo + 50 mg DCI (40:1), twice daily.", "warning": "Do not take standalone high-dose DCI for fertility."}, {"id": "p11", "members": ["Lutein + Zeaxanthin"], "kind": "mechanism-complementary", "strength": 5, "goal": "Macular pigment density / AMD prevention", "rationale": "Lutein and zeaxanthin concentrate in different macular regions. AREDS2 formula combines them.", "dose": "10 mg L + 2 mg Z with fat.", "existing_entry": "Lutein + Zeaxanthin (single combined entry in data)"}, {"id": "p12", "members": ["Alpha-GPC", "Aniracetam"], "kind": "side-effect-offset", "strength": 4, "goal": "Prevent racetam-induced headaches", "rationale": "Racetams upregulate ACh turnover; added choline prevents the choline-depletion headache.", "dose": "Racetam as prescribed + 300-600 mg alpha-GPC or 250 mg CDP-choline.", "also_applies_to": ["Oxiracetam", "Piracetam"]}, {"id": "p13", "members": ["Magnesium glycinate", "Vitamin D3"], "kind": "cofactor", "strength": 4, "goal": "Active vitamin D (calcitriol) production", "rationale": "Mg is a cofactor for hepatic 25-hydroxylation and renal 1-alpha hydroxylation of D3. Low Mg = low active D even with adequate dose.", "dose": "Mg glycinate 200-400 mg + D3 1,000-2,000 IU."}, {"id": "p14", "members": ["Pea protein", "Rice protein"], "kind": "complementary-amino-acids", "strength": 4, "goal": "Complete plant-protein amino-acid profile", "rationale": "Pea is low in Met/Cys; rice is low in Lys. Together they rival whey's leucine / BCAA profile.", "dose": "20-40 g combined, ~70:30 pea:rice."}, {"id": "p15", "members": ["Whey protein", "L-Leucine (standalone)"], "kind": "threshold-amplifier", "strength": 3, "goal": "Maximal muscle protein synthesis in older adults", "rationale": "Per-meal leucine must exceed ~2.5 g to trigger mTORC1. Adults over 65 have anabolic resistance and often need 3-4 g.", "dose": "20-30 g protein + 2-3 g leucine per meal."}, {"id": "p16", "members": ["Omega-3 (EPA/DHA)", "Vitamin E (mixed tocopherols)"], "kind": "protective", "strength": 2, "goal": "Reduce oxidation of PUFAs", "rationale": "Most omega-3 products already include tocopherol as antioxidant, but high-dose EPA/DHA users benefit from ~15-30 mg mixed tocopherols.", "dose": "EPA/DHA 1-4 g + 15-30 mg mixed tocopherols."}, {"id": "p17", "members": ["CoQ10 (Ubiquinol)", "PQQ (Pyrroloquinoline quinone)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Mitochondrial biogenesis + electron-transport support", "rationale": "PQQ appears to promote mitochondrial biogenesis while CoQ10 acts as an electron carrier. Data entry notes the synergy is commonly cited; human trial data for the combination is limited.", "dose": "Ubiquinol 100-200 mg + PQQ 10-20 mg with fat."}, {"id": "p18", "members": ["Elderberry (Sambucus nigra)", "Zinc"], "kind": "independent-complementary", "strength": 3, "goal": "Shorten cold duration (acute)", "rationale": "Each has independent RCT evidence for ~2-day reduction in cold duration when started <48 h from onset.", "dose": "15 mL elderberry + 75-92 mg Zn (lozenges) for up to 5 days.", "existing_entry": "Elderberry + Zinc combo"}, {"id": "p19", "members": ["Glucosamine / Chondroitin"], "kind": "mechanism-complementary", "strength": 3, "goal": "Modest cartilage and joint-pain protection in moderate osteoarthritis", "rationale": "GAIT trial found the combination outperformed either component alone in the moderate-to-severe pain subgroup.", "dose": "Glucosamine sulfate 1,500 mg + chondroitin sulfate 800-1,200 mg."}, {"id": "p20", "members": ["Boswellia serrata", "Curcumin (bioavailable form)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Joint inflammation (osteoarthritis)", "rationale": "Boswellic acids inhibit 5-LOX; curcumin inhibits NF-kB and COX-2. Non-overlapping pathways.", "dose": "Boswellia 300 mg + curcumin 500 mg with fat."}, {"id": "p21", "members": ["Aged garlic extract (Kyolic)", "Omega-3 (EPA/DHA)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Cardiovascular risk reduction", "rationale": "Garlic modestly reduces BP and LDL; omega-3 addresses triglycerides and inflammation.", "dose": "AGE 600-1,200 mg + EPA/DHA 1-2 g."}, {"id": "p22", "members": ["Hesperidin", "Vitamin C (moderate dose)", "Rutin"], "kind": "mechanism-complementary", "strength": 2, "goal": "Venous tone / capillary fragility", "rationale": "Classic European bioflavonoid + C formula for chronic venous insufficiency.", "dose": "Hesperidin 500 mg + rutin 500-1,000 mg + C 500 mg."}, {"id": "p23", "members": ["Ivy leaf extract (Hedera helix)", "Thyme extract (Thymus vulgaris)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Acute bronchitis / cough", "rationale": "Both are expectorants; RCTs support the combination for cough frequency and duration.", "dose": "Ivy 300 mg + thyme 300-600 mg."}, {"id": "p24", "members": ["Nicotinamide riboside (NR)", "Pterostilbene"], "kind": "mechanism-complementary", "strength": 2, "goal": "NAD+ precursor + sirtuin activator", "rationale": "NR raises NAD+ substrate; pterostilbene activates sirtuins that use it. Basis protocol raised NAD+ and improved liver markers; clinical longevity endpoints unproven.", "dose": "NR 250 mg + pterostilbene 50 mg.", "existing_entry": "NR + Pterostilbene stack (basis-type)"}, {"id": "p25", "members": ["Lactoferrin", "Iron"], "kind": "absorption-enhancer", "strength": 3, "goal": "Iron repletion with fewer GI side-effects", "rationale": "Lactoferrin binds iron for controlled release, improving hemoglobin response with less GI upset than ferrous sulfate.", "dose": "Lactoferrin 100-250 mg + ferrous bisglycinate 25-50 mg."}, {"id": "p26", "members": ["NAC (N-Acetyl Cysteine)", "Glycine"], "kind": "substrate-pair", "strength": 3, "goal": "Raise intracellular glutathione", "rationale": "NAC provides the rate-limiting cysteine; glycine is the other key substrate. The GlyNAC concept shows improved redox in aging pilots.", "dose": "NAC 600-1,200 mg + glycine 3 g."}, {"id": "p27", "members": ["Citrulline (L-citrulline, pure form)", "Dietary Nitrate / Beetroot"], "kind": "mechanism-complementary", "strength": 2, "goal": "Nitric oxide bioavailability for endurance / blood pressure", "rationale": "Citrulline via the L-arginine / NOS pathway; nitrate via the nitrate-nitrite-NO pathway. Additive in some small trials.", "dose": "Citrulline 6-8 g + beetroot 400-500 mg nitrate, 2-3 h pre-exercise."}, {"id": "p28", "members": ["Magnesium taurate", "Taurine"], "kind": "synergy", "strength": 2, "goal": "Blood pressure and cardiac rhythm support", "rationale": "Mg-taurate already pairs the two, but adding extra taurine (1-3 g) may provide additive cardiac support in some patients."}, {"id": "p29", "members": ["HMB (β-Hydroxy-β-methylbutyrate)", "Creatine monohydrate"], "kind": "independent-complementary", "strength": 2, "goal": "Sarcopenia / older-adult muscle preservation", "rationale": "Creatine builds PCr stores and supports strength; HMB suppresses proteolysis. Each has independent evidence; head-to-head combo trials are thin.", "dose": "Creatine 3-5 g + HMB 3 g daily.", "existing_entry": "HMB + Creatine stack"}, {"id": "p30", "members": ["Calcium", "Magnesium", "Vitamin D3", "Vitamin K2 (MK-7)", "Boron"], "kind": "goal-stack", "strength": 4, "goal": "Comprehensive bone protocol (post-menopausal / fracture risk)", "rationale": "Builds on the WHI Ca+D trial; adds Mg (cofactor), K2 (bone deposition), and optional boron for matrix support.", "dose": "Ca 500 mg x2/day + Mg 200-400 mg + D3 1,000-2,000 IU + MK-7 90-200 mcg + boron 3 mg."}, {"id": "p31", "members": ["Calcium hydroxyapatite (MCHC)", "Vitamin D3", "Vitamin K2 (MK-7)"], "kind": "mechanism-complementary", "strength": 4, "goal": "Bone density via food-form calcium matrix", "rationale": "MCHC carries calcium plus native collagen/phosphate; still requires D3 for absorption and K2 for bone-deposition routing. Variant of p2/p30 for people using whole-bone calcium sources.", "dose": "MCHC 1,000 mg/day + D3 1,000-2,000 IU + MK-7 90-200 mcg, with food.", "contraindications": ["warfarin (for K2)", "hypercalcemia"], "source_field": "desc/tips on Calcium hydroxyapatite entry"}, {"id": "p32", "members": ["Uridine monophosphate (UMP)", "Omega-3 (EPA/DHA)", "Choline"], "kind": "mechanism-complementary", "strength": 3, "goal": "Neuronal membrane synthesis / cognition", "rationale": "UMP + DHA + choline together supply all three substrates for phosphatidylcholine in neurons (Wurtman/MIT work, Souvenaid trials). UMP alone is weakly supported; the combination is the evidenced form.", "dose": "UMP 250-500 mg + DHA 500-1,000 mg + Alpha-GPC 300 mg or CDP-choline 250 mg.", "source_field": "UMP entry: 'synergistic effect with DHA is better evidenced than standalone'"}, {"id": "p33", "members": ["Tributyrin / Butyrate", "Probiotics", "Inulin / FOS (prebiotic fibre)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Gut barrier / short-chain fatty acid support", "rationale": "Tributyrin delivers butyrate to the colon; probiotics + prebiotic fibre also produce butyrate via fermentation. Layering a direct donor with substrate-driven production gives continuous SCFA coverage.", "dose": "Tributyrin 300-600 mg + 1-10B CFU probiotic + 5-10 g soluble fibre.", "source_field": "Tributyrin entry: 'Can be combined with probiotics for synergistic gut barrier support'"}, {"id": "p34", "members": ["Betaine TMG (trimethylglycine)", "Folate (5-MTHF)", "Vitamin B12", "Vitamin B6 (P5P)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Homocysteine reduction / methylation backup pathway", "rationale": "TMG provides methyl groups via the BHMT pathway in liver/kidney; 5-MTHF + B12 drive the methionine synthase pathway everywhere else; B6 supports the transsulfuration branch. Together they cover both arms of homocysteine clearance.", "dose": "TMG 1,000-3,000 mg + 5-MTHF 400-800 mcg + methyl-B12 500 mcg + P5P 25-50 mg.", "source_field": "TMG entry: 'Safe to combine with B12 and folate' + Choline bitartrate entry: 'Works synergistically with B12 and folate'"}, {"id": "p35", "members": ["NAC (N-Acetyl Cysteine)", "Glycine", "Vitamin B6 (P5P)", "Zinc"], "kind": "substrate-pair", "strength": 3, "goal": "GlyNAC extended — glutathione synthesis + transsulfuration support", "rationale": "Extends p26. L-cysteine/NAC + glycine are the two limiting substrates for glutathione; P5P and Zn are cofactors for the transsulfuration enzymes (CBS, CSE) that produce endogenous cysteine.", "dose": "NAC 600-1,200 mg + glycine 3 g + P5P 25 mg + Zn 15-25 mg (with Cu 1-2 mg if long-term).", "source_field": "L-Cysteine entry: 'Synergistic with glycine (GlyNAC stack); add B6 and zinc to support the transsulfuration pathway'"}, {"id": "p36", "members": ["Borage oil (GLA)", "Omega-3 (EPA/DHA)"], "kind": "side-effect-offset", "strength": 4, "goal": "Prevent arachidonic-acid buildup from high-dose GLA", "rationale": "GLA can be elongated to arachidonic acid (pro-inflammatory) if the pathway is not balanced by EPA/DHA intake. This pairing is more than convenience — it is a safety-relevant balance.", "dose": "Borage oil 500-1,000 mg GLA + EPA/DHA 1-2 g.", "source_field": "Borage oil entry: 'combine with fish oil to prevent arachidonic-acid buildup from GLA'"}, {"id": "p37", "members": ["Quercetin", "Luteolin", "Kaempferol", "Fisetin"], "kind": "goal-stack", "strength": 2, "goal": "Broad flavonoid / senolytic-adjacent stack", "rationale": "Overlapping but non-identical effects on mast cells, NF-kB, and senescent cells. Kaempferol and luteolin entries both explicitly cite quercetin; fisetin has the strongest senolytic evidence.", "dose": "Quercetin 500 mg + luteolin 100 mg + kaempferol 50 mg + fisetin 100 mg daily (or fisetin 1,000 mg x2 days/month pulse).", "source_field": "Kaempferol entry: 'broader flavonoid longevity stack'; Luteolin entry: 'synergistic with quercetin'"}, {"id": "p38", "members": ["Galacto-oligosaccharides (GOS)", "Probiotics"], "kind": "synergy", "strength": 4, "goal": "Targeted bifidogenic synbiotic", "rationale": "GOS selectively feeds bifidobacteria — a specific case of p8 with stronger trial data than generic fibre for raising Bifidobacterium counts.", "dose": "GOS 3.5-5 g + Bifidobacterium-containing probiotic 1-10B CFU.", "source_field": "GOS entry: 'highly synergistic with probiotic supplementation'"}, {"id": "p39", "members": ["2'-Fucosyllactose (2'-FL HMO)", "Galacto-oligosaccharides (GOS)", "Probiotics"], "kind": "synergy", "strength": 2, "goal": "Broad bifidogenic coverage (infant-HMO-style prebiotic)", "rationale": "HMOs and GOS feed overlapping but distinct Bifidobacterium species; combining broadens coverage closer to the breast-milk substrate pattern.", "dose": "2'-FL 1-3 g + GOS 3-5 g + probiotic 1-10B CFU.", "source_field": "2'-FL entry: 'combined with other HMOs or GOS for broader prebiotic coverage'"}, {"id": "p40", "members": ["Oat beta-glucan (cholesterol)", "Oat avenanthramides"], "kind": "mechanism-complementary", "strength": 2, "goal": "Complete oat matrix — cholesterol + vascular antioxidant", "rationale": "Beta-glucan handles LDL via bile-acid sequestration; avenanthramides add endothelial antioxidant activity. Whole oats deliver both; isolated supplementation loses one.", "dose": "Beta-glucan 3-10 g + avenanthramides (dose not standardised — whole oat sources preferred).", "source_field": "Avenanthramides entry: 'synergistic with oat beta-glucan for complete oat benefits'"}, {"id": "p41", "members": ["Cluster dextrin (HBCD)", "EAAs (Essential amino acids)", "Electrolyte complex (Na/K/Mg)"], "kind": "goal-stack", "strength": 3, "goal": "Intra-workout fuelling for long/endurance sessions", "rationale": "HBCD supplies rapid low-osmolality carbs; EAAs supply amino-acid substrate without requiring digestion; electrolytes replace sweat losses. Common endurance protocol.", "dose": "HBCD 30-60 g/h + EAAs 10-15 g + electrolytes per sweat rate.", "source_field": "HBCD entry: 'Can be combined with electrolytes and amino acids'"}, {"id": "p42", "members": ["Adenosylcobalamin (dibencozide)", "Methylcobalamin (high-dose neurological)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Comprehensive B12 coverage (both active coenzyme forms)", "rationale": "Adenosyl-B12 is the mitochondrial coenzyme for methylmalonyl-CoA mutase; methyl-B12 is the cytosolic cofactor for methionine synthase. The body needs both; supplementing both avoids relying on