{
  "_meta": {
    "generated": "2026-04-23",
    "last_reviewed": "2026-05-11 (weekly pairing-coverage refresh \u2014 appended 56 entries; auto-apply mode)",
    "source": "data.js (733 supplements; mod date 2026-04-24, no net add/remove vs prior 733 count)",
    "schema_version": "1.3",
    "notes": "Each pairing references supplement `n` (name) strings as they appear in `data.js`. `kind` describes WHY the pair belongs together; `strength` is 1-5 (5 = mandatory for the effect, 1 = speculative). `apart_from` lists things the supplement competes with for absorption.",
    "changelog": [
      "v1.3 (2026-05-01): Full-database audit. Renamed 30 orphan member references to canonical supplement names; added 25 new pairings covering methylation, mineral interactions, sleep stack, BP/glucose synergies, depression adjuncts, and absorption boosters.",
      "v1.1 (2026-04-23 PM): Added 25 additional pairings (p31-p55) surfaced from a complete re-read of data.js prose. All existing pairings (p1-p30) remain unchanged.",
      "v1.2 (2026-04-25): Added 7 additional pairings (p56-p62) surfaced from data.js entries modified 2026-04-24 \u2014 chiefly explicit stack entries (Adaptogen stack, HA+Chondroitin stack), prose synergies (Casein vs Whey timing, Theacrine+Caffeine, Beta-alanine+Creatine, Proline+C+Glycine), and the Dan Shen/Sanqi TCM pair. Existing p1-p55 unchanged.",
      "v1.4 (2026-05-11): Weekly pairing-coverage refresh \u2014 appended 56 entries (p138-p193) covering thin-coverage Tier-1 supplements. Auto-apply mode for medium/high confidence with PMIDs; Tier-1 supp-Rx high antagonisms escalated to human review."
    ]
  },
  "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 (\u03b2-Hydroxy-\u03b2-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 \u2014 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 \u2014 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 \u2014 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 \u2014 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 \u2014 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 \u2014 ideal post-workout to drive an acute MPS response. Casein clots in the stomach and releases amino acids slowly over ~7 h \u2014 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 \u2014 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 \u2014 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 \u22652 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\u00d7/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 \u2014 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 \u22652 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\u00d7/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+ \u2192 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 \u22651,000 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 \u226525 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\u00d7. 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\u2192T3 and for glutathione-peroxidase that protects the thyroid from peroxide damage.",
      "dose": "Iodine \u2264150 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 \u2264500 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 = \u03b3-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 \u03b2-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 \u22653 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 \u22652 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 \u22652 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 \u2265500 mg, calcium and magnesium compete for absorption transporters. Smaller doses (\u2264250 mg each) co-administered are less affected.",
      "dose": "Separate doses \u22651,000 mg by \u22652 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 \u22651 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 (\u22651 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 \u22651 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 \u2014 supplement timing",
      "rationale": "Levothyroxine absorption is blunted by minerals (Ca, Fe, Mg, Al), soy, fiber, and coffee. Separate by \u22654 hours from any of these.",
      "dose": "Take levothyroxine 30-60 min before food/coffee; separate Ca/Fe/Mg/soy by \u22654 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 \u22654 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 \u22654 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 \u22642,000 IU; retinol \u22643,000 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 \u22654h.",
      "separation_hours": 4,
      "id": "p118"
    },
    {
      "members": [
        "Probiotics",
        "Caffeine (standardised)"
      ],
      "kind": "absorption-conflict",
      "strength": 1,
      "goal": "Avoid heat-killed strains",
      "rationale": "Hot beverages (\u226550\u00b0C) 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 \u22651 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 \u226560 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 \u22654h preserves both effects.",
      "dose": "Separate by \u22654 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 \u22651 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\u00d7 higher when co-ingested with fat (\u226510 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 \u2014 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 \u2014 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 \u2014 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 \u2014 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 \u2014 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 \u2014 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 \u2014 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 \u2014 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 \u2014 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 \u2192 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 \u2014 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\u20133 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 \u2014 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 \u2014 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\u20133 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 \u2014 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 \u2265300 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 \u22652 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 \u22654 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 \u2014 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 1\u03b1-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 \u22654 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 \u2014 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 \u22652 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"
      ]
    }
  ],
  "medication_depletion_pairings": [
    {
      "med": "Statin",
      "add": [
        "CoQ10 (Ubiquinol)"
      ],
      "reason": "Statins inhibit HMG-CoA reductase (shared with CoQ10 synthesis)"
    },
    {
      "med": "Metformin",
      "add": [
        "Vitamin B12"
      ],
      "reason": "Chronic metformin reduces B12 absorption"
    },
    {
      "med": "PPI (omeprazole / lansoprazole)",
      "add": [
        "Vitamin B12",
        "Magnesium"
      ],
      "reason": "Long-term acid suppression impairs both"
    },
    {
      "med": "Oral contraceptive pill",
      "add": [
        "Folate (5-MTHF)",
        "Vitamin B6 (P5P)"
      ],
      "reason": "OCPs deplete folate and B6"
    },
    {
      "med": "Corticosteroids (long-term)",
      "add": [
        "Calcium",
        "Vitamin D3",
        "Zinc"
      ],
      "reason": "Bone density loss and Zn depletion"
    },
    {
      "med": "Antibiotics",
      "add": [
        "Probiotics"
      ],
      "reason": "Restore gut flora; take 2+ h apart from the antibiotic dose"
    },
    {
      "med": "Anti-seizure (valproate, phenytoin, carbamazepine)",
      "add": [
        "Folate (5-MTHF)",
        "Vitamin D3"
      ],
      "reason": "Hepatic induction depletes both"
    },
    {
      "med": "Loop diuretics (furosemide)",
      "add": [
        "Magnesium",
        "Potassium supplementation (clinical)",
        "Thiamine (Vitamin B1)"
      ],
      "reason": "Loop diuretics increase urinary loss of Mg, K, and thiamine; chronic use causes deficiency."
