Herb-Drug Interactions: The Critical Reference

The Terrain Between Two Medicines

Functional medicine lives at the intersection of botanical and pharmaceutical worlds. Patients rarely arrive on zero medications, and the practitioner who adds curcumin to a warfarin regimen without understanding CYP450 enzymes is practicing hope, not medicine.

The uncomfortable truth: most herb-drug interactions are poorly studied. We have strong data on a handful of major interactions and largely theoretical concerns for hundreds of others. The clinical challenge is distinguishing genuine danger from overcautious avoidance that denies patients beneficial therapies.

This requires understanding the machinery — how the body processes both drugs and herbs through the same metabolic pathways.

The Metabolic Machinery

CYP450 Enzyme System

The cytochrome P450 (CYP450) family is the liver’s primary drug-metabolizing system. These enzymes, concentrated in hepatocytes, transform lipophilic compounds into water-soluble forms that the kidneys can excrete. About 75% of all pharmaceutical drugs are metabolized by CYP450 enzymes.

The key players:

• CYP3A4: Metabolizes approximately 50% of all drugs. The most clinically significant enzyme for interactions.
• CYP2D6: Metabolizes about 25% of drugs, including many antidepressants, antipsychotics, beta-blockers, and opioids.
• CYP1A2: Metabolizes caffeine, theophylline, clozapine, some SSRIs.
• CYP2C9: Metabolizes warfarin, NSAIDs, sulfonylureas.
• CYP2C19: Metabolizes proton pump inhibitors, clopidogrel, some antidepressants.

An inducer speeds up the enzyme, causing the drug to be metabolized faster — reducing its blood level and therapeutic effect. An inhibitor slows down the enzyme, causing the drug to accumulate — increasing blood levels and side effect/toxicity risk.

Think of it like a highway. An inducer widens the road — drugs move through faster. An inhibitor creates a bottleneck — drugs pile up.

P-glycoprotein (P-gp)

P-glycoprotein is a transmembrane efflux pump, primarily in the gut, liver, kidneys, and blood-brain barrier. It actively pushes substances back out of cells. P-gp inhibition increases drug absorption and tissue penetration. P-gp induction decreases drug bioavailability.

Many compounds that affect CYP3A4 also affect P-gp, creating a double interaction.

Phase II Conjugation

Phase II reactions (glucuronidation, sulfation, methylation, glutathione conjugation) are generally less prone to clinically significant herb-drug interactions but are not immune. Curcumin, for example, inhibits glucuronidation — the same pathway that clears acetaminophen and many hormones.

Major CYP450 Interactions

St. John’s Wort (Hypericum perforatum)

The most dangerous botanical for drug interactions, and the most well-documented. St. John’s Wort is a potent inducer of CYP3A4, CYP2C9, CYP1A2, and P-glycoprotein. It accelerates the metabolism of a staggering number of medications.

Critical contraindications:

• Oral contraceptives: Breakthrough bleeding and unintended pregnancies documented. Absolute contraindication.
• Warfarin: Reduced anticoagulant effect. INR drops, clotting risk increases.
• SSRIs/SNRIs: Dual risk — reduced antidepressant blood levels AND serotonin syndrome risk (St. John’s Wort itself has serotonergic activity). Never combine.
• Cyclosporine and tacrolimus: Reduced immunosuppressant levels. Organ transplant rejection has been documented. Absolute contraindication.
• HIV protease inhibitors and NNRTIs: Reduces antiviral blood levels. Absolute contraindication.
• Chemotherapy agents: Reduces effectiveness of irinotecan, imatinib, docetaxel, and others.
• Digoxin: Reduced blood levels via P-gp induction.
• Statins: Reduced statin levels (simvastatin, atorvastatin).
• Benzodiazepines: Reduced blood levels of alprazolam, midazolam.

The effect persists for up to two weeks after discontinuation. When stopping St. John’s Wort, monitor drug levels carefully as they will rise.

Clinical stance: St. John’s Wort has genuine antidepressant efficacy for mild to moderate depression, comparable to SSRIs in some trials. But it is essentially incompatible with most pharmaceutical regimens. Reserve for patients on zero or minimal medications.