intracellular conversion.", "dose": "Adeno-B12 1-5 mg + methyl-B12 1-5 mg, sublingual, daily or weekly.", "source_field": "Adenosylcobalamin entry: 'combine with methylcobalamin for comprehensive B12 coverage'"}, {"id": "p43", "members": ["Acerola cherry extract", "Rutin", "Hesperidin", "Quercetin"], "kind": "mechanism-complementary", "strength": 2, "goal": "Food-matrix vitamin C with capillary/vascular bioflavonoids", "rationale": "Food-matrix variant of p22. Acerola provides ascorbate in a bioflavonoid context, mirroring traditional European venotropic formulas.", "dose": "Acerola 500-1,000 mg (std. 17-25% C) + rutin 500 mg + hesperidin 500 mg + quercetin 500 mg.", "source_field": "Acerola entry: 'ascorbic acid alongside synergistic bioflavonoids including rutin, hesperidin, and quercetin'"}, {"id": "p44", "members": ["Magnolia bark (honokiol + magnolol)", "Ashwagandha (KSM-66)", "L-Theanine"], "kind": "goal-stack", "strength": 2, "goal": "Evening wind-down / stress-reducing sleep formula", "rationale": "Non-sedative, non-GABAergic stack: magnolia (anxiolytic via GABA-A modulation + cortisol), ashwagandha (cortisol reduction), theanine (alpha-waves). Often combined in pre-sleep formulas.", "dose": "Magnolia 200-400 mg + KSM-66 ashwagandha 300-600 mg + theanine 100-200 mg, 60 min pre-bed.", "contraindications": ["thyroid hormone (for ashwagandha)", "sedatives / benzodiazepines"], "source_field": "Magnolia bark entry: 'Commonly combined with ashwagandha or L-theanine in sleep formulas'"}, {"id": "p45", "members": ["Cistanche tubulosa (Rou Cong Rong)", "Horny goat weed (Epimedium)"], "kind": "goal-stack", "strength": 1, "goal": "Traditional TCM vitality / libido / cognition formula", "rationale": "Classical Chinese herbal pairing. Mechanisms are preliminary and human RCT data is limited; label as traditional-use.", "dose": "Cistanche 300-1,000 mg + epimedium 250-1,000 mg.", "source_field": "Cistanche entry: 'Often combined with Epimedium in traditional formulas'"}, {"id": "p46", "members": ["Protocatechuic acid", "Quercetin", "Other polyphenols"], "kind": "goal-stack", "strength": 1, "goal": "Broad polyphenol antioxidant coverage", "rationale": "Non-overlapping polyphenol targets; mostly additive. Clinical endpoints for the specific pair are thin.", "dose": "Dose not well-standardised; typically food-form or extract blend.", "source_field": "Protocatechuic acid entry: 'Pairs well with quercetin and other phenolics in a polyphenol stack'"}, {"id": "p47", "members": ["Ferulic acid", "Vitamin C (moderate dose)", "Vitamin E (mixed tocopherols)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Topical (and oral-adjacent) UV / oxidative-stress protection", "rationale": "The classical Duke dermatology stack for skin antioxidant protection; ferulic acid stabilises C and E in formulation and extends photoprotective effect. Topical evidence is strongest; oral synergy extrapolated.", "dose": "Topical serum: ferulic acid 0.5% + L-ascorbic acid 15% + tocopherol 1%. Oral: ferulic acid 250 mg + C 500 mg + E 15-30 mg mixed tocopherols.", "source_field": "Ferulic acid entry: 'synergistic UV protection and anti-aging combination'"}, {"id": "p48", "members": ["Phytosterols (beta-sitosterol complex)", "Oat beta-glucan (cholesterol)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Additive LDL-C reduction", "rationale": "Phytosterols displace cholesterol at intestinal absorption; beta-glucan sequesters bile acids. Different mechanisms; FDA recognises both as authorised cholesterol-lowering health claims. Additive ~5-10% each.", "dose": "Phytosterols 2 g/day (with fat-containing meal) + beta-glucan 3-10 g/day.", "source_field": "Phytosterols entry (fat requirement) + Oat beta-glucan entry"}, {"id": "p49", "members": ["L-Arginine", "L-Ornithine"], "kind": "synergy", "strength": 2, "goal": "Growth-hormone support / ammonia clearance", "rationale": "Ornithine and arginine recycle through the urea cycle; the combination shows larger GH responses in older trials than either alone. Modern practice often prefers L-citrulline for the NO endpoint.", "dose": "L-Arg 3-6 g + L-Orn 2-5 g, pre-bed.", "source_field": "L-Ornithine entry: 'Often combined with L-arginine for growth hormone release'"}, {"id": "p50", "members": ["Pantethine", "Omega-3 (EPA/DHA)", "Phytosterols (beta-sitosterol complex)"], "kind": "goal-stack", "strength": 2, "goal": "Non-statin lipid management", "rationale": "Pantethine modestly lowers LDL and TG; omega-3 targets TG; phytosterols lower LDL. Non-overlapping mechanisms for combined lipid panels.", "dose": "Pantethine 600-900 mg + EPA/DHA 1-2 g + phytosterols 2 g.", "source_field": "Pantethine entry: 'Can be combined with omega-3s or plant sterols for additional cholesterol support'"}, {"id": "p51", "members": ["Calcium D-glucarate", "DIM (Diindolylmethane)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Estrogen metabolism / Phase II conjugation support", "rationale": "Ca-D-glucarate inhibits beta-glucuronidase (reducing estrogen reabsorption); DIM shifts hydroxylation toward less-active 2-OH estrogens. Popular combo in functional-medicine estrogen-clearance protocols; direct combo RCTs are limited.", "dose": "Ca-D-glucarate 500-1,000 mg + DIM 100-200 mg.", "contraindications": ["pregnancy", "hormone-modulating drugs (consult clinician)"], "source_field": "Calcium D-glucarate entry: 'Sometimes combined with DIM for estrogen metabolism support'"}, {"id": "p52", "members": ["D-Mannose", "Cranberry PAC (A-type proanthocyanidins)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Recurrent UTI prophylaxis", "rationale": "D-Mannose blocks E. coli FimH adhesin at the bladder wall; cranberry PACs also inhibit bacterial adherence via a related mechanism. Both are listed in UTI guidelines; combination is additive.", "dose": "D-Mannose 2 g 1-2x/day + cranberry extract 500 mg (std. PACs 36 mg)."}, {"id": "p53", "members": ["L-Lysine", "Vitamin C (moderate dose)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Collagen / connective-tissue support (Pauling concept)", "rationale": "Both are substrates/cofactors for collagen synthesis. Lysine is the limiting amino acid for collagen cross-links; C is the cofactor. Cardiovascular-endpoint claims are unproven, but the connective-tissue rationale is sound.", "dose": "L-Lysine 1-3 g + Vitamin C 500-1,000 mg."}, {"id": "p54", "members": ["Maqui berry (Aristotelia chilensis)", "Lutein + Zeaxanthin"], "kind": "independent-complementary", "strength": 1, "goal": "Dry-eye / macular support", "rationale": "Maqui delphinidins have small dry-eye trials; lutein/zeaxanthin are the AREDS2 pigments. Independent evidence bases; combination not RCT-tested.", "dose": "Maqui 60-120 mg + lutein 10 mg + zeaxanthin 2 mg."}, {"id": "p55", "members": ["Creatine monohydrate", "Whey protein", "Carbohydrate"], "kind": "absorption-enhancer", "strength": 3, "goal": "Maximise creatine uptake into muscle", "rationale": "Insulin drives creatine transport into muscle. Taking creatine with protein + carbs (post-workout or meal) raises muscle creatine accumulation vs fasted dosing.", "dose": "Creatine 3-5 g + whey 20-30 g + 30-50 g carbohydrate, post-workout.", "source_field": "Creatine and whey entries; carb-insulin pairing is standard performance-nutrition practice"}, {"id": "p56", "members": ["Casein protein", "Whey protein"], "kind": "temporal-complementary", "strength": 3, "goal": "24-hour muscle protein synthesis coverage", "rationale": "Whey is rapidly digested and spikes plasma amino acids — ideal post-workout to drive an acute MPS response. Casein clots in the stomach and releases amino acids slowly over ~7 h — ideal pre-bed to suppress overnight proteolysis. Layering the two by timing (not by mixing) covers both the post-exercise anabolic window and the overnight fasted period.", "dose": "Whey 20-30 g within 1-2 h post-workout + casein 30-40 g 30-60 min pre-bed on training days.", "source_field": "Casein protein entry: 'Casein before bed beats whey for overnight muscle building'"}, {"id": "p57", "members": ["Ashwagandha (KSM-66)", "Rhodiola rosea"], "kind": "goal-stack", "strength": 3, "goal": "Adaptogen stack — calming + activating", "rationale": "KSM-66 ashwagandha lowers cortisol and supports recovery from chronic stress; Rhodiola rosea is a stimulating adaptogen that supports energy and mental endurance. Complementary mechanisms (GABAergic/HPA-axis dampening + monoaminergic/fatigue resistance). No head-to-head RCT of the combination, but both have independent evidence and the combination is in clinical use.", "dose": "KSM-66 ashwagandha 300-600 mg/day (food, AM or PM) + Rhodiola rosea 200-400 mg/day (empty stomach, AM only). Cycle 8-12 weeks on, 2-4 weeks off.", "contraindications": ["thyroid hormone (ashwagandha)", "benzodiazepines / sedatives", "immunosuppressants (ashwagandha)", "bipolar disorder (Rhodiola)"], "existing_entry": "Adaptogen stack (Ashwagandha + Rhodiola)", "source_field": "Explicit 'Adaptogen stack' entry in data.js"}, {"id": "p58", "members": ["Hyaluronic acid (oral)", "Chondroitin sulfate (standalone)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Joint lubrication + cartilage matrix support", "rationale": "Oral HA contributes to synovial fluid viscosity and joint lubrication; chondroitin supports cartilage GAG matrix and modestly reduces joint pain. A 2024 RCT of the combination found reduced knee stiffness and improved mobility at 3 months. Either alone is modest; combined evidence is the entry's basis.", "dose": "HA 80-200 mg/day (low-MW oral) + chondroitin sulfate 400-800 mg/day, with food. Allow 3 months.", "existing_entry": "Hyaluronic acid + Chondroitin stack", "source_field": "Explicit 'Hyaluronic acid + Chondroitin stack' entry in data.js"}, {"id": "p59", "members": ["Theacrine (TeaCrine)", "Caffeine (standardised)"], "kind": "synergy", "strength": 3, "goal": "Energy and focus without tolerance buildup or cardiovascular stimulation", "rationale": "Distinct from p5 (L-theanine + caffeine). Theacrine acts on adenosine and dopaminergic pathways with minimal HR/BP effect and shows no tolerance even after 8 weeks of daily use. Combining with caffeine extends effective duration and broadens the neurochemical hit without the jitter or tolerance penalty. Useful when L-theanine has been tried and the user wants a longer-duration option.", "dose": "Theacrine 100-200 mg + caffeine 50-150 mg, morning or early afternoon. Avoid PM dosing.", "contraindications": ["anxiety disorders", "uncontrolled hypertension (caffeine portion)"], "source_field": "Theacrine entry: 'Can be combined with caffeine for synergistic effect without jitters'"}, {"id": "p60", "members": ["Proline (L-Proline)", "Vitamin C (moderate dose)", "Glycine"], "kind": "substrate-cofactor-stack", "strength": 2, "goal": "Comprehensive collagen-synthesis substrate triad", "rationale": "Proline (~28% of collagen residues) and glycine (~33%) are the two dominant amino acids in the collagen triple helix; vitamin C is the obligate cofactor for prolyl/lysyl hydroxylases. Supplementing all three together provides both substrate and cofactor and is more rationale-driven than collagen + C alone (p4) for users who do not consume collagen peptides.", "dose": "L-Proline 500-2,000 mg + Vitamin C 500 mg + Glycine 3-10 g daily.", "source_field": "L-Proline entry: 'alongside vitamin C and glycine for collagen synthesis support'"}, {"id": "p61", "members": ["Carnosyn beta-alanine (sustained release)", "Creatine monohydrate"], "kind": "independent-complementary", "strength": 3, "goal": "High-intensity / sprint / strength-endurance performance", "rationale": "Independent and additive ergogenic mechanisms. Beta-alanine raises muscle carnosine, buffering H+ during 1-10 min efforts. Creatine raises phosphocreatine, supporting <30 s maximal efforts and total work output. Stacking covers both ATP-PCr and glycolytic energy systems. Multiple meta-analyses support each individually; combination is standard sports-nutrition practice.", "dose": "Beta-alanine 3.2-6.4 g/day (split or sustained-release) + Creatine monohydrate 3-5 g/day. Beta-alanine requires 4-6 weeks loading.", "source_field": "Carnosyn beta-alanine entry: 'Stacks well with creatine'"}, {"id": "p62", "members": ["Red sage / Danshen (Salvia miltiorrhiza)", "Sanqi (Panax notoginseng)"], "kind": "traditional-formula", "strength": 1, "goal": "TCM cardiovascular / circulation support", "rationale": "Classical TCM cardiovascular pairing (often as 'Compound Danshen Dripping Pill'). Both have anti-platelet and vasodilatory activity in lab and Chinese clinical studies; independent replication outside China is limited. Listed for completeness — additive bleeding risk is the dominant practical consideration.", "dose": "Dan Shen 1,500-3,000 mg/day + Sanqi 500-1,500 mg/day standardised extract.", "contraindications": ["warfarin / DOAC / aspirin / NSAID (additive bleeding)", "pre-surgical period (stop ≥2 weeks prior)"], "source_field": "Dan Shen compound entry: 'traditionally combined with Sanqi (Panax notoginseng)'"}, {"members": ["Beta-Alanine", "Creatine monohydrate"], "goal": "Anaerobic performance + endurance buffering", "kind": "synergy", "strength": 4, "rationale": "Creatine increases short-burst phosphocreatine; beta-alanine raises muscle carnosine to buffer H+ in 1-4 min efforts. Loaded together cover overlapping intensity zones.", "dose": "Creatine 3-5 g/day + Beta-alanine 3.2-6.4 g/day in divided 800 mg doses to minimise paresthesia.", "id": "p63"}, {"members": ["Calcium", "Magnesium", "Zinc"], "goal": "Mineral absorption competition warning", "kind": "absorption-conflict", "strength": 4, "rationale": "Divalent cations (Ca2+, Mg2+, Zn2+) compete for the same divalent metal transporters (DMT-1) in the intestine. Doses >800 mg of any one significantly reduce uptake of the others.", "dose": "Take large mineral doses (>500 mg) at least 2 hours apart. Smaller everyday doses can usually be co-ingested without major loss.", "id": "p64"}, {"members": ["Lactobacillus rhamnosus GG", "Acacia fiber (prebiotic)"], "goal": "Synbiotic gut support", "kind": "synergy", "strength": 3, "rationale": "Selective fermentation of acacia by Lactobacillus enhances strain persistence and short-chain-fatty-acid production.", "dose": "1-10 billion CFU LGG + 5-15 g acacia, separately or in same