    },
    {
      "med": "Thiazide diuretics (HCTZ)",
      "add": [
        "Magnesium",
        "Potassium supplementation (clinical)",
        "Zinc"
      ],
      "reason": "Thiazides cause urinary loss of Mg, K, and Zn."
    },
    {
      "med": "ACE inhibitors / ARBs",
      "add": [
        "Zinc"
      ],
      "reason": "Some ACE inhibitors (captopril) increase urinary zinc; chronic use can cause taste disturbance and zinc deficiency."
    },
    {
      "med": "OCPs / Combined oral contraceptives",
      "add": [
        "Vitamin B6 (P5P)",
        "Folate (5-MTHF)",
        "Vitamin B12",
        "Magnesium",
        "Zinc"
      ],
      "reason": "OCPs deplete B6, folate, B12, Mg, Zn \u2014 relevant for both contraceptive use and pre-conception planning when stopping OCPs."
    },
    {
      "med": "Isoniazid (TB therapy)",
      "add": [
        "Vitamin B6 (P5P)"
      ],
      "reason": "Isoniazid is a B6 antagonist; B6 supplementation is standard to prevent peripheral neuropathy."
    },
    {
      "med": "Glucocorticoids (chronic prednisone)",
      "add": [
        "Calcium",
        "Vitamin D3",
        "Magnesium",
        "Vitamin K2 (MK-7)"
      ],
      "reason": "Chronic steroids cause bone loss and Ca/Mg/K losses."
    },
    {
      "med": "Sulfasalazine",
      "add": [
        "Folate (5-MTHF)"
      ],
      "reason": "Sulfasalazine inhibits intestinal folate absorption."
    },
    {
      "med": "Methotrexate",
      "add": [
        "Folate (5-MTHF)"
      ],
      "reason": "Methotrexate is a folate antagonist; daily folate supplementation reduces side effects without blunting therapeutic effect."
    },
    {
      "med": "Long-term PPI (>1 year)",
      "add": [
        "Magnesium",
        "Vitamin B12",
        "Calcium",
        "Iron"
      ],
      "reason": "Acid suppression reduces absorption of B12 (cyanocobalamin form), magnesium, calcium, and non-heme iron."
    },
    {
      "med": "Cholestyramine / bile-acid sequestrants",
      "add": [
        "Vitamin A (retinol, low-dose)",
        "Vitamin D3",
        "Vitamin E (mixed tocopherols)",
        "Vitamin K1 (phylloquinone)"
      ],
      "reason": "Bile-acid sequestrants reduce absorption of fat-soluble vitamins."
