Understanding Phytopharmacology, Toxicology, and Risk Assessment in Practice

This comprehensive guide explores the scientific foundations of herbal safety, providing the depth of understanding needed for serious students of herbalism, healthcare practitioners, and those seeking mastery of botanical medicine practice.

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Table of Contents

1. Understanding Phytopharmacology
2. Toxicology Principles Applied to Herbs
3. Drug-Herb Interaction Mechanisms
4. Special Population Safety
5. Quality, Adulteration & Contamination
6. Allergenicity & Immunological Reactions
7. Organ-Specific Safety Considerations
8. Evidence-Based Risk Assessment
9. Clinical Decision-Making Framework
10. NZ Regulatory Context

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A Note on Rongoā Māori and Indigenous Knowledge Systems

Rongoā Māori represents centuries of sophisticated traditional Māori healing knowledge with its own pharmacological understanding, safety protocols, and toxicology expertise.

Important distinctions for practitioners:

This guide covers Western phytopharmacology and toxicology. Rongoā Māori:

• Has its own qualified practitioners (tohunga) trained in traditional knowledge transmission
• Uses native plants as taonga (treasures) with cultural protocols and restrictions
• Follows different diagnostic frameworks, therapeutic approaches, and safety considerations
• Cannot be reduced to Western pharmacological models without losing essential cultural context
• Has traditional safety knowledge about native plant toxicity, dosing, and contraindications

For practitioners integrating Māori clients or native plants:

• Consult with qualified rongoā practitioners for culturally appropriate approaches
• Recognise that native plants (kawakawa, manuka, horopito, etc.) have cultural significance beyond phytochemistry
• Understand that rongoā Māori safety knowledge may differ from Western toxicology
• Never extract or commercially use native plants without understanding cultural protocols
• Support Māori-led native plant research and conservation initiatives

Professional boundaries:

• Western-trained herbalists should not claim expertise in rongoā Māori
• Refer Māori clients seeking traditional approaches to qualified rongoā practitioners
• Acknowledge the limitations of Western phytopharmacology in understanding indigenous medicine

This guide provides Western scientific frameworks for herbal safety while recognising that other valid, sophisticated knowledge systems exist with their own evidence bases and safety protocols.

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Understanding Phytopharmacology

The Fundamental Difference: Phytocomplexity vs. Single Molecules

Pharmaceutical drugs typically consist of single, isolated chemical entities with well-defined pharmacokinetic and pharmacodynamic profiles. Herbs, conversely, contain hundreds to thousands of bioactive compounds working in concert—a phenomenon known as phytocomplexity or synergy.

Why this matters for safety:

When you consume chamomile tea, you’re not ingesting a single compound like apigenin (though that’s one key constituent). You’re consuming:

• Multiple flavonoids (apigenin, luteolin, quercetin)
• Volatile oils (bisabolol, chamazulene, farnesene)
• Coumarins (herniarin, umbelliferone)
• Phenolic acids
• Polysaccharides
• And dozens more

Each compound has its own pharmacological profile, but they don’t work in isolation. Synergy means the combined effect is greater than (or different from) the sum of individual parts.

Safety implications:

1. Difficult to predict interactions: Standard drug interaction databases focus on single molecules. Herb interactions are harder to predict because multiple constituents may interact via different mechanisms simultaneously.
2. Variable potency: Phytochemical profiles vary based on:

• Growing conditions (soil, climate, rainfall)
• Harvest timing and methods
• Post-harvest processing (drying temperature, storage)
• Extraction methods (water, alcohol, vinegar pull different compounds)

1. Potential for unexpected effects: Minor constituents present at low levels might interact with major constituents or drugs in ways not predicted by studying isolated compounds.

Bioavailability and First-Pass Metabolism

Bioavailability is the proportion of an ingested substance that reaches systemic circulation in active form.

For herbs, this is complex because:

Oral administration involves:

1. Gastric survival: Acids and enzymes may destroy some constituents
2. Intestinal absorption: Only compounds with appropriate molecular weight, lipophilicity, and structure cross the gut membrane
3. First-pass metabolism: Before reaching systemic circulation, absorbed compounds pass through the portal vein to the liver, where CYP450 enzymes metabolize many of them
4. Gut microbiome transformation: Gut bacteria can transform phytochemicals into more (or less) active metabolites

Example: Curcumin from turmeric

Curcumin has notoriously poor bioavailability (~1-3% oral bioavailability) due to:

• Limited intestinal absorption
• Rapid metabolism in intestinal and hepatic cells
• Quick elimination

But: Traditional use combines turmeric with black pepper (containing piperine), which inhibits intestinal and hepatic metabolism, increasing curcumin bioavailability by up to 2000%. This is practical application of pharmacokinetic knowledge.

Dose-Response Relationships

The fundamental principle of toxicology, attributed to Paracelsus: “The dose makes the poison.”

Hormesis: Some herbs exhibit biphasic dose-response curves. At low doses, they have beneficial effects; at high doses, they become toxic or produce opposite effects.

Example: Licorice root

• Low doses (1-2g dried root): Anti-inflammatory, soothing to mucous membranes, adrenal support
• Moderate doses (>5g/day for weeks): Can cause pseudoaldosteronism—sodium retention, potassium loss, hypertension, edema
• High doses (sustained): Life-threatening electrolyte imbalances, cardiac arrhythmias

Mechanism: Glycyrrhizin in licorice inhibits 11β-hydroxysteroid dehydrogenase type 2, which normally inactivates cortisol in kidney tissues. Inhibition allows cortisol to activate mineralocorticoid receptors, mimicking aldosterone.