dose with cool water (heat kills probiotics).", "id": "p65"}, {"members": ["Quercetin", "Bromelain"], "goal": "Quercetin absorption + anti-inflammatory synergy", "kind": "absorption-enhancer", "strength": 3, "rationale": "Bromelain enzymes increase intestinal absorption of quercetin; both have additive mast-cell stabilizing effects in allergy/inflammation.", "dose": "Quercetin 500 mg + Bromelain 100-250 mg, on empty stomach.", "id": "p66"}, {"members": ["Vitamin C (moderate dose)", "Zinc"], "goal": "Common-cold severity reduction", "kind": "synergy", "strength": 3, "rationale": "Independent meta-analyses show modest cold-symptom reduction; combining at first symptom is the most-studied protocol.", "dose": "Vitamin C 1000 mg + Zinc lozenge 13-23 mg every 2 hours within 24 h of symptom onset (max 5 days).", "id": "p67"}, {"members": ["Magnesium", "Pyridoxal 5-phosphate (P5P)"], "goal": "PMS symptom reduction", "kind": "synergy", "strength": 3, "rationale": "Two RCTs (Fathizadeh 2010; De Souza 2000) show greater PMS symptom reduction with Mg + B6 vs Mg alone.", "dose": "Magnesium 200-360 mg + P5P 40-80 mg from luteal phase through menstruation.", "id": "p68"}, {"members": ["Choline", "Omega-3 (EPA/DHA)"], "goal": "Brain phospholipid synthesis (especially pregnancy/infancy)", "kind": "mechanism-complementary", "strength": 4, "rationale": "Phosphatidylcholine + DHA together build neuronal membranes; large prenatal cohorts find compounded cognitive benefits in offspring.", "dose": "Choline 450-550 mg + DHA 200-300 mg/day during pregnancy and lactation.", "id": "p69"}, {"members": ["Iron"], "apart_from": ["Calcium", "Zinc", "tea", "coffee", "dairy", "Magnesium"], "goal": "Iron absorption protection", "kind": "absorption-conflict", "strength": 5, "rationale": "Tannins (tea/coffee), divalent cations, and casein phosphopeptides each significantly reduce non-heme iron uptake.", "dose": "Take iron on empty stomach with vitamin C; separate from calcium, zinc, magnesium, dairy, tea, coffee by 2 hours.", "id": "p70"}, {"members": ["Vitamin D3", "Magnesium"], "goal": "Vitamin D activation", "kind": "cofactor", "strength": 4, "rationale": "Magnesium is a cofactor for the enzymes converting vitamin D to its active form. Vitamin D supplementation increases magnesium needs.", "dose": "Vitamin D3 1000-2000 IU + Magnesium 200-400 mg/day with food.", "id": "p71"}, {"members": ["Berberine", "Bergamot citrus polyphenol extract"], "goal": "Lipid + glucose support without statin", "kind": "synergy", "strength": 3, "rationale": "Berberine activates AMPK; bergamot inhibits HMG-CoA reductase via brutieridin/melitidin. Italian RCTs combine for additive LDL reduction.", "dose": "Berberine 500 mg 2-3×/day + Bergamot 500-1000 mg/day with meals.", "id": "p72"}, {"members": ["Citrulline malate", "Beta-Alanine"], "goal": "Resistance + endurance pre-workout stack", "kind": "synergy", "strength": 3, "rationale": "Citrulline boosts NO/blood flow during reps; beta-alanine buffers H+ for the 1-4 min ATP-PC + glycolytic crossover.", "dose": "Citrulline malate 6-8 g + Beta-alanine 3.2 g, 30-45 min pre-workout.", "id": "p73"}, {"members": ["Lutein + Zeaxanthin", "Omega-3 (EPA/DHA)"], "goal": "Macular pigment density", "kind": "synergy", "strength": 4, "rationale": "AREDS2 + LUTEGA trials: omega-3 enhances retinal carotenoid uptake. Effect on macular pigment optical density is greater than either alone.", "dose": "Lutein 10 mg + Zeaxanthin 2 mg + DHA 350 mg/day with a fatty meal.", "id": "p74"}, {"members": ["Selenium", "Iodine"], "goal": "Thyroid hormone production support", "kind": "cofactor", "strength": 4, "rationale": "Iodine is the substrate; selenium-dependent iodothyronine deiodinases convert T4 to T3 and protect the gland from peroxide damage.", "dose": "Selenium 100-200 mcg + Iodine 150 mcg/day. Higher iodine without selenium can worsen autoimmune thyroiditis.", "id": "p75"}, {"members": ["Glycine", "Magnesium glycinate"], "goal": "Sleep onset + maintenance", "kind": "synergy", "strength": 3, "rationale": "Glycine lowers core body temperature; magnesium activates GABA receptors. Bambico/Inagawa trials show subjective sleep improvement.", "dose": "Glycine 3 g + Magnesium glycinate 300-400 mg, 30-60 min before bed.", "id": "p76"}, {"members": ["L-Theanine", "Magnesium"], "goal": "Anxiety + stress reduction", "kind": "synergy", "strength": 3, "rationale": "Both raise GABA tone via different routes (theanine ionotropic; magnesium NMDA antagonism + GABA-A modulation).", "dose": "L-Theanine 200 mg + Magnesium 200-300 mg, evening or under acute stress.", "id": "p77"}, {"members": ["Saffron (Crocus sativus)", "Curcumin (bioavailable form)"], "goal": "Adjunct depression support", "kind": "synergy", "strength": 3, "rationale": "Both modulate inflammation + monoamine signalling; combined saffron-curcumin has equivalent efficacy to fluoxetine 20 mg in mild-moderate depression (Akhondzadeh trial).", "dose": "Saffron 30 mg + Curcumin 500-1000 mg/day; 8-12 week trial.", "contraindications": ["SSRI/SNRI", "MAOI", "lithium"], "id": "p78"}, {"members": ["Magnesium glycinate", "Vitamin B6 (P5P)"], "kind": "cofactor", "strength": 4, "goal": "Magnesium uptake + cofactor activation for ~300 enzymes", "rationale": "B6 (pyridoxal-5-phosphate) is required for many magnesium-dependent enzymes; trials show greater PMS, anxiety, and migraine benefit when paired vs. magnesium alone.", "dose": "Magnesium glycinate 200-400 mg + P5P 25-50 mg/day, evening with food.", "id": "p79"}, {"members": ["Vitamin D3", "Vitamin K2 (MK-7)", "Magnesium glycinate"], "kind": "mechanism-complementary", "strength": 5, "goal": "Bone deposition triad — calcium absorbed (D3), directed to bone (K2), enzymes activated (Mg)", "rationale": "Magnesium is the cofactor that activates vitamin D and converts inactive osteocalcin; K2 then directs the calcium D3 absorbs into bone instead of arteries.", "dose": "D3 1000-2000 IU + MK-7 100-200 mcg + Mg glycinate 200-400 mg, with the largest meal.", "contraindications": ["warfarin (for K2)"], "id": "p80"}, {"members": ["Iron", "Calcium"], "kind": "absorption-conflict", "strength": 5, "goal": "Avoid mineral absorption conflict", "rationale": "Calcium reduces non-heme iron absorption by up to 60% via DMT-1 competition. Even ~165 mg calcium with iron blocks half the iron uptake.", "dose": "Separate iron and calcium doses by ≥2 hours (and avoid dairy with iron).", "apart_from": ["Calcium", "dairy"], "id": "p81"}, {"members": ["Berberine", "Milk thistle (Silymarin)"], "kind": "synergy", "strength": 3, "goal": "Metabolic + hepatoprotection support", "rationale": "Berberine improves insulin sensitivity but is hepatically processed; silymarin protects hepatocytes during chronic use. Italian RCTs (Berberol K) combine for NAFLD and metabolic syndrome.", "dose": "Berberine 500 mg 2-3×/day + Silymarin 200-400 mg/day with meals.", "id": "p82"}, {"members": ["Whey protein", "Creatine monohydrate"], "kind": "synergy", "strength": 5, "goal": "Hypertrophy + strength gains", "rationale": "Largest meta-analysis (Morton 2018) shows protein + creatine adds ~30% more LBM gain than protein alone in trained subjects.", "dose": "Whey 0.4 g/kg per meal + Creatine 3-5 g/day, post-workout convenient but timing not critical.", "id": "p83"}, {"members": ["Probiotics", "Inulin / FOS (prebiotic fibre)"], "kind": "synergy", "strength": 4, "goal": "Synbiotic gut colonisation", "rationale": "Prebiotic fibre selectively feeds the live bacteria; combined synbiotics outperform probiotics alone for IBS, immune, and metabolic outcomes in several meta-analyses.", "dose": "Multi-strain probiotic 5-30 billion CFU + inulin/FOS 5-10 g/day. Start low to avoid bloating.", "id": "p84"}, {"members": ["Folate (5-MTHF)", "Methylcobalamin (high-dose neurological)"], "kind": "mechanism-complementary", "strength": 5, "goal": "Homocysteine reduction + nervous system maintenance", "rationale": "Both required for the methionine cycle; deficiency in either causes hyperhomocysteinemia and demyelination. The methylated forms bypass MTHFR and MTRR polymorphisms.", "dose": "5-MTHF 400-800 mcg + Methylcobalamin 1000 mcg sublingual daily, AM.", "id": "p85"}, {"members": ["Iron", "Vitamin C (moderate dose)", "Lactoferrin"], "kind": "synergy", "strength": 3, "goal": "Gentler iron repletion in deficiency", "rationale": "Lactoferrin enhances iron uptake while reducing GI side effects; vitamin C still aids reduction of Fe3+ → Fe2+. Useful in pregnancy and IBD trials.", "dose": "Ferrous bisglycinate 25-50 mg + Vitamin C 100-250 mg + Lactoferrin 100-200 mg, on empty stomach.", "apart_from": ["Calcium", "Zinc", "tea", "coffee", "dairy"], "id": "p86"}, {"members": ["Magnesium glycinate", "Glycine", "L-Theanine"], "kind": "synergy", "strength": 3, "goal": "Sleep onset + anxiety reduction", "rationale": "Three different GABAergic / cooling routes converge: glycine lowers core body temp, magnesium activates GABA-A, theanine modulates inhibitory tone via alpha-waves.", "dose": "Mg glycinate 300-400 mg + Glycine 3 g + L-Theanine 200 mg, 30-60 min before bed.", "id": "p87"}, {"members": ["Magnesium", "Vitamin D3"], "kind": "cofactor", "strength": 5, "goal": "Vitamin D activation", "rationale": "Magnesium is a required cofactor for the hepatic and renal hydroxylases that activate vitamin D. Mg-deficient subjects show poor 25-OH-D response to D3 supplementation.", "dose": "Mg 300-400 mg/day with D3 ≥1,000 IU; both with food.", "id": "p88"}, {"members": ["Zinc", "Copper"], "kind": "cofactor", "strength": 4, "goal": "Long-term zinc supplementation balance", "rationale": "Zinc downregulates intestinal copper absorption via metallothionein. Chronic zinc >25-30 mg/day without copper causes anemia and neuropathy.", "dose": "If Zn ≥25 mg/day, add Cu 1-2 mg/day. Optimal ratio ~8-15:1 Zn:Cu.", "optimal_ratio": "Zn:Cu 10:1", "id": "p89"}, {"members": ["Iron", "Vitamin C (moderate dose)"], "kind": "absorption-enhancer", "strength": 5, "goal": "Non-heme iron absorption", "rationale": "Ascorbate reduces ferric to ferrous iron in the gut, increasing absorption ~2-3×. Especially helpful with plant-based iron sources.", "dose": "Iron 30-60 mg + Vitamin C 100-250 mg, taken together on empty stomach if tolerated.", "evidence_grade": "A", "id": "p90"}, {"members": ["Iron", "Vitamin B12", "Folate (5-MTHF)"], "kind": "cofactor", "strength": 5, "goal": "Anemia recovery panel", "rationale": "All three are required for normal RBC production; deficiency in any one limits the others' effect. Empirical iron without verifying B12/folate misses dimorphic anemias.", "dose": "Test ferritin + B12 + folate before dosing; correct deficits per labs.", "evidence_grade": "A", "id": "p91"}, {"members": ["Vitamin B6 (P5P)", "Vitamin B12", "Folate (5-MTHF)"], "kind": "cofactor", "strength": 5, "goal": "Methylation cycle / homocysteine reduction", "rationale": "All three are required cofactors in homocysteine remethylation and transsulfuration. Single-vitamin deficits will not normalize Hcy alone.", "dose": "B6 25-50 mg + B12 500-1,000 mcg methylcobalamin + 5-MTHF 400-800 mcg, daily.", "evidence_grade": "A", "id": "p92"}, {"members": ["Magnesium", "Vitamin B6 (P5P)"], "kind": "cofactor", "strength": 4, "goal": "Magnesium uptake into cells", "rationale": "B6 facilitates Mg transport into cells; combined Mg-B6 outperforms Mg alone in PMS, anxiety, and cramp endpoints in several RCTs.", "dose": "Mg 300 mg + B6 25-50 mg daily.", "id": "p93"}, {"members": ["CoQ10 (Ubiquinol)", "Vitamin E (mixed tocopherols)"], "kind": "cofactor", "strength": 3, "goal": "Lipophilic antioxidant cycling", "rationale": "Vitamin E quenches lipid peroxyl radicals; CoQ10 (and vitamin C) regenerate tocopheroxyl radicals back to active vitamin E. The pair maintains the lipid antioxidant cycle.", "dose": "CoQ10 100-200 mg + mixed tocopherols 100-200 IU with fat.", "id": "p94"}, {"members": ["Selenium", "Iodine"], "kind": "cofactor", "strength": 5, "goal": "Thyroid hormone synthesis and conversion", "rationale": "Iodine is the substrate for T3/T4; selenium is the cofactor for deiodinases that activate T4→T3 and for glutathione-peroxidase that protects the thyroid from peroxide damage.", "dose": "Iodine ≤150 mcg/day (avoid in autoimmune thyroid) + Selenium 100-200 mcg selenomethionine.", "evidence_grade": "A", "id": "p95"}, {"members": ["Calcium", "Vitamin D3", "Vitamin K2 (MK-7)"], "kind": "cofactor", "strength": 5, "goal": "Bone-targeted calcium deposition", "rationale": "D3 increases gut Ca absorption; K2 activates osteocalcin (bone) and MGP (vascular protection), directing Ca to bone rather than arteries. Mg is also required for D activation.", "dose": "Ca ≤500 mg/dose + D3 1,000-2,000 IU + MK-7 90-200 mcg + Mg 300 mg.", "evidence_grade": "B", "id": "p96"}, {"members": ["Choline", "Vitamin B12", "Folate (5-MTHF)"], "kind": "cofactor", "strength": 4, "goal": "Methylation triad / phosphatidylcholine synthesis", "rationale": "Choline, B12, and folate share the methyl pool. Low choline status raises folate/B12 demand and vice versa. Pregnancy demands all three.", "dose": "Choline 425-550 mg + B12 + folate per cycle requirements.", "evidence_grade": "B", "id": "p97"}, {"members": ["Glycine", "NAC (N-Acetyl Cysteine)"], "kind": "substrate-pair", "strength": 4, "goal": "Glutathione synthesis (older adults)", "rationale": "Glutathione = γ-glutamyl-cysteinyl-glycine. NAC supplies cysteine; glycine supplies the third amino acid. Older adults are typically deficient in BOTH substrates; supplementing one alone gives diminishing returns.", "dose": "Glycine 100 mg/kg + NAC 100 mg/kg daily, divided BID.", "evidence_grade": "B", "id": "p98"}, {"members": ["Acetyl-L-Carnitine (ALCAR)", "Alpha-Lipoic Acid (ALA)", "CoQ10 (Ubiquinol)"], "kind": "mechanism-complementary", "strength": 4, "goal": "Mitochondrial support stack", "rationale": "ALCAR shuttles fatty acids into mitochondria for β-oxidation; ALA recycles antioxidants and is a mitochondrial cofactor; CoQ10 carries electrons in the ETC. The triad supports mitochondrial bioenergetics from substrate to electron transport.", "dose": "ALCAR 1-2 g + ALA 600 mg + CoQ10 100-200 mg daily.", "id": "p99"}, {"members": ["Whey protein", "Creatine monohydrate", "L-Leucine (standalone)"], "kind": "goal-stack", "strength": 4, "goal": "Muscle protein synthesis (older adults / sarcopenia)", "rationale": "Whey provides the full EAA spectrum; leucine drives mTORC1 to peak; creatine provides the energetic substrate for high-power work. Older adults need ~3 g leucine to hit the synthesis threshold.", "dose": "Whey 25-40 g + Creatine 3-5 g + Leucine 2-3 g around training/major meals.", "id": "p100"}, {"members": ["Collagen peptides", "Vitamin C (moderate dose)"], "kind": "cofactor", "strength": 4, "goal": "Collagen synthesis cofactor", "rationale": "Vitamin C is required for prolyl/lysyl hydroxylase, the enzymes that stabilize collagen triple helix. Collagen amino-acid supply without vitamin C produces under-hydroxylated, unstable collagen.", "dose": "Collagen 10-20 g + Vitamin C 50-100 mg ~1 hour pre-loading-activity (Shaw 2017 protocol).", "id": "p101"}, {"members": ["Riboflavin (Vitamin B2)", "Magnesium", "CoQ10 (Ubiquinol)"], "kind": "goal-stack", "strength": 4, "goal": "Migraine prophylaxis triad", "rationale": "Each has independent evidence; the trio addresses mitochondrial energy production failure thought to underlie migraine. Riboflavin 400 mg, Mg 400-600 mg, CoQ10 100 mg each have their own RCT support.", "dose": "Riboflavin 400 mg + Mg 400 mg + CoQ10 100 mg daily for ≥3 months.", "id": "p102"}, {"members": ["Calcium", "Iron"], "kind": "absorption-conflict", "strength": 5, "goal": "Avoid iron-absorption blunting", "rationale": "Calcium competitively inhibits both heme and non-heme iron absorption at any dose. The effect is large enough to cause clinical iron deficiency in heavy calcium users.", "dose": "Separate by ≥2 hours.", "separation_hours": 2, "evidence_grade": "A", "id": "p103"}, {"members": ["Zinc", "Iron"], "kind": "absorption-conflict", "strength": 4, "goal": "Avoid mutual divalent-cation competition", "rationale": "Iron and zinc share intestinal divalent metal transporters. Co-dosing reduces zinc absorption by 30-50% and iron absorption by similar amounts.", "dose": "Separate by ≥2 hours.", "separation_hours": 2, "evidence_grade": "A", "id": "p104"}, {"members": ["Calcium", "Magnesium"], "kind": "absorption-conflict", "strength": 3, "goal": "Avoid divalent-cation competition", "rationale": "At doses ≥500 mg, calcium and magnesium compete for absorption transporters. Smaller doses (≤250 mg each) co-administered are less affected.", "dose": "Separate doses ≥1,000 mg by ≥2 hours; smaller co-doses are fine.", "separation_hours": 2, "id": "p105"}, {"members": ["Caffeine (standardised)", "Iron"], "kind": "absorption-conflict", "strength": 3, "goal": "Avoid iron blunting", "rationale": "Coffee/tea polyphenols (chlorogenic acid, tannins) bind iron in the gut, reducing non-heme iron absorption by 60-90% when co-consumed. Effect persists ~1 hour after the beverage.", "dose": "Separate iron from coffee/tea by ≥1 hour either side.", "separation_hours": 1, "evidence_grade": "A", "id": "p106"}, {"members": ["Caffeine (standardised)", "Calcium"], "kind": "absorption-conflict", "strength": 2, "goal": "Modest calcium loss with high caffeine", "rationale": "Each 100 mg caffeine increases urinary calcium loss by ~5 mg. Effect is small but adds up across high coffee/energy drink consumption.", "dose": "If high caffeine intake, ensure adequate calcium status.", "id": "p107"}, {"members": ["Vitamin B6 (P5P)", "Pantothenic acid (Vitamin B5)"], "kind": "absorption-conflict", "strength": 2, "goal": "B-vitamin balance at high doses", "rationale": "High-dose isolated B6 can outcompete B5 absorption when taken together. Balanced B-complex avoids this.", "dose": "Use balanced B-complex rather than mega-doses of single Bs.", "id": "p108"}, {"members": ["Niacin (Vitamin B3)", "Folate (5-MTHF)", "Vitamin B12"], "kind": "side-effect-offset", "strength": 3, "goal": "Methylation depletion offset", "rationale": "High-dose niacin (≥1 g/day) consumes methyl groups for methyl-niacinamide excretion, depleting SAM-e. Adding methyl donors (folate, B12, choline) prevents the homocysteine elevation seen with chronic high-dose niacin.", "dose": "If on niacin ≥1 g/day, add 5-MTHF 800 mcg + B12 1 mg + choline 500 mg.", "id": "p109"}, {"members": ["Soy isoflavones", "Iodine"], "kind": "absorption-conflict", "strength": 3, "goal": "Avoid thyroid hormone interference", "rationale": "Soy isoflavones inhibit thyroid peroxidase. Iodine repletion mitigates the effect. In iodine-deficient individuals, high-soy + low-iodine diets are linked to hypothyroidism.", "dose": "If consuming high soy, ensure iodine status is adequate (urine spot check).", "id": "p110"}, {"members": ["Levothyroxine substrate pairings (separate)", "Calcium", "Iron", "Soy isoflavones", "Magnesium", "Coffee"], "kind": "absorption-conflict", "strength": 5, "goal": "Levothyroxine absorption — supplement timing", "rationale": "Levothyroxine absorption is blunted by minerals (Ca, Fe, Mg, Al), soy, fiber, and coffee. Separate by ≥4 hours from any of these.", "dose": "Take levothyroxine 30-60 min before food/coffee; separate Ca/Fe/Mg/soy by ≥4 h.", "separation_hours": 4, "evidence_grade": "A", "contraindications": ["thyroid"], "id": "p111"}, {"members": ["Magnesium glycinate", "Caffeine (standardised)"], "kind": "absorption-conflict", "strength": 2, "goal": "Daytime vs evening separation", "rationale": "Caffeine is renally excreted with small magnesium loss; high caffeine + Mg-deficiency state correlates with worse sleep. Take Mg evening, caffeine morning.", "dose": "Mg evening; caffeine before noon.", "id": "p112"}, {"members": ["Probiotics", "Berberine"], "kind": "absorption-conflict", "strength": 3, "goal": "Avoid antimicrobial blunting of probiotic strains", "rationale": "Berberine has broad-spectrum antimicrobial activity that can reduce probiotic viability when co-administered. Separate dosing windows preserves both effects.", "dose": "Separate by ≥4 hours.", "separation_hours": 4, "id": "p113"}, {"members": ["Probiotics", "Oregano oil (Origanum vulgare)"], "kind": "absorption-conflict", "strength": 3, "goal": "Avoid antimicrobial blunting", "rationale": "Carvacrol/thymol in oregano oil have antibacterial activity against probiotic strains. Separation preserves both.", "dose": "Separate by ≥4 hours.", "separation_hours": 4, "id": "p114"}, {"members": ["Caffeine (standardised)", "L-Theanine"], "kind": "side-effect-offset", "strength": 4, "goal": "Reduce caffeine-induced jitter", "rationale": "L-theanine increases alpha-wave activity and blunts the sympathetic spike from caffeine without reducing the cognitive boost. The 1:2 caffeine:theanine ratio is best-studied.", "dose": "Caffeine 100 mg + L-theanine 200 mg.", "evidence_grade": "B", "id": "p115"}, {"members": ["Caffeine (standardised)", "Ashwagandha (KSM-66)"], "kind": "absorption-conflict", "strength": 2, "goal": "Effect cancellation", "rationale": "Caffeine raises sympathetic tone; ashwagandha lowers it. Co-dosing tends to cancel the calming effect of ashwagandha.", "dose": "If using ashwagandha for stress reduction, take it on the opposite end of the day from caffeine.", "id": "p116"}, {"members": ["Vitamin A (retinol, low-dose)", "Vitamin D3"], "kind": "absorption-conflict", "strength": 2, "goal": "Avoid mutual antagonism at high doses", "rationale": "At extreme doses, retinol and D3 can antagonize each other's nuclear receptor effects. At normal supplemental doses (D3 ≤2,000 IU; retinol ≤3,000 IU), this is rarely clinically meaningful.", "dose": "Avoid simultaneous mega-doses; balanced AD3K formulas are fine.", "id": "p117"}, {"members": ["Iron", "Calcium carbonate/citrate (bone health)"], "kind": "absorption-conflict", "strength": 5, "goal": "Iron deficit recovery while on bone protocol", "rationale": "Bone-protocol calcium doses (1,000+ mg/day) heavily blunt iron absorption. Heavy menstruating women on calcium often present with iron deficiency despite oral iron.", "dose": "Iron AM, fasting; calcium with lunch/dinner; separate by ≥4h.", "separation_hours": 4, "id": "p118"}, {"members": ["Probiotics", "Caffeine (standardised)"], "kind": "absorption-conflict", "strength": 1, "goal": "Avoid heat-killed strains", "rationale": "Hot beverages (≥50°C) directly damage non-spore probiotic strains. Take with cool/room-temp water.", "dose": "Don't swallow probiotics with hot coffee/tea.", "id": "p119"}, {"members": ["Melatonin (0.1-0.5 mg physiological dose)", "Caffeine (standardised)"], "kind": "absorption-conflict", "strength": 4, "goal": "Sleep onset", "rationale": "Caffeine half-life is 5-7 hours; even afternoon coffee blunts melatonin's sleep-onset effect. Last caffeine should be ~8 hours before intended sleep.", "dose": "Caffeine cutoff 14:00 if sleeping by 22:00.", "separation_hours": 8, "evidence_grade": "A", "id": "p120"}, {"members": ["Zinc", "Coffee (tannins)"], "kind": "absorption-conflict", "strength": 3, "goal": "Avoid tannin chelation", "rationale": "Tea and coffee tannins reduce zinc absorption by ~30-50% when co-consumed. Less severe than the iron interaction but real.", "dose": "Separate zinc from coffee/tea by ≥1 hour.", "separation_hours": 1, "id": "p121"}, {"members": ["Whey protein", "Inulin / FOS (prebiotic fibre)"], "kind": "absorption-conflict", "strength": 2, "goal": "Slowed protein absorption (intentional vs unintentional)", "rationale": "Soluble fibre slows gastric emptying. For overnight casein-style sustained release this is fine; for fast post-workout absorption, separate them.", "dose": "If post-workout fast absorption is the goal, take whey alone; otherwise co-dosing is fine.", "id": "p122"}, {"members": ["Bisphosphonates substrate pairings (separate)", "Calcium", "Iron", "Magnesium", "Multivitamins (healthy adults)"], "kind": "absorption-conflict", "strength": 5, "goal": "Bisphosphonate absorption (oral)", "rationale": "Oral bisphosphonates have <1% bioavailability and any mineral or food blocks them entirely. Take FIRST THING with plain water; no supplements/food/coffee for 30-60 min.", "dose": "Bisphosphonate FIRST THING with water; supplements ≥60 min later.", "separation_hours": 1, "evidence_grade": "A", "contraindications": ["bisphosphonate"], "id": "p123"}, {"members": ["Saw palmetto (Serenoa repens)", "Iron"], "kind": "absorption-conflict", "strength": 1, "goal": "Avoid GI upset", "rationale": "Both can cause mild GI upset; co-dosing on empty stomach amplifies it. Take with food or separate.", "dose": "Take with food.", "id": "p124"}, {"members": ["Berberine", "Probiotics"], "kind": "absorption-conflict", "strength": 3, "goal": "Preserve probiotic viability", "rationale": "Same as berberine + probiotics caution above; separation by ≥4h preserves both effects.", "dose": "Separate by ≥4 hours.", "separation_hours": 4, "id": "p125"}, {"members": ["Methylcobalamin (high-dose neurological)", "Vitamin C (megadose)"], "kind": "absorption-conflict", "strength": 1, "goal": "Avoid B12 oxidation", "rationale": "Mega-doses of vitamin C can degrade B12 in vitro; in practice, in-vivo effect at typical supplement doses is small.", "dose": "Separate B12 from mega-dose vitamin C by ≥1 hour.", "id": "p126"}, {"members": ["Lutein + Zeaxanthin", "High-fat meal"], "kind": "absorption-enhancer", "strength": 4, "goal": "Carotenoid absorption", "rationale": "Lutein and zeaxanthin are fat-soluble; absorption is 3-5× higher when co-ingested with fat (≥10 g).", "dose": "Take with breakfast containing eggs/avocado/nuts.", "id": "p127"}, {"members": ["Omega-3 (high dose)", "Ginkgo biloba", "Aged garlic extract (Kyolic)", "Vitamin E (mixed tocopherols)", "Nattokinase"], "kind": "risk-additive", "strength": 5, "goal": "Bleeding risk additive — AVOID stacking", "rationale": "Each item has antiplatelet or fibrinolytic activity at supplement doses. Stacking 3+ adds clinically meaningful bleeding risk; combined with anticoagulants, risk becomes serious.", "dose": "Limit to 1-2 of these at a time; flag any to anticoagulation clinic.", "evidence_grade": "B", "contraindications": ["warfarin", "doac", "antiplatelet", "heparin_lmwh"], "id": "p128"}, {"members": ["Kava (high-dose/extract)", "Green tea extract (EGCG)", "Niacin (Vitamin B3)"], "kind": "risk-additive", "strength": 5, "goal": "Hepatotoxic risk additive — AVOID stacking", "rationale": "Each can cause idiosyncratic hepatotoxicity. Stacking 2+ multiplies risk. Add alcohol or acetaminophen and risk increases further.", "dose": "Avoid combining; rotate or eliminate.", "evidence_grade": "B", "id": "p129"}, {"members": ["5-HTP", "S-Adenosylmethionine (SAMe)", "Saffron (Crocus sativus)", "St. John's Wort"], "kind": "risk-additive", "strength": 5, "goal": "Serotonin syndrome risk — AVOID stacking, AVOID with serotonergic Rx", "rationale": "Each raises serotonin via different mechanisms. Stacking elevates risk; co-administration with SSRI/SNRI/MAOI is dangerous.", "dose": "Use one at a time; never combine with serotonergic prescription drugs.", "evidence_grade": "A", "contraindications": ["ssri", "maoi", "tricyclic", "atypical_antidep"], "id": "p130"}, {"members": ["Berberine", "Alpha-Lipoic Acid (ALA)", "Chromium picolinate", "Cinnamon extract (Ceylon)"], "kind": "risk-additive", "strength": 4, "goal": "Hypoglycemia-additive — caution in diabetics", "rationale": "Each has modest glucose-lowering effects. Stacking + insulin/sulfonylurea can cause hypoglycemia. Otherwise safe when stacked in non-diabetic prediabetes contexts under monitoring.", "dose": "If on insulin/sulfonylurea, monitor glucose closely when adding any of these.", "contraindications": ["diabetes"], "id": "p131"}, {"members": ["Hibiscus sabdariffa", "Olive leaf extract", "Magnesium", "Taurine", "Dietary Nitrate / Beetroot"], "kind": "risk-additive", "strength": 3, "goal": "Hypotension-additive — caution on antihypertensives", "rationale": "Each has mild BP-lowering effect. Stacking 3+ can produce additive hypotension, especially in those already on antihypertensives.", "dose": "Monitor BP; reduce antihypertensive dose only under prescriber guidance.", "contraindications": ["bp", "ace_arb", "ccb", "beta_blocker", "diuretic"], "id": "p132"}, {"members": ["Kava (high-dose/extract)", "Valerian root", "GABA (standalone supplement)", "Glycine", "Melatonin"], "kind": "risk-additive", "strength": 4, "goal": "CNS depression additive — caution in OSA, on benzo/opioids", "rationale": "Sedating supplements stack additively. Combined with benzodiazepines, opioids, alcohol, or untreated