Grapefruit and Grapefruit Juice

Not an herb per se, but universally relevant. Grapefruit contains furanocoumarins that irreversibly inhibit intestinal CYP3A4. A single glass of grapefruit juice can inhibit CYP3A4 for up to 72 hours (the body must synthesize new enzyme).

Major interactions:

• Statins: Simvastatin and atorvastatin levels can increase 3-15x. Pravastatin and rosuvastatin are safer alternatives (not CYP3A4 substrates).
• Calcium channel blockers: Felodipine, nifedipine — increased hypotensive effect.
• Cyclosporine: Increased immunosuppressant levels.
• Certain benzodiazepines: Midazolam, triazolam — increased sedation.
• Some antihistamines: Terfenadine (withdrawn from market partly for this reason).

Clinical note: Seville oranges, pomelos, and tangelos contain the same furanocoumarins. Regular sweet oranges do not.

Curcumin

A potent inhibitor of CYP1A2, CYP2C9, CYP3A4, and CYP2D6 at high doses. Also inhibits glucuronidation and P-glycoprotein.

Key interactions:

• Warfarin (CYP2C9): Increased anticoagulant effect. Monitor INR closely. Start low, increase slowly.
• NSAIDs (CYP2C9): Increased NSAID blood levels. Paradoxically, the anti-inflammatory effect may allow NSAID dose reduction — but monitor for GI bleeding.
• Sulfasalazine: Curcumin inhibits its metabolism. Use caution in IBD patients taking both.
• Tamoxifen: Some evidence curcumin may inhibit tamoxifen metabolism. Conflicting data on whether it enhances or impairs tamoxifen efficacy. Conservative approach: avoid in breast cancer patients on tamoxifen until better data emerges.
• Acetaminophen: Inhibited glucuronidation could theoretically increase acetaminophen toxicity risk. Clinically significant? Probably not at standard curcumin doses, but worth noting.

Clinical stance: Curcumin is generally safe alongside most medications at standard doses (500-1000mg of enhanced-bioavailability forms). Extra vigilance with anticoagulants, antiplatelet agents, and narrow-therapeutic-index drugs.

Berberine

A botanical alkaloid with impressive metabolic effects — it activates AMPK (like metformin), lowers blood glucose, improves lipid profiles, and has antimicrobial activity. But it inhibits CYP2D6, CYP3A4, and P-glycoprotein.

Key interactions:

• Metformin: Berberine and metformin both lower blood glucose through AMPK activation. Combined, hypoglycemia risk increases. Additionally, berberine may increase metformin blood levels via P-gp inhibition. If combining, reduce metformin dose and monitor blood glucose closely.
• Cyclosporine: Berberine increases cyclosporine blood levels by 20-30% via P-gp and CYP3A4 inhibition. Dose adjustment required. This interaction has actually been studied in a clinical trial and is well-documented.
• CYP2D6 substrates: Many antidepressants (fluoxetine, paroxetine, venlafaxine), antipsychotics (haloperidol, risperidone), beta-blockers (metoprolol), and codeine/tramadol. Monitor for increased side effects.
• Statins: CYP3A4 inhibition could increase statin levels (simvastatin, atorvastatin).

Anticoagulant Interactions

This is the territory of greatest clinical anxiety — and the greatest discrepancy between theoretical risk and actual evidence.

Fish Oil (Omega-3 Fatty Acids)

The traditional warning that fish oil increases bleeding risk with anticoagulants has been substantially challenged. Large meta-analyses (including the REDUCE-IT trial with 4g EPA daily) show no increased bleeding, even at high doses, even combined with antiplatelet or anticoagulant therapy. Current evidence supports combined use with monitoring. Perioperative guidelines suggesting discontinuation 7-10 days before surgery are increasingly questioned.

Ginkgo Biloba

Theoretical antiplatelet effect via PAF (platelet-activating factor) inhibition. Case reports of bleeding exist but are rare and poorly controlled. Systematic reviews have not found significantly increased bleeding risk at standard doses (120-240mg standardized extract). However, caution remains reasonable with warfarin, and INR should be monitored.