    }
  ],
  "avoid_pairings_absorption": [
    {
      "apart_hours": 2,
      "items": [
        "Iron",
        "Calcium",
        "Zinc",
        "Magnesium"
      ],
      "reason": "Divalent cation competition"
    },
    {
      "apart_hours": 2,
      "items": [
        "Iron",
        "tea / coffee / dairy"
      ],
      "reason": "Polyphenols and calcium block Fe absorption"
    },
    {
      "apart_hours": 4,
      "items": [
        "Levothyroxine",
        "Calcium",
        "Iron",
        "Magnesium",
        "Zinc",
        "Iodine"
      ],
      "reason": "Thyroid-hormone absorption is blocked by minerals"
    },
    {
      "apart_hours": 2,
      "items": [
        "Fibre / Psyllium husk",
        "any oral medication"
      ],
      "reason": "Fibre binds drugs in the gut"
    },
    {
      "apart_hours": 2,
      "items": [
        "Probiotics",
        "Antibiotics"
      ],
      "reason": "Antibiotic kills the live culture"
    }
  ],
  "dangerous_pairings": [
    {
      "members": [
        "5-HTP",
        "SSRI/SNRI/MAOI/triptan/tramadol"
      ],
      "risk": "Serotonin syndrome (potentially fatal)"
    },
    {
      "members": [
        "L-Tryptophan",
        "SSRI/SNRI/MAOI"
      ],
      "risk": "Serotonin syndrome"
    },
    {
      "members": [
        "St. John's Wort",
        "SSRI/SNRI/MAOI/oral contraceptive/warfarin/cyclosporine/many others"
      ],
      "risk": "Serotonin syndrome; CYP3A4 induction (drug failure)"
    },
    {
      "members": [
        "SAMe",
        "SSRI/MAOI"
      ],
      "risk": "Serotonin syndrome"
    },
    {
      "members": [
        "Methylene blue (pharmaceutical grade)",
        "SSRI/MAOI"
      ],
      "risk": "Severe serotonin syndrome"
    },
    {
      "members": [
        "Saffron (Crocus sativus) high dose",
        "SSRI/SNRI/MAOI"
      ],
      "risk": "Serotonin syndrome at high doses"
    },
    {
      "members": [
        "Vitamin K2 (MK-7)",
        "Warfarin"
      ],
      "risk": "Direct antagonism of anticoagulation"
    },
    {
      "members": [
        "Ginkgo biloba / Ginger / high-dose Omega-3 / Curcumin / Nattokinase / Lumbrokinase / Dan Shen / Dong quai / Red sage / White willow / Meadowsweet",
        "Warfarin / DOAC / aspirin / NSAID"
      ],
      "risk": "Additive bleeding"
    },
    {
      "members": [
        "Berberine",
        "Insulin / sulfonylurea / other glucose-lowering drugs"
      ],
      "risk": "Hypoglycemia"
    },
    {
      "members": [
        "Berberine",
        "Statin / cyclosporine"
      ],
      "risk": "CYP3A4 inhibition elevates drug levels"
    },
    {
      "members": [
        "Ashwagandha (KSM-66)",
        "Thyroid hormone / benzodiazepines / immunosuppressants"
      ],
      "risk": "Thyroid disruption, excessive sedation, immune counteraction"
    },
    {
      "members": [
        "Kava (high-dose/extract)",
        "Alcohol / acetaminophen / any hepatotoxin"
      ],
      "risk": "Liver failure"
    },
    {
      "members": [
        "Echinacea / Astragalus / Cat's claw / Cycloastragenol",
        "Immunosuppressants"
      ],
      "risk": "Counteracts immunosuppressive therapy (transplant / autoimmune)"
    },
    {
      "members": [
        "Caffeine",
        "Synephrine (bitter orange) / Ephedra analogues / Yohimbine / DMAA / DMHA"
      ],
      "risk": "Cardiac events, stroke, hypertensive crisis"
    },
    {
      "members": [
        "Huperzine A",
        "Donepezil / Rivastigmine / Galantamine"
      ],
      "risk": "Additive cholinesterase inhibition"
    },
    {
      "members": [
        "GHB precursors (1,4-butanediol / GBL)",
        "Alcohol / benzodiazepines / opioids"
      ],
      "risk": "Respiratory depression, coma, death"
    },
    {
      "members": [
        "Methylene blue (oral)",
        "SSRI/SNRI/MAOI/triptan/tramadol"
      ],
      "risk": "Fatal serotonin syndrome \u2014 methylene blue is a potent MAO-A inhibitor; FDA black-box-equivalent warning."
    },
    {
      "members": [
        "Yohimbe bark (Pausinystalia yohimbe)",
        "MAOI"
      ],
      "risk": "Hypertensive crisis; banned combination in psychiatric care."
    },
    {
      "members": [
        "Ephedra analogues (synephrine)",
        "Caffeine (standardised)",
        "Yohimbe bark (Pausinystalia yohimbe)"
      ],
      "risk": "Cardiovascular events including MI, stroke, sudden cardiac death (Ephedra-caffeine combos were banned by FDA in 2004 for this reason)."
    },
    {
      "members": [
        "Phenibut",
        "Alcohol or benzodiazepines"
      ],
      "risk": "Severe CNS depression, respiratory depression, coma. Phenibut also causes withdrawal seizures with abrupt cessation after chronic use."
    },
    {
      "members": [
        "Tianeptine (\"gas station heroin\")",
        "Opioids"
      ],
      "risk": "Respiratory depression, opioid-like withdrawal, addiction; tianeptine has mu-opioid agonism at supra-therapeutic doses sold in supplements."
    },
    {
      "members": [
        "7-Hydroxymitragynine (concentrated kratom alkaloid)",
        "Benzodiazepines or alcohol"
      ],
      "risk": "Mu-opioid + benzodiazepine combination: respiratory depression and overdose."
    },
    {
      "members": [
        "DNP (2,4-Dinitrophenol)",
        "Anything"
      ],
      "risk": "DNP uncouples mitochondrial oxidative phosphorylation; lethal hyperthermia at supra-supplement doses. NOT a supplement; sold illegally for weight loss; multiple confirmed deaths annually."
    },
    {
      "members": [
        "Vitamin K2 (MK-7)",
        "Warfarin"
      ],
      "risk": "Antagonizes warfarin at any meaningful dose; can drop INR rapidly and cause thrombosis. NEVER add or remove without anticoagulation-clinic supervision."
    }
  ]
}