sleep apnea, the additive effect can be dangerous.", "dose": "Avoid combining sedating supplements with sedating prescription drugs or alcohol.", "contraindications": ["benzo", "opioid", "sleep_rx", "gabapentinoid"], "id": "p133"}, {"members": ["Caffeine (standardised)", "Yohimbe bark (Pausinystalia yohimbe)", "Bitter orange (Citrus aurantium)", "Theacrine (TeaCrine)"], "kind": "risk-additive", "strength": 5, "goal": "Sympathomimetic additive — AVOID in CV disease, AFib", "rationale": "Each raises heart rate / BP / sympathetic tone via different mechanisms. Stacking causes palpitations, hypertension, and (in vulnerable individuals) arrhythmia.", "dose": "Avoid combining; especially avoid in CVD, AFib, hypertension, anxiety disorders.", "evidence_grade": "B", "contraindications": ["bp", "atrial_fibrillation", "ssri", "maoi"], "id": "p134"}, {"members": ["Soy isoflavones", "Red clover (Trifolium pratense)", "DIM (Diindolylmethane)", "Black cohosh (Cimicifuga racemosa)"], "kind": "risk-additive", "strength": 3, "goal": "Estrogenic additive — caution in oestrogen-sensitive cancers", "rationale": "Phyto-oestrogenic supplements stack. Useful in symptomatic perimenopause; risky in oestrogen-receptor-positive breast cancer history. DIM is anti-oestrogenic but in the same hormonal pathway.", "dose": "Discuss with oncologist if any history of ER+ breast cancer.", "contraindications": ["tamoxifen", "ai_aromatase"], "id": "p135"}, {"members": ["Saw palmetto (Serenoa repens)", "Pygeum africanum", "Beta-sitosterol", "Pumpkin seed oil"], "kind": "goal-stack", "strength": 4, "goal": "BPH symptom relief — additive for symptom control", "rationale": "Each has small but real effect on urinary symptoms via 5-alpha reductase / inflammatory pathways. Stacking improves symptom score modestly but does NOT replace 5-ARI prescription drugs in moderate-severe BPH.", "dose": "Saw palmetto 320 mg + Beta-sitosterol 60-130 mg + Pygeum 100 mg + Pumpkin seed oil 320 mg, daily.", "id": "p136"}, {"members": ["NAC (N-Acetyl Cysteine)", "Glycine", "Vitamin C (moderate dose)"], "kind": "goal-stack", "strength": 4, "goal": "Glutathione recovery (oxidative stress / older adults)", "rationale": "NAC + glycine give substrate; vitamin C recycles oxidized glutathione (GSSG → GSH). The triad is more effective than NAC alone for raising tissue glutathione.", "dose": "NAC 600-1,200 mg + Glycine 3-5 g + Vitamin C 500 mg, divided BID.", "id": "p137"}, {"id": "p138", "members": ["Bifidobacterium infantis EVC001", "Probiotics"], "kind": "redundancy", "strength": 2, "goal": "Avoid overlap with broad multi-strain probiotic blends", "rationale": "EVC001 is a specific HMO-utilising strain for breast-fed infants; many infant probiotic blends overlap on Bifidobacterium spp. but lack HMO-cleavage activity, so combining can be redundant without added benefit.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["31474262"]}, {"id": "p139", "members": ["Bifidobacterium infantis EVC001", "Acacia fiber (prebiotic)"], "kind": "synergy", "strength": 3, "goal": "Prebiotic substrate (post-weaning bridge)", "rationale": "After breastfeeding ends, HMO substrate is lost; soluble prebiotic fibre helps maintain Bifidobacterium-favourable luminal environment via short-chain fatty acid production.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["29951588"]}, {"id": "p140", "members": ["Acacia fiber (prebiotic)", "Probiotics"], "kind": "synergy", "strength": 4, "goal": "Synbiotic — prebiotic substrate for Bifidobacterium/Lactobacillus", "rationale": "Acacia gum is selectively fermented by Bifidobacterium and Lactobacillus species, raising counts and SCFA output in human trials.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["18491071"]}, {"id": "p141", "members": ["Acacia fiber (prebiotic)", "Psyllium husk (soluble fibre)"], "kind": "redundancy", "strength": 2, "goal": "Multi-fibre blend overlap", "rationale": "Both are soluble, viscous, fermentable fibres; total daily dose, not stacking, drives the laxation and prebiotic effects.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["28507400"]}, {"id": "p142", "members": ["Acacia fiber (prebiotic)", "Iron"], "kind": "timing-separation", "strength": 3, "goal": "Avoid mineral binding", "rationale": "Soluble fibres can bind divalent cations including iron and reduce absorption when co-ingested at high doses.", "direction": "timing-separation", "confidence": "medium", "evidence_pmids": ["19234945"], "apart_from": ["Iron", "Calcium", "Zinc"]}, {"id": "p143", "members": ["L-Leucine (standalone)", "Vitamin D3"], "kind": "mechanism-complementary", "strength": 4, "goal": "Sarcopenia (older adults)", "rationale": "Leucine-enriched protein + vitamin D improved muscle mass and lower-extremity function in sarcopenic elderly (PROVIDE trial).", "direction": "synergy", "confidence": "high", "evidence_pmids": ["29065859"]}, {"id": "p144", "members": ["L-Leucine (standalone)", "EAAs (Essential amino acids)"], "kind": "redundancy", "strength": 2, "goal": "Avoid double-dosing leucine in EAA blends", "rationale": "Commercial EAA powders already contain 2.5–3 g leucine per serving; standalone leucine on top often pushes intake past diminishing-returns threshold (~3 g).", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["24257722"]}, {"id": "p145", "members": ["Melatonin (0.1-0.5 mg physiological dose)", "Magnesium bisglycinate"], "kind": "synergy", "strength": 3, "goal": "Sleep onset + maintenance", "rationale": "Magnesium glycinate down-regulates NMDA tone and supports GABA-A function; layered with low-dose melatonin to phase-anchor sleep onset.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["23853635"]}, {"id": "p146", "members": ["Melatonin (0.1-0.5 mg physiological dose)", "Melatonin"], "kind": "redundancy", "strength": 3, "goal": "Avoid stacking with standard-dose melatonin", "rationale": "Pharmacological-dose melatonin (1-10 mg) and the physiological 0.1-0.5 mg dose target the same MT1/MT2 receptors; combining gives no additional sleep benefit and may worsen morning grogginess.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["28503116"]}, {"id": "p147", "members": ["L-Carnitine", "CoQ10 (Ubiquinol)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Mitochondrial fatty-acid oxidation support", "rationale": "L-carnitine shuttles long-chain fatty acids into mitochondria; CoQ10 sustains electron-transport-chain capacity to oxidise them.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["18227072"]}, {"id": "p148", "members": ["L-Carnitine", "Levothyroxine (thyroid hormone)"], "kind": "risk-additive", "strength": 3, "goal": "Carnitine antagonises thyroid hormone action", "rationale": "L-carnitine inhibits thyroid hormone entry into cell nuclei; can blunt levothyroxine effect and is itself used off-label for thyrotoxicosis.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["11713228"], "contraindications": ["levothyroxine"]}, {"id": "p149", "members": ["L-Carnitine"], "kind": "redundancy", "strength": 3, "goal": "Multivitamin/energy-blend overlap", "rationale": "Many 'energy' and weight-loss blends already include carnitine (often as acetyl-L-carnitine); stacking with standalone L-carnitine adds cost without proportional benefit above ~2 g/day.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["20682999"]}, {"id": "p150", "members": ["Citrulline (L-citrulline, pure form)", "L-Arginine"], "kind": "mechanism-complementary", "strength": 3, "goal": "Plasma arginine / NO substrate pool", "rationale": "Oral citrulline raises plasma arginine more efficiently than oral arginine itself by bypassing hepatic first-pass arginase, so co-supplementation lifts NO precursor pool with smaller arginine doses.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["17182482"]}, {"id": "p151", "members": ["Citrulline (L-citrulline, pure form)", "Citrulline malate"], "kind": "redundancy", "strength": 2, "goal": "Same active moiety", "rationale": "Citrulline malate is L-citrulline complexed with malic acid; do not stack — total elemental citrulline is what matters for plasma arginine.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["20386132"]}, {"id": "p152", "members": ["Citrulline (L-citrulline, pure form)", "PDE5"], "kind": "risk-additive", "strength": 3, "goal": "Additive hypotension with PDE5 inhibitors / nitrates", "rationale": "Citrulline raises NO; combination with sildenafil/tadalafil or organic nitrates can lower blood pressure beyond intended targets.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["22050691"], "contraindications": ["nitrates", "PDE5 inhibitors"]}, {"id": "p153", "members": ["Saccharomyces boulardii CNCM I-745", "Antibiotic"], "kind": "synergy", "strength": 5, "goal": "Antibiotic-associated diarrhoea (AAD) prevention", "rationale": "S. boulardii is a yeast and is not killed by antibacterials; co-administration during antibiotic courses reduces AAD and C. difficile recurrence per a Cochrane-level meta-analysis.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["25922896"]}, {"id": "p154", "members": ["Saccharomyces boulardii CNCM I-745", "Saccharomyces boulardii"], "kind": "redundancy", "strength": 4, "goal": "Same organism — different SKUs", "rationale": "CNCM I-745 and generic S. boulardii listings refer to the same Florastor strain or close equivalents; do not double-dose.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["27709480"]}, {"id": "p155", "members": ["Potassium supplementation (clinical)", "Magnesium"], "kind": "cofactor", "strength": 4, "goal": "Magnesium repletion is required to correct hypokalaemia", "rationale": "Intracellular potassium retention depends on Na/K ATPase, which requires magnesium; in Mg-depleted patients, K supplementation alone fails to correct serum K.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["17984161"]}, {"id": "p156", "members": ["Potassium supplementation (clinical)", "ACE inhibitors / ARBs"], "kind": "risk-additive", "strength": 5, "goal": "Hyperkalaemia risk", "rationale": "ACE inhibitors, ARBs, aldosterone antagonists and potassium-sparing diuretics all raise serum K; adding K supplementation can precipitate dangerous hyperkalaemia, especially in CKD.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["19925985"], "contraindications": ["ACE inhibitors", "ARBs", "spironolactone", "eplerenone", "amiloride", "triamterene"]}, {"id": "p157", "members": ["Potassium supplementation (clinical)", "Electrolyte complex (Na/K/Mg)"], "kind": "redundancy", "strength": 3, "goal": "Avoid double-dosing K from electrolyte blends", "rationale": "Clinical K supplementation already targets daily K replacement; co-administering electrolyte powders with substantial K adds to the prescribed dose and increases hyperkalaemia risk.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["19925985"]}, {"id": "p158", "members": ["Protein supplementation (clinical sarcopenia)", "Vitamin D3"], "kind": "mechanism-complementary", "strength": 5, "goal": "Sarcopenia treatment (PROVIDE trial)", "rationale": "Leucine-enriched whey + vitamin D improved muscle mass and chair-rise time in sarcopenic elderly versus iso-caloric control.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["29065859"]}, {"id": "p159", "members": ["Protein supplementation (clinical sarcopenia)", "L-Leucine (standalone)"], "kind": "redundancy", "strength": 3, "goal": "Clinical sarcopenia formulas already leucine-enriched", "rationale": "Most sarcopenia protein products contain 2.5–3 g leucine per serving; adding standalone leucine has diminishing returns once threshold is crossed.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["24257722"]}, {"id": "p160", "members": ["Protein supplementation (clinical sarcopenia)", "Whey protein"], "kind": "redundancy", "strength": 2, "goal": "Same primary substrate", "rationale": "Clinical sarcopenia formulations are typically whey-based with added leucine and vitamin D; stacking with extra whey gives marginal benefit unless protein intake is below target.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["28698222"]}, {"id": "p161", "members": ["Calcium carbonate/citrate (bone health)", "Vitamin D3"], "kind": "mechanism-complementary", "strength": 5, "goal": "Bone health / fracture prevention", "rationale": "Vitamin D upregulates intestinal calcium absorption; calcium + D combined reduces hip-fracture risk in older adults more than either alone.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["17720017"]}, {"id": "p162", "members": ["Calcium carbonate/citrate (bone health)", "Vitamin K2 (MK-7)"], "kind": "mechanism-complementary", "strength": 4, "goal": "Direct calcium into bone, not arteries", "rationale": "K2 activates osteocalcin and matrix-Gla protein, supporting deposition into bone and limiting vascular calcification when calcium intake is high.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["23525894"], "contraindications": ["warfarin (for K2)"]}, {"id": "p163", "members": ["Calcium carbonate/citrate (bone health)", "Levothyroxine (thyroid hormone)"], "kind": "absorption-conflict", "strength": 4, "goal": "Thyroid-hormone absorption", "rationale": "Calcium binds levothyroxine in the gut; separate by 4 h.", "direction": "timing-separation", "confidence": "medium", "evidence_pmids": ["10982317"]}, {"id": "p164", "members": ["Oral rehydration salts (WHO formula)", "Probiotics"], "kind": "synergy", "strength": 4, "goal": "Acute paediatric diarrhoea", "rationale": "Probiotics (S. boulardii, L. rhamnosus GG) shorten diarrhoea duration when added to ORS in acute infectious gastroenteritis.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["21069673"]}, {"id": "p165", "members": ["Oral rehydration salts (WHO formula)", "Lithium"], "kind": "risk-additive", "strength": 4, "goal": "Sodium load alters lithium clearance", "rationale": "Lithium is renally cleared in competition with sodium; abrupt sodium-load changes from ORS can shift serum lithium up or down.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["9430148"], "contraindications": ["lithium"]}, {"id": "p166", "members": ["Oral rehydration salts (WHO formula)", "Electrolyte replacement (clinical)"], "kind": "redundancy", "strength": 3, "goal": "Overlapping electrolyte products", "rationale": "WHO ORS and clinical electrolyte replacement target the same Na/K/glucose rehydration; pick one — do not stack to avoid sodium overdose.