Garlic (Allium sativum)

Contains ajoene and allicin with mild antiplatelet activity. At culinary doses, insignificant. At therapeutic supplement doses (600-1200mg aged garlic extract), theoretical additive risk with anticoagulants. One well-documented case report of postoperative bleeding. Conservative approach: discontinue 7-10 days before surgery.

Nattokinase

A fibrinolytic enzyme from fermented soybeans. Unlike the above, nattokinase has direct thrombolytic activity — it actually dissolves fibrin. This is a genuine interaction, not theoretical. Absolute contraindication with warfarin, heparin, and direct oral anticoagulants (DOACs). Also contraindicated before surgery.

Vitamin E (high-dose)

At doses above 800 IU, alpha-tocopherol inhibits platelet aggregation. At standard supplemental doses (200-400 IU), risk is minimal. The ATBC trial showed slightly increased hemorrhagic stroke risk at 50 IU daily, but only in male smokers.

Dong Quai (Angelica sinensis)

Contains coumarins with demonstrated warfarin interaction (INR elevation). Avoid with anticoagulants. The interaction is well-documented and clinically significant.

Blood Sugar Interactions

When patients on insulin or oral hypoglycemics add glucose-lowering botanicals, hypoglycemia becomes a real risk.

The main players:

• Berberine (500mg 2-3x daily): Lowers fasting glucose by 20-30 mg/dL on average. With metformin, monitor closely and potentially reduce metformin dose.
• Gymnema sylvestre (400-600mg daily): Reduces sugar absorption and may regenerate beta cells. Can potentiate sulfonylureas and insulin. Start low.
• Cinnamon (Ceylon variety, 1-6g daily): Modest glucose-lowering effect. Less likely to cause clinical hypoglycemia, but additive with medications.
• Alpha-lipoic acid (600mg daily): Improves insulin sensitivity. Can potentiate insulin and metformin. Monitor blood glucose, especially during the first 2-4 weeks of combined use.
• Chromium (200-1000mcg daily): Enhances insulin signaling. Modest effect in most people, but can be significant in true chromium deficiency.

Clinical guidance: Never add glucose-lowering botanicals to insulin or sulfonylurea therapy without discussing with the prescribing physician and establishing home glucose monitoring.

Thyroid Medication Interactions

Levothyroxine is one of the most interaction-prone medications — not because of CYP450, but because of absorption interference.

Absorption blockers (take 4 hours apart from levothyroxine):

• Calcium (any form)
• Iron supplements
• Magnesium
• Aluminum-containing antacids
• Cholestyramine and other bile acid sequestrants
• Fiber supplements (psyllium)
• Soy protein (especially concentrated soy isoflavones)
• Coffee (can reduce absorption by up to 36% — take thyroid medication with plain water, then wait 30-60 minutes before coffee)

Biotin and lab interference: High-dose biotin (5000-10,000 mcg, common in hair/nail supplements) interferes with the streptavidin-biotin immunoassay platform used in many thyroid tests. It causes falsely low TSH and falsely high free T4 and free T3 — mimicking hyperthyroidism. This is a lab artifact, not a true interaction. Stop biotin 48-72 hours before thyroid lab work.

Serotonin Syndrome Risks

Serotonin syndrome is a potentially life-threatening condition caused by excess serotonergic activity. Symptoms range from mild (tremor, diarrhea, agitation) to severe (hyperthermia, rigidity, seizures, death).

Botanical serotonin boosters that interact with serotonergic drugs:

• 5-HTP (50-300mg daily): Direct serotonin precursor. Significant risk with SSRIs, SNRIs, MAOIs, tramadol, and triptans. If combining (which some practitioners do at low doses), start at 50mg and increase slowly with careful monitoring.
• L-tryptophan (500-2000mg): Serotonin precursor, one step upstream of 5-HTP. Same interaction profile, somewhat lower risk per milligram.
• SAMe (S-adenosyl-L-methionine, 400-1600mg daily): Increases serotonin, dopamine, and norepinephrine. Case reports of serotonin syndrome with SSRIs. Use extreme caution.
• St. John’s Wort: Dual mechanism — inhibits serotonin reuptake AND induces CYP450 enzymes that metabolize SSRIs. Never combine with any serotonergic drug.

Clinical guidance: As a general rule, choose either pharmaceutical serotonin support OR botanical serotonin support, not both simultaneously. If transitioning from SSRI to 5-HTP or St. John’s Wort, allow a washout period appropriate to the drug’s half-life (5-14 days for most SSRIs, 4-6 weeks for fluoxetine due to its long-acting metabolite).

Immunosuppressant Interactions

For patients with organ transplants or autoimmune diseases on immunosuppressive therapy (cyclosporine, tacrolimus, azathioprine, mycophenolate, biologics), the immune-modulating effects of certain herbs create a theoretical — and sometimes real — conflict.

Potentially immunostimulating herbs to use cautiously:

• Medicinal mushrooms (reishi, turkey tail, lion’s mane, cordyceps): Upregulate NK cells, macrophages, and cytokine production. Contraindicated in organ transplant patients. In autoimmune conditions on biologics, the situation is nuanced — mushrooms may modulate rather than simply stimulate immunity, but data is insufficient for confident recommendation.
• Echinacea: Traditionally warned against in autoimmunity. Recent evidence suggests it may be more immunomodulatory than immunostimulatory, but conservative practice avoids it with immunosuppressants.
• Astragalus: Enhances T-cell and NK cell function. Avoid with transplant immunosuppression. Consider carefully in autoimmune patients.
• Elderberry: Stimulates cytokine production. The theoretical concern about “cytokine storm” in COVID-19 was largely unfounded, but caution with immunosuppressed transplant patients remains reasonable.

Safe Combinations and Synergies

Not all interactions are dangerous. Some herbs genuinely enhance drug efficacy or mitigate drug side effects.

• CoQ10 + statins: Statins inhibit CoQ10 synthesis (same mevalonate pathway). Supplementing 100-300mg CoQ10 may reduce statin-induced myalgia. Standard of care in Japan.
• Milk thistle + hepatotoxic drugs: Silymarin is hepatoprotective and supports glutathione. May help protect the liver during methotrexate or acetaminophen use.
• Probiotics + antibiotics: Reduce antibiotic-associated diarrhea and C. difficile risk. Take 2-3 hours apart from antibiotic doses.
• Ginger + chemotherapy: Reduces chemotherapy-induced nausea. Generally safe and evidence-based (1-2g daily).
• Vitamin D + corticosteroids: Long-term corticosteroids cause bone loss and vitamin D depletion. Supplementation is protective and standard practice.
• Magnesium + thiazide diuretics: Thiazides deplete magnesium. Supplementation prevents hypomagnesemia-related arrhythmias and muscle cramps.

Clinical Decision Framework

When a patient presents on medications and you’re considering botanical or nutritional interventions:

1. Check the interaction database. Natural Medicines Comprehensive Database, Lexicomp, or Micromedex. These are more reliable than a quick internet search.
2. Assess the clinical significance. Is this a narrow-therapeutic-index drug (warfarin, digoxin, cyclosporine, lithium, phenytoin, theophylline)? If yes, even theoretical interactions warrant caution.
3. Start low, go slow. When adding a potentially interacting herb to a medication, begin at the lowest therapeutic dose and increase gradually with appropriate monitoring (INR for warfarin, blood glucose for diabetes meds, drug levels for cyclosporine).
4. Monitor more frequently. When combining, increase monitoring frequency for the first 4-8 weeks.
5. Communicate with the prescriber. Document and disclose all supplements to the patient’s physician. The era of “don’t ask, don’t tell” between conventional and integrative medicine serves nobody.
6. When in doubt, substitute. If the interaction risk is too high, find an alternative herb that achieves the therapeutic goal without the metabolic conflict.

The body does not distinguish between a molecule from a plant and a molecule from a pharmacy. Both travel the same pathways, compete for the same enzymes, bind the same receptors. Respecting this shared biochemistry is not caution — it is competence.

Where does confidence end and recklessness begin in combining the two oldest forms of medicine?