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["21069673"]}, {"id": "p167", "members": ["Ferrous bisglycinate (gentle iron)", "Vitamin C (moderate dose)"], "kind": "absorption-enhancer", "strength": 5, "goal": "Maximal non-heme iron absorption", "rationale": "Ascorbate reduces Fe3+ to Fe2+ and chelates it for uptake, raising absorption two-to-threefold.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["15743017"]}, {"id": "p168", "members": ["Ferrous bisglycinate (gentle iron)", "Calcium"], "kind": "absorption-conflict", "strength": 4, "goal": "Mineral absorption competition", "rationale": "Calcium ≥300 mg/dose halves non-heme iron absorption; separate by 2 h.", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["1985396"], "apart_from": ["Calcium", "Zinc"]}, {"id": "p169", "members": ["Ferrous bisglycinate (gentle iron)", "PPI"], "kind": "absorption-conflict", "strength": 4, "goal": "Acid-dependent iron absorption", "rationale": "Proton-pump inhibitors raise gastric pH and reduce non-heme iron solubility and absorption; chronic PPI use is an under-recognised contributor to iron-deficiency anaemia.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["26922476"], "contraindications": ["chronic PPI"]}, {"id": "p170", "members": ["Ferrous bisglycinate (gentle iron)", "Iron"], "kind": "redundancy", "strength": 3, "goal": "Same elemental iron pool", "rationale": "Multivitamins-with-iron and standalone iron supplements overlap; total elemental Fe intake matters more than form for repletion.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["28676671"]}, {"id": "p171", "members": ["Electrolyte replacement (clinical)", "Magnesium"], "kind": "cofactor", "strength": 3, "goal": "Magnesium repletion supports K and Ca homeostasis", "rationale": "Hypomagnesaemia perpetuates hypokalaemia and hypocalcaemia; correcting Mg is required for the other electrolytes to stay corrected.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["17984161"]}, {"id": "p172", "members": ["Electrolyte replacement (clinical)", "ACE inhibitors / ARBs"], "kind": "risk-additive", "strength": 4, "goal": "Hyperkalaemia risk", "rationale": "K-containing electrolyte formulas combined with renin-angiotensin-aldosterone blockade can produce hyperkalaemia, especially in CKD.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["19925985"], "contraindications": ["ACE inhibitors", "ARBs"]}, {"id": "p173", "members": ["Electrolyte replacement (clinical)", "Oral rehydration salts (WHO formula)"], "kind": "redundancy", "strength": 3, "goal": "Avoid double sodium load", "rationale": "WHO ORS and clinical electrolyte mixes overlap on Na, K and glucose; using both can drive serum Na too high in adults.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["21069673"]}, {"id": "p174", "members": ["Psyllium husk (soluble fibre)", "Probiotics"], "kind": "synergy", "strength": 3, "goal": "Synbiotic / SCFA production", "rationale": "Psyllium is partially fermentable and supports SCFA-producing commensals when paired with probiotic strains.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["31091184"]}, {"id": "p175", "members": ["Psyllium husk (soluble fibre)", "Levothyroxine (thyroid hormone)"], "kind": "absorption-conflict", "strength": 4, "goal": "Drug binding by viscous fibre", "rationale": "Psyllium can bind and delay absorption of many oral medications including levothyroxine; separate by ≥2 h.", "direction": "timing-separation", "confidence": "medium", "evidence_pmids": ["17716169"]}, {"id": "p176", "members": ["Psyllium husk (soluble fibre)", "Iron"], "kind": "absorption-conflict", "strength": 3, "goal": "Mineral absorption", "rationale": "Soluble fibres can reduce iron and zinc absorption when co-ingested in large doses; separate by 2 h.", "direction": "timing-separation", "confidence": "medium", "evidence_pmids": ["19234945"], "apart_from": ["Iron", "Zinc", "Calcium"]}, {"id": "p177", "members": ["Psyllium husk (soluble fibre)", "Acacia fiber (prebiotic)"], "kind": "redundancy", "strength": 2, "goal": "Multi-fibre stacking", "rationale": "Both soluble fibres improve laxation and prebiotic effect; total g/day is the active variable rather than stacking.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["28507400"]}, {"id": "p178", "members": ["Magnesium bisglycinate", "Vitamin D3"], "kind": "cofactor", "strength": 4, "goal": "Vitamin D activation requires magnesium", "rationale": "Mg is a cofactor for the enzymes converting 25(OH)D to 1,25(OH)2D and for vitamin-D-binding protein; Mg deficiency blunts response to D3 supplementation.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["29480918"]}, {"id": "p179", "members": ["Magnesium bisglycinate", "Magnesium citrate"], "kind": "redundancy", "strength": 4, "goal": "Same elemental Mg pool", "rationale": "Glycinate and citrate forms differ in tolerability but contribute to the same elemental Mg intake; stacking risks exceeding tolerable upper limit (350 mg/day from supplements).", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["18557994"]}, {"id": "p180", "members": ["Magnesium bisglycinate", "Fluoroquinolone"], "kind": "absorption-conflict", "strength": 5, "goal": "Chelation of antibiotic", "rationale": "Magnesium chelates fluoroquinolones and tetracyclines in the gut, sharply reducing antibiotic absorption; separate by ≥4 h (Mg taken AFTER antibiotic).", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["8517703"], "apart_from": ["fluoroquinolones", "tetracyclines", "bisphosphonates"]}, {"id": "p181", "members": ["Chamomile extract (Matricaria chamomilla)", "L-Theanine"], "kind": "synergy", "strength": 3, "goal": "Calming / pre-sleep stack", "rationale": "Chamomile apigenin partially agonises GABA-A benzodiazepine site; theanine raises alpha-wave activity — non-overlapping calming mechanisms.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["19865069"]}, {"id": "p182", "members": ["Chamomile extract (Matricaria chamomilla)", "Benzodiazepine"], "kind": "risk-additive", "strength": 3, "goal": "Additive CNS depression", "rationale": "Chamomile's GABA-A activity can compound with benzodiazepines and z-drugs, increasing daytime sedation.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["19865069"], "contraindications": ["benzodiazepines", "sleep_rx"]}, {"id": "p183", "members": ["Magnesium citrate", "Vitamin D3"], "kind": "cofactor", "strength": 4, "goal": "Vitamin D activation cofactor", "rationale": "Magnesium is a cofactor for 25-hydroxylase and 1α-hydroxylase; Mg-deficient patients respond less to vitamin D supplementation.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["29480918"]}, {"id": "p184", "members": ["Magnesium citrate", "Magnesium bisglycinate"], "kind": "redundancy", "strength": 4, "goal": "Same elemental Mg pool", "rationale": "Citrate is more laxative-prone, glycinate is gentler; stacking risks exceeding the supplement upper limit and produces additive osmotic diarrhoea.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["18557994"]}, {"id": "p185", "members": ["Magnesium citrate", "Fluoroquinolone"], "kind": "absorption-conflict", "strength": 5, "goal": "Chelation of antibiotics", "rationale": "Citrate-form Mg still chelates fluoroquinolones, tetracyclines and bisphosphonates; separate by ≥4 h.", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["8517703"], "apart_from": ["fluoroquinolones", "tetracyclines", "bisphosphonates"]}, {"id": "p186", "members": ["Saccharomyces boulardii", "Antibiotic"], "kind": "synergy", "strength": 5, "goal": "Antibiotic-associated diarrhoea prevention", "rationale": "S. boulardii is yeast — survives antibacterial exposure; co-administration during antibiotic courses reduces AAD.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["25922896"]}, {"id": "p187", "members": ["Saccharomyces boulardii", "Saccharomyces boulardii CNCM I-745"], "kind": "redundancy", "strength": 4, "goal": "Same organism", "rationale": "Generic S. boulardii listings and CNCM I-745 (Florastor) refer to the same probiotic species; do not double-dose.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["27709480"]}, {"id": "p188", "members": ["Lactobacillus rhamnosus GG", "Antibiotic"], "kind": "absorption-conflict", "strength": 4, "goal": "Antibiotics kill bacterial probiotics", "rationale": "Antibacterials reduce LGG viability if co-ingested; separate by ≥2 h and continue LGG for 1-2 weeks past antibiotic end.", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["28198303"], "apart_from": ["antibiotics"]}, {"id": "p189", "members": ["Lactobacillus rhamnosus GG", "Probiotics"], "kind": "redundancy", "strength": 2, "goal": "Multi-strain probiotic blend overlap", "rationale": "Many multi-strain blends include L. rhamnosus or close LGG analogues; total CFU and strain identity matter for clinical claims.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["31474262"]}, {"id": "p190", "members": ["Electrolyte complex (Na/K/Mg)", "Magnesium"], "kind": "cofactor", "strength": 3, "goal": "Mg supports K and Na ATPase function", "rationale": "Mg is the cofactor for Na/K ATPase; without Mg sufficiency, K supplementation fails to correct serum K.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["17984161"]}, {"id": "p191", "members": ["Electrolyte complex (Na/K/Mg)", "ACE inhibitors / ARBs"], "kind": "risk-additive", "strength": 4, "goal": "Hyperkalaemia risk", "rationale": "K in electrolyte blends adds to the K-retaining effect of RAAS blockade and potassium-sparing diuretics, especially in CKD.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["19925985"], "contraindications": ["ACE inhibitors", "ARBs", "spironolactone"]}, {"id": "p192", "members": ["Electrolyte complex (Na/K/Mg)", "Lithium"], "kind": "risk-additive", "strength": 3, "goal": "Sodium load alters lithium clearance", "rationale": "Lithium and sodium compete at renal tubule; high or variable sodium intake from electrolyte mixes can shift lithium levels.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["9430148"], "contraindications": ["lithium"]}, {"id": "p193", "members": ["Electrolyte complex (Na/K/Mg)", "Potassium supplementation (clinical)"], "kind": "redundancy", "strength": 3, "goal": "Avoid double K load", "rationale": "Stacking clinical K replacement with electrolyte powders containing K can precipitate hyperkalaemia.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["19925985"]}, {"id": "p194", "members": ["Bifidobacterium infantis EVC001", "2'-Fucosyllactose (2'-FL HMO)"], "kind": "synergy", "strength": 4, "goal": "HMO-substrate match for infant gut colonisation", "rationale": "EVC001 expresses a dedicated H1 cluster that cleaves human milk oligosaccharides; 2'-FL is the most abundant HMO and a preferred substrate, supporting persistent colonisation.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["28467287"]}, {"id": "p195", "members": ["Bifidobacterium infantis EVC001", "Antibiotic"], "kind": "absorption-conflict", "strength": 4, "goal": "Preserve probiotic viability during antibiotic course", "rationale": "Broad-spectrum antibiotics inactivate live B. infantis; separating doses by ≥2 hours reduces direct kill and preserves colonisation, mirroring guidance for other gut probiotics.", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["22529959"]}, {"id": "p196", "members": ["Melatonin (0.1-0.5 mg physiological dose)", "Glycine"], "kind": "mechanism-complementary", "strength": 3, "goal": "Sleep onset + slow-wave architecture", "rationale": "Physiologic melatonin shortens sleep latency; glycine 3 g lowers core body temperature and improves subjective sleep quality. Mechanisms are distinct and clinically complementary.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["17198601"]}, {"id": "p197", "members": ["L-Carnitine", "Alpha-Lipoic Acid (ALA)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Mitochondrial bioenergetics in aging", "rationale": "The Ames Lab pairing combines L-carnitine (fatty-acid transport into mitochondria) with alpha-lipoic acid (PDH cofactor / Nrf2 activator). The combination improved mitochondrial function and reduced oxidative damage in aged rats and underpins several geroscience formulations.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["12414737"]}, {"id": "p198", "members": ["L-Carnitine", "Acetyl-L-Carnitine (ALCAR)"], "kind": "redundancy", "strength": 4, "goal": "Same carnitine pool — avoid double dosing", "rationale": "ALCAR and L-carnitine share the same systemic carnitine pool; stacking both at high dose simply elevates the carnitine load. Pick one form for the indication (ALCAR for CNS effects, L-carnitine for cardiac/muscle).", "direction": "redundancy", "confidence": "high", "evidence_pmids": []}, {"id": "p199", "members": ["Saccharomyces boulardii CNCM I-745", "Antifungal"], "kind": "absorption-conflict", "strength": 4, "goal": "Preserve S. boulardii viability around azole/echinocandin dosing", "rationale": "Systemic antifungals (fluconazole, nystatin, amphotericin) are active against S. boulardii in vitro and abolish its protective effect when co-administered. Separate doses by ≥2 hours, and avoid use entirely in patients on long-term systemic antifungal therapy or with central venous catheters.", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["10770730"]}, {"id": "p200", "members": ["Saccharomyces boulardii CNCM I-745", "Oral rehydration salts (WHO formula)"], "kind": "mechanism-complementary", "strength": 4, "goal": "Acute pediatric gastroenteritis — shorten diarrhoea duration", "rationale": "S. boulardii reduces diarrhoea duration by ~24 hours; ORS replaces ongoing fluid/electrolyte losses. ESPGHAN/ESPID guidance supports S. boulardii as an adjunct to rehydration in acute infectious diarrhoea.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["24299826"]}, {"id": "p201", "members": ["Protein supplementation (clinical sarcopenia)", "Creatine monohydrate"], "kind": "mechanism-complementary", "strength": 4, "goal": "Older-adult lean mass and strength with resistance training", "rationale": "Creatine added to a sufficient protein intake further increases lean mass and upper-body strength in older adults performing resistance training compared with protein alone. Effect size is modest but consistent across meta-analyses.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["24576864"]}, {"id": "p202", "members": ["Protein supplementation (clinical sarcopenia)", "HMB (β-Hydroxy-β-methylbutyrate)"], "kind": "redundancy", "strength": 3, "goal": "Leucine metabolite overlap in older adults already meeting protein target", "rationale": "HMB is a leucine metabolite. In patients hitting 1.2-1.5 g/kg/day high-leucine protein, additional HMB shows diminishing returns outside of disuse atrophy or critical illness. Reserve HMB for bedrest or anorexia of aging where intake is inadequate.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["23193624"]}, {"id": "p203", "members": ["Chamomile extract (Matricaria chamomilla)", "SSRI"], "kind": "synergy", "strength": 3, "goal": "Adjunctive anxiolysis in generalised anxiety disorder", "rationale": "Standardised chamomile extract (Matricaria recutita, 1500 mg/day) reduced GAD severity in two University of Pennsylvania RCTs; no pharmacokinetic interaction with SSRIs has been reported, and the combination is commonly used clinically.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["27912875"]}, {"id": "p204", "members": ["Saccharomyces boulardii", "Antifungal"], "kind": "absorption-conflict", "strength": 4, "goal": "Antifungals inactivate the probiotic yeast", "rationale": "Systemic antifungals act on S. boulardii; separate dosing by ≥2 hours and avoid in immunocompromised patients with central lines (fungaemia risk).", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["10770730"]}, {"id": "p205", "members": ["Saccharomyces boulardii", "Oral rehydration salts (WHO formula)"], "kind": "mechanism-complementary", "strength": 4, "goal": "Adjunct to rehydration in acute infectious diarrhoea", "rationale": "Meta-analysis shows S. boulardii shortens acute diarrhoea by ~1 day; ORS remains the primary intervention. The combination is widely used in pediatric care.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["24299826"]}, {"id": "p206", "members": ["Lactobacillus rhamnosus GG", "Oral rehydration salts (WHO formula)"], "kind": "mechanism-complementary", "strength": 4, "goal": "Acute pediatric gastroenteritis adjunct", "rationale": "ESPGHAN positions LGG among the probiotics with evidence to shorten acute infectious diarrhoea by roughly one day when added to standard rehydration.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["25274571"]}, {"id": "p207", "members": ["Potassium citrate", "Magnesium citrate"], "kind": "mechanism-complementary", "strength": 3, "goal": "Calcium oxalate kidney-stone prevention", "rationale": "Both alkalinise urine, increase urinary citrate, and inhibit calcium oxalate crystal formation. AUA stone-prevention guidance acknowledges both as adjuncts when dietary correction is insufficient.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["23643203"]}, {"id": "p208", "members": ["Potassium citrate", "Electrolyte complex (Na/K/Mg)"], "kind": "redundancy", "strength": 4, "goal": "Avoid double potassium load", "rationale": "Many electrolyte powders already contribute 200–600 mg of potassium per serving; layering clinical-dose K-citrate on top can drive serum K out of range.", "direction": "redundancy", "confidence": "high", "evidence_pmids": []}, {"id": "p209", "members": ["Ginger (Zingiber officinale)", "Antiplatelet (aspirin/clopidogrel)"], "kind": "risk-additive", "strength": 3, "goal": "Additive antiplatelet effect", "rationale": "Ginger inhibits cyclo-oxygenase / thromboxane synthesis at high doses; combined chronic use with aspirin or clopidogrel could increase bruising and bleeding times. Effect size is modest at typical culinary doses.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["11354556"]}, {"id": "p210", "members": ["Ginger (Zingiber officinale)", "Vitamin B6 (P5P)"], "kind": "mechanism-complementary", "strength": 4, "goal": "Nausea and vomiting of pregnancy (NVP)", "rationale": "ACOG endorses both ginger 250 mg QID and vitamin B6 (pyridoxine) 10–25 mg TID as first-line non-pharmacological options for NVP. They act via distinct mechanisms and can be combined.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["24102992"]}, {"id": "p211", "members": ["Ginger (Zingiber officinale)", "Curcumin (bioavailable form)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Anti-inflammatory stack for osteoarthritis symptoms", "rationale": "Ginger inhibits COX/LOX pathways; curcumin inhibits NF-κB. Both reduce knee OA pain in meta-analyses; the combination is plausible but head-to-head trial evidence is limited.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["27913739"]}, {"id": "p212", "members": ["Casein protein", "Creatine monohydrate"], "kind": "mechanism-complementary", "strength": 3, "goal": "Resistance-training lean-mass response", "rationale": "Cribb (PMID 16766878) showed greater fat-free mass and strength gains when creatine was co-ingested with a milk protein blend than with protein alone, with casein's slow leucine release pairing well with creatine's phosphagen support.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["16766878"]}, {"id": "p213", "members": ["Casein protein", "Calcium"], "kind": "redundancy", "strength": 3, "goal": "Calcium already present in casein", "rationale": "A 30-g casein serving delivers ~200–300 mg calcium. Layering 1000 mg supplemental calcium on top of high-casein intake can exceed RDA targets and contributes to the vascular-calcification debate; pair with K2 if calcium intake is high.", "direction": "redundancy", "confidence": "high", "evidence_pmids": []}, {"id": "p214", "members": ["Saffron (Crocus sativus)", "Omega-3 (EPA/DHA)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Adjunctive depression support", "rationale": "Both saffron (30 mg/day) and EPA-predominant omega-3 (≥1 g EPA/day) have antidepressant signals in meta-analyses of mild-to-moderate MDD; mechanisms are distinct (serotonergic modulation vs membrane lipid composition / neuroinflammation).", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["31412879"]}, {"id": "p215", "members": ["Saffron (Crocus sativus)", "SSRI"], "kind": "synergy", "strength": 3, "goal": "Adjunctive antidepressant effect in MDD", "rationale": "Saffron 30 mg/day matched fluoxetine 40 mg/day in head-to-head trials and improved sexual-function side effects of SSRIs as adjunct. Watch for serotonin-related symptoms with high-dose serotonergic stacks.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["23280545"]}, {"id": "p216", "members": ["Citrulline malate", "L-Arginine"], "kind": "redundancy", "strength": 4, "goal": "Citrulline more efficiently raises plasma arginine than oral L-arginine", "rationale": "Oral L-arginine is heavily metabolised first-pass; oral citrulline bypasses gut/liver and elevates plasma arginine more reliably. Stacking both is rarely necessary; pick citrulline if NO support is the goal.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["17684207"]}, {"id": "p217", "members": ["Citrulline malate", "Dietary Nitrate / Beetroot"], "kind": "redundancy", "strength": 3, "goal": "Overlapping NO/vasodilation mechanisms", "rationale": "Citrulline raises NO via the arginine/NOS pathway; beetroot raises NO via dietary nitrate / nitrite reduction. Both are ergogenic at similar magnitudes; stacking shows additive effects in some trials but with diminishing returns.", "direction": "redundancy", "confidence": "medium", "evidence_pmids": ["26900538"]}, {"id": "p218", "members": ["Citrulline malate", "PDE5 inhibitor (sildenafil/tadalafil)"], "kind": "risk-additive", "strength": 3, "goal": "Additive vasodilation and hypotension risk", "rationale": "Both raise cGMP-mediated vasodilation; combining 6 g citrulline malate pre-workout with on-demand PDE5 inhibitors may potentiate dizziness, especially with concurrent antihypertensives or nitrates.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["21908956"]}, {"id": "p219", "members": ["Collagen peptides", "Marine collagen (fish-derived)"], "kind": "redundancy", "strength": 4, "goal": "Equivalent amino-acid delivery", "rationale": "Bovine and marine collagen hydrolysates share a near-identical glycine/proline/hydroxyproline profile and comparable plasma di-/tri-peptide kinetics. Stacking both adds cost without unique benefit; pick one based on dietary preference.", "direction": "redundancy", "confidence": "high", "evidence_pmids": []}, {"id": "p220", "members": ["Lactobacillus plantarum 299v", "Iron"], "kind": "mechanism-complementary", "strength": 4, "goal": "Enhance non-heme iron absorption in women", "rationale": "Lp299v co-ingested with a fruit-drink iron source increased non-heme iron absorption by ~50% in women of reproductive age, likely via lactic-acid lowering of luminal pH.", "direction": "synergy", "confidence": "high", "evidence_pmids": ["18937897"]}, {"id": "p221", "members": ["Lactobacillus plantarum 299v", "Antibiotic"], "kind": "absorption-conflict", "strength": 4, "goal": "Separate dosing to preserve viability", "rationale": "Like other lactic-acid bacteria, Lp299v is susceptible to most oral antibiotics; dose ≥2 hours apart and continue for the antibiotic course plus one week.", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["22529959"]}, {"id": "p222", "members": ["Lactobacillus plantarum 299v", "Probiotics"], "kind": "redundancy", "strength": 2, "goal": "Strain overlap with multi-strain blends", "rationale": "Some broad-spectrum probiotic blends already contain L. plantarum strains; check the label to avoid paying for redundant strain mass at sub-clinical CFU counts.", "direction": "redundancy", "confidence": "high", "evidence_pmids": []}, {"id": "p223", "members": ["Lactobacillus plantarum 299v", "Psyllium husk (soluble fibre)"], "kind": "mechanism-complementary", "strength": 3, "goal": "IBS symptom relief — synbiotic", "rationale": "Lp299v showed IBS symptom relief in the Ducrotté RCT; soluble fibre provides fermentable substrate and contributes its own benefit on stool form. Combination is rational for mixed-IBS.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["22652640"]}, {"id": "p224", "members": ["Iberogast (STW 5)", "Peppermint oil (enteric-coated)"], "kind": "redundancy", "strength": 3, "goal": "Overlapping spasmolytic mechanism", "rationale": "Both Iberogast and enteric-coated peppermint oil act as smooth-muscle relaxants for functional dyspepsia and IBS. Combining them adds cost and oesophageal-reflux risk without proven additive benefit.", "direction": "redundancy", "confidence": "high", "evidence_pmids": []}, {"id": "p225", "members": ["Hibiscus sabdariffa", "ACE inhibitor / ARB"], "kind": "risk-additive", "strength": 3, "goal": "Additive BP-lowering", "rationale": "Hibiscus tea lowers SBP by ~7 mmHg in meta-analysis; adding to ACE/ARB therapy may produce symptomatic hypotension or orthostasis, especially in elderly patients.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["25875025"]}, {"id": "p226", "members": ["Hibiscus sabdariffa", "Diuretic"], "kind": "risk-additive", "strength": 3, "goal": "Additive diuresis and BP-lowering", "rationale": "Hibiscus has mild diuretic activity; stacking with hydrochlorothiazide or loop diuretics may compound orthostatic symptoms and electrolyte shifts. Monitor BP and electrolytes during initiation.", "direction": "antagonism", "confidence": "medium", "evidence_pmids": ["25875025"]}, {"id": "p227", "members": ["Hibiscus sabdariffa", "Dietary Nitrate / Beetroot"], "kind": "redundancy", "strength": 2, "goal": "Overlapping antihypertensive effect", "rationale": "Both lower SBP by ~5–8 mmHg via vasodilation pathways; pick one if the goal is BP and avoid layering on top of existing antihypertensive regimen without monitoring.", "direction": "redundancy", "confidence": "high", "evidence_pmids": []}, {"id": "p228", "members": ["EGCG concentrate (decaffeinated green-tea catechin)", "Green tea extract (EGCG)"], "kind": "redundancy", "strength": 4, "goal": "Same active constituent — hepatotoxicity dose risk", "rationale": "Stacking a concentrated decaf EGCG product with standard green tea extract drives EGCG exposure past the EFSA 800 mg/day no-observed-adverse-effect threshold, compounding idiosyncratic hepatotoxicity risk.", "direction": "redundancy", "confidence": "high", "evidence_pmids": ["32624662"]}, {"id": "p229", "members": ["EGCG concentrate (decaffeinated green-tea catechin)", "Iron"], "kind": "absorption-conflict", "strength": 3, "goal": "Catechins chelate non-heme iron", "rationale": "EGCG and other green-tea catechins reduce non-heme iron absorption by up to 70%. In iron-deficiency anaemia, separate EGCG and iron supplements by ≥2 hours.", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["19594223"]}, {"id": "p230", "members": ["EGCG concentrate (decaffeinated green-tea catechin)", "Beta-blocker"], "kind": "absorption-conflict", "strength": 3, "goal": "Reduces nadolol absorption via OATP1A2 inhibition", "rationale": "Green tea catechins inhibit intestinal OATP1A2 and lower nadolol Cmax by ~85%. Separate dosing or choose a beta-blocker not dependent on OATP1A2 (e.g., bisoprolol, metoprolol).", "direction": "timing-separation", "confidence": "high", "evidence_pmids": ["19185546"]}, {"id": "p231", "members": ["Sulforaphane (broccoli isothiocyanate)", "NAC (N-Acetyl Cysteine)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Glutathione support via Nrf2 + cysteine substrate", "rationale": "Sulforaphane activates the Nrf2/Keap1 pathway driving GSH-synthesising enzymes; NAC provides the rate-limiting cysteine. The combination raises GSH more than either alone in cell-line and small clinical studies.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["33272091"]}, {"id": "p232", "members": ["Sulforaphane (broccoli isothiocyanate)", "Curcumin (bioavailable form)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Nrf2 + NF-κB modulation stack", "rationale": "Sulforaphane activates Nrf2; curcumin both activates Nrf2 and inhibits NF-κB. The pair is widely used in chemoprevention research with consistent additive effects on phase II enzyme induction.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["22001305"]}, {"id": "p233", "members": ["Eggshell membrane (NEM)", "Glucosamine / Chondroitin"], "kind": "mechanism-complementary", "strength": 3, "goal": "Joint pain — complementary matrix supports", "rationale": "NEM (500 mg/day) reduces joint pain and stiffness within 7–30 days in OA RCTs; glucosamine/chondroitin act on cartilage matrix metabolism over longer horizons. The pair is rational for new-onset OA.", "direction": "synergy", "confidence": "medium", "evidence_pmids": ["19568322"]}, {"id": "p234", "members": ["Chamomile extract (Matricaria chamomilla)", "Lemon balm (Melissa officinalis)"], "kind": "mechanism-complementary", "strength": 3, "goal": "Mild anxiolysis and sleep onset", "rationale": "Both modulate GABA-A receptors; combined use in traditional formulas for sleep/anxiety relies on additive sedative/anxiolytic effects with low side-effect burden.", "direction": "synergy", "confidence": "high"}, {"id": "p235", "members": ["Chamomile extract (Matricaria chamomilla)", "Magnesium glycinate"], "kind": "mechanism-complementary", "strength": 3, "goal": "Sleep onset / relaxation stack", "rationale": "Magnesium (NMDA antagonism + GABA-A potentiation) plus apigenin from chamomile (GABA-A binding) is a common bedtime stack; mechanisms are complementary, not overlapping.", "direction": "synergy", "confidence": "high"}, {"id": "p236", "members": ["Chamomile extract (Matricaria chamomilla)", "Multivitamins (healthy adults)"], "kind": "redundancy", "strength": 2, "goal": "Avoid overlap in sleep/anxiety blends", "rationale": "Many \"calm\" or \"sleep\" multi-herb blends already include chamomile extract; check label to avoid double-dosing apigenin.", "direction": "redundancy", "confidence": "high"}, {"id": "p237", "members": ["Potassium citrate", "Calcium carbonate/citrate (bone health)"], "kind": "redundancy", "strength": 2, "goal": "Avoid citrate overload in stone-prevention stacks", "rationale": "When stacking calcium citrate with potassium citrate the citrate component is additive; both raise urinary citrate. Count total citrate load to avoid overshooting alkalinization in stone-prevention stacks.", "direction": "redundancy", "confidence": "high"}, {"id": "p238", "members": ["Potassium citrate", "Oral rehydration salts (WHO formula)"], "kind": "redundancy", "strength": 3, "goal": "Avoid potassium overdose in rehydration stacks", "rationale": "WHO ORS already provides potassium; stacking with potassium citrate can overshoot K intake, especially in CKD or with K-sparing drugs.", "direction": "redundancy", "confidence": "high"}, {"id": "p239", "members": ["Ginger (Zingiber officinale)", "Multivitamins (healthy adults)"], "kind": "redundancy", "strength": 2, "goal": "Avoid overlap in digestive multi-blends", "rationale": "Some \"digestive\" or \"immune\" multi-herb blends include ginger extract; check label before adding standalone ginger to avoid stacking.", "direction": "redundancy", "confidence": "high"}, {"id": "p240", "members": ["Collagen peptides", "Glycine"], "kind": "redundancy", "strength": 3, "goal": "Avoid double-counting glycine", "rationale": "Collagen is ~22% glycine by weight; a 10 g collagen dose already provides ~2.2 g glycine, overlapping with glycine sleep dosing — count both.", "direction": "redundancy", "confidence": "high"}, {"id": "p241", "members": ["Iberogast (STW 5)", "Chamomile extract (Matricaria chamomilla)"], "kind": "redundancy", "strength": 3, "goal": "Avoid component-stacking with multi-herb formulas", "rationale": "Iberogast already contains chamomile (Matricaria recutita) as one of its 9 herbs; standalone chamomile stacked on top is redundant and increases hepatotoxicity-monitoring burden.", "direction": "redundancy", "confidence": "high"}, {"id": "p242", "members": ["EGCG concentrate (decaffeinated green-tea catechin)", "Multivitamins (healthy adults)"], "kind": "redundancy", "strength": 4, "goal": "Avoid total EGCG > 800 mg/day (EFSA flag)", "rationale": "Many \"antioxidant\" or \"metabolism\" blends contain green-tea extract; combining with standalone EGCG concentrate raises the catechin dose into the hepatotoxicity-flagged range (EFSA: >800 mg EGCG/day).", "direction": "redundancy", "confidence": "high"}, {"id": "p243", "members": ["Sulforaphane (broccoli isothiocyanate)", "Broccoli sprout extract (BroccoMax / Avmacol)"], "kind": "redundancy", "strength": 3, "goal": "Avoid double-counting sulforaphane", "rationale": "Broccoli sprout extract already supplies sulforaphane (and the myrosinase enzyme needed to release it from glucoraphanin). Standalone sulforaphane on top of a sprout extract is duplicative.", "direction": "redundancy", "confidence": "high"}, {"id": "p244", "members": ["Eggshell membrane (NEM)", "Multivitamins (healthy adults)"], "kind": "redundancy", "strength": 2, "goal": "Avoid overlap in joint-stack blends", "rationale": "NEM appears in many \"joint support\" formulas alongside glucosamine/chondroitin; check label before adding standalone NEM.", "direction": "redundancy", "confidence": "high"}, {"id": "p245", "members": ["Phytosterols (beta-sitosterol complex)", "Red yeast rice"], "kind": "mechanism-complementary", "strength": 4, "goal": "LDL reduction — dual-mechanism stack", "rationale": "Phytosterols block intestinal cholesterol absorption; monacolin K (red yeast rice) inhibits hepatic HMG-CoA reductase. Mechanisms are complementary in LDL lowering — classic dual-pathway stack.", "direction": "synergy", "confidence": "high"}, {"id": "p246", "members": ["Phytosterols (beta-sitosterol complex)", "Multivitamins (healthy adults)"], "kind": "redundancy", "strength": 3, "goal": "Avoid phytosterol > 3 g/day plateau", "rationale": "Functional foods (margarines, yogurts) and several cardiovascular blends already contain 1-3 g phytosterols; double-dosing past ~3 g/day shows no added LDL benefit and worsens carotenoid depletion.", "direction": "redundancy", "confidence": "high"}, {"id": "p247", "members": ["Fenugreek seed extract (Testofen / standardised)", "Multivitamins (healthy adults)"], "kind": "redundancy", "strength": 2, "goal": "Avoid overlap in male-vitality blends", "rationale": "Many male-vitality blends already contain standardized fenugreek; verify label before adding standalone Testofen.", "direction": "redundancy", "confidence": "high"}, {"id": "p248", "members": ["Fenugreek seed extract (Testofen / standardised)", "Iron"], "kind": "timing-separation", "strength": 3, "goal": "Preserve iron absorption", "rationale": "Fenugreek is high in mucilaginous fiber and tannins that bind dietary iron; separate by ≥2 hours from iron supplementation.", "direction": "timing-separation", "confidence": "high"}, {"id": "p249", "members": ["Chia seed oil", "Flaxseed oil (ALA omega-3)"], "kind": "redundancy", "strength": 3, "goal": "Avoid double ALA dose", "rationale": "Chia seed oil and flaxseed oil are both ALA-dominant omega-3 oils; combining doubles ALA load without adding new fatty acids. Pick one or alternate.", "direction": "redundancy", "confidence": "high"}, {"id": "p250", "members": ["Chia seed oil", "Vitamin E (mixed tocopherols)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Oxidation protection for PUFA stack", "rationale": "Vitamin E protects PUFAs from peroxidation; small amounts (~5-15 IU per gram PUFA) preserve ALA integrity in vivo and in supplement form.", "direction": "synergy", "confidence": "high"}, {"id": "p251", "members": ["Chia seed oil", "Algal oil (vegan DHA/EPA)"], "kind": "mechanism-complementary", "strength": 4, "goal": "Complete vegan omega-3 coverage", "rationale": "Chia ALA conversion to EPA/DHA in humans is ~5-10%; algal EPA/DHA bypasses the conversion bottleneck. Combining gives complete omega-3 spectrum for vegans.", "direction": "synergy", "confidence": "high"}, {"id": "p252", "members": ["Algal oil (vegan DHA/EPA)", "Omega-3 (EPA/DHA)"], "kind": "redundancy", "strength": 4, "goal": "Avoid double EPA/DHA dose", "rationale": "Both supply EPA/DHA; algal oil is the vegan substitute for fish oil. Combining them is duplicative — choose one source.", "direction": "redundancy", "confidence": "high"}, {"id": "p253", "members": ["Algal oil (vegan DHA/EPA)", "Vitamin E (mixed tocopherols)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Oxidation protection", "rationale": "EPA/DHA are oxidation-prone; mixed tocopherols protect against peroxidation in capsule and in vivo.", "direction": "synergy", "confidence": "high"}, {"id": "p254", "members": ["Algal oil (vegan DHA/EPA)", "DHA (standalone, algal)"], "kind": "redundancy", "strength": 3, "goal": "Avoid duplicating algal DHA", "rationale": "Algal \"DHA standalone\" is the same source as full-spectrum algal oil minus EPA; combining a DHA-only product on top of a mixed algal oil double-doses DHA.", "direction": "redundancy", "confidence": "high"}, {"id": "p255", "members": ["Perilla oil", "Flaxseed oil (ALA omega-3)"], "kind": "redundancy", "strength": 3, "goal": "Avoid double ALA dose", "rationale": "Perilla and flaxseed oils are both ALA-dominant (~55-65% ALA); combining doubles ALA without new fatty acids.", "direction": "redundancy", "confidence": "high"}, {"id": "p256", "members": ["Perilla oil", "Perilla seed oil"], "kind": "redundancy", "strength": 4, "goal": "Naming-variant overlap", "rationale": "\"Perilla oil\" and \"Perilla seed oil\" are common naming variants for the same source (Perilla frutescens seed oil). Same product, do not double-dose.", "direction": "redundancy", "confidence": "high"}, {"id": "p257", "members": ["Perilla oil", "Vitamin E (mixed tocopherols)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Oxidation protection", "rationale": "Tocopherols protect ALA against peroxidation; oils stored without vitamin E lose omega-3 content faster.", "direction": "synergy", "confidence": "high"}, {"id": "p258", "members": ["Sacha inchi oil (Plukenetia volubilis)", "Flaxseed oil (ALA omega-3)"], "kind": "redundancy", "strength": 3, "goal": "Avoid double ALA dose", "rationale": "Sacha inchi (~48% ALA) and flaxseed oil are both ALA-dominant plant oils; combining is redundant.", "direction": "redundancy", "confidence": "high"}, {"id": "p259", "members": ["Sacha inchi oil (Plukenetia volubilis)", "Algal oil (vegan DHA/EPA)"], "kind": "mechanism-complementary", "strength": 4, "goal": "Complete vegan omega-3 coverage", "rationale": "Sacha inchi supplies ALA only; algal oil supplies preformed EPA/DHA. Combined gives full omega-3 chain for vegans.", "direction": "synergy", "confidence": "high"}, {"id": "p260", "members": ["Sacha inchi oil (Plukenetia volubilis)", "Vitamin E (mixed tocopherols)"], "kind": "mechanism-complementary", "strength": 2, "goal": "Oxidation protection", "rationale": "Tocopherols protect ALA from oxidation; small additions stabilize potency.", "direction": "synergy", "confidence": "high"}, {"id": "p261", "members": ["Zinc gluconate", "Zinc"], "kind": "redundancy", "strength": 4, "goal": "Avoid double elemental Zn", "rationale": "Zinc gluconate is a specific form of zinc; combining with another zinc form (picolinate, bisglycinate) double-doses elemental zinc.", "direction": "redundancy", "confidence": "high"}, {"id": "p262", "members": ["Zinc gluconate", "Copper (as glycinate)"], "kind": "depletion-offset", "strength": 4, "goal": "Prevent Zn-induced Cu deficiency", "rationale": "Long-term zinc >25 mg/day induces metallothionein and depletes copper; co-supplementation prevents Zn-induced copper deficiency.", "direction": "synergy", "confidence": "high"}, {"id": "p263", "members": ["Zinc gluconate", "Iron"], "kind": "timing-separation", "strength": 4, "goal": "Avoid Zn/Fe absorption competition", "rationale": "Zinc and iron compete for divalent metal transporter 1 (DMT-1); separate by ≥2 hours.", "direction": "timing-separation", "confidence": "high"}, {"id": "p264", "members": ["Zinc gluconate", "Calcium"], "kind": "timing-separation", "strength": 3, "goal": "Preserve Zn absorption", "rationale": "Calcium >300 mg per meal reduces zinc absorption ~30%; separate doses by ≥2 hours.", "direction": "timing-separation", "confidence": "high"}, {"id": "p265", "members": ["Zinc bisglycinate", "Zinc"], "kind": "redundancy", "strength": 4, "goal": "Avoid double elemental Zn", "rationale": "Zinc bisglycinate is a specific chelated zinc form; combining with other zinc forms double-doses elemental zinc.", "direction": "redundancy", "confidence": "high"}, {"id": "p266", "members": ["Zinc bisglycinate", "Copper (as glycinate)"], "kind": "depletion-offset", "strength": 4, "goal": "Prevent Zn-induced Cu deficiency", "rationale": "Chronic zinc supplementation depletes copper via metallothionein induction; co-pairing is the standard offset.", "direction": "synergy", "confidence": "high"}, {"id": "p267", "members": ["Zinc bisglycinate", "Iron"], "kind": "timing-separation", "strength": 4, "goal": "Avoid Zn/Fe competition", "rationale": "Zinc and iron compete for DMT-1 absorption; separate by ≥2 hours.", "direction": "timing-separation", "confidence": "high"}, {"id": "p268", "members": ["Zinc bisglycinate", "Multivitamins (healthy adults)"], "kind": "redundancy", "strength": 3, "goal": "Avoid > 40 mg total Zn (UL)", "rationale": "Most multivitamins supply 8-15 mg zinc; adding standalone bisglycinate can push past the 40 mg UL when combined.", "direction": "redundancy", "confidence": "high"}, {"id": "p269", "members": ["Bacillus clausii", "Antibiotics"], "kind": "timing-separation", "strength": 3, "goal": "Antibiotic-associated diarrhea protocol", "rationale": "B. clausii is one of the few probiotics with documented antibiotic-resistance enabling co-administration, but for non-resistant strains a 2-hour separation is the conservative default.", "direction": "timing-separation", "confidence": "high"}, {"id": "p270", "members": ["Bacillus subtilis (spore probiotic)", "Antibiotics"], "kind": "timing-separation", "strength": 3, "goal": "Probiotic + antibiotic timing", "rationale": "Spore probiotics survive antibiotic exposure better than vegetative strains, but a 2-hour separation is the conservative default to preserve colony delivery.", "direction": "timing-separation", "confidence": "high"}, {"id": "p271", "members": ["DMG (Dimethylglycine)", "Trimethylglycine (TMG / betaine anhydrous)"], "kind": "redundancy", "strength": 4, "goal": "Avoid stacking methyl-donor metabolites", "rationale": "TMG → DMG is the methyl-donation reaction; supplementing both does not add a methyl donor — TMG already produces DMG as a downstream metabolite.", "direction": "redundancy", "confidence": "high"}];