Practical implication: Dose matters profoundly. The same herb safe at culinary doses can be dangerous at excessive medicinal doses.

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Toxicology Principles Applied to Herbs

Classification of Herbal Toxicity

Intrinsic toxicity: The plant naturally contains toxic compounds

• Acute: Immediate effects (e.g., hemlock alkaloids cause rapid paralysis)
• Chronic: Long-term exposure causes cumulative damage (e.g., comfrey’s pyrrolizidine alkaloids cause hepatotoxicity over time)

Extrinsic toxicity: Contamination from external sources

• Heavy metals (lead, arsenic, cadmium from contaminated soil)
• Pesticides and herbicides
• Microbial contamination (aflatoxins from mold)
• Adulteration (intentional addition of pharmaceutical drugs or wrong species)

Idiosyncratic reactions: Unpredictable, individual responses

• Genetic polymorphisms in metabolic enzymes
• Individual immune responses
• Unknown underlying conditions

Understanding Therapeutic Index

Therapeutic Index (TI) = Toxic Dose / Effective Dose

High TI (wide safety margin): Chamomile, peppermint, calendula

• Large difference between effective and toxic doses
• Generally safe even with dosing errors

Low TI (narrow safety margin): Foxglove (cardiac glycosides), comfrey (PAs)

• Small difference between therapeutic and toxic doses
• Easy to overdose; requires precise dosing
• Generally avoided in modern herbalism or used only by specialists

Most culinary herbs have high therapeutic indices. This is why they’re used in food—consistent use doesn’t cause toxicity.

Target Organ Toxicity

Different herbs have affinities for different organ systems:

Hepatotoxic herbs (liver damage):

• Pyrrolizidine alkaloid-containing plants: comfrey root (Symphytum officinale), coltsfoot, borage (very small amounts)
• Kava (Piper methysticum) in some individuals
• Greater celandine (Chelidonium majus) in excessive doses

Mechanism: PAs are metabolized by liver CYP450 enzymes into toxic pyrroles that alkylate DNA and proteins, causing hepatocyte necrosis and veno-occlusive disease.

Nephrotoxic herbs (kidney damage):

• Aristolochic acid-containing plants (Aristolochia species—sometimes mistakenly substituted for safe herbs)
• Excessive oxalate-containing plants (rhubarb leaves)

Cardiotoxic herbs:

• Cardiac glycoside-containing plants: foxglove (Digitalis purpurea), lily of the valley (Convallaria majalis), oleander (Nerium oleander)

Mechanism: Inhibition of Na+/K+-ATPase pump in cardiac cells, leading to increased intracellular calcium, enhanced contractility, but also arrhythmias.

Genotoxicity and Mutagenicity

Some plant constituents can damage DNA:

Aristolochic acids: Potent carcinogens and mutagens

• Found in Aristolochia species
• Cause urothelial cancers
• Banned in many countries, but contamination still occurs

Pyrrolizidine alkaloids: Genotoxic at high doses

• Risk is cumulative and dose-dependent
• Comfrey leaf contains lower levels than root; short-term use appears safe but long-term oral use avoided

Safrole and estragole: Found in sassafras, basil (small amounts), fennel

• Metabolized to potential carcinogens in rodent studies
• Risk at culinary levels appears negligible in humans
• Concentrated essential oils might pose higher risk

Practical approach: Herbs with known genotoxic constituents are avoided for long-term internal use, though short-term or topical use may be acceptable depending on concentration and form.

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Drug-Herb Interaction Mechanisms

Pharmacokinetic Interactions

These occur when herbs alter the absorption, distribution, metabolism, or excretion (ADME) of co-administered drugs.

1. Cytochrome P450 Enzyme Modulation

The CYP450 superfamily is a group of liver enzymes responsible for metabolizing ~75% of all pharmaceutical drugs. In humans, key enzymes include:

• CYP3A4: Metabolises ~50% of drugs (statins, immunosuppressants, many antibiotics, calcium channel blockers)
• CYP2D6: Metabolises antidepressants, antipsychotics, beta-blockers, opioids
• CYP2C9: Metabolises warfarin, NSAIDs, sulfonylureas
• CYP2C19: Metabolises proton pump inhibitors, some antidepressants
• CYP1A2: Metabolises caffeine, theophylline, some antidepressants

Enzyme Induction:

Herbs can increase expression of CYP enzymes, speeding drug metabolism and reducing drug blood levels.

St. John’s Wort (Hypericum perforatum)—The Classic Example:

Hyperforin and hypericin activate the pregnane X receptor (PXR), a nuclear receptor that upregulates CYP3A4, CYP2C9, and P-glycoprotein expression.

Clinical consequences:

• Cyclosporine/Tacrolimus: Reduced blood levels → organ rejection in transplant patients (documented cases)
• Oral contraceptives: Reduced effectiveness → unplanned pregnancies (multiple documented cases)
• Warfarin: Reduced anticoagulation → thromboembolic events
• Indinavir/other HIV protease inhibitors: Reduced antiviral efficacy
• Chemotherapy agents: Potentially reduced efficacy

Timeframe: Enzyme induction takes 1-2 weeks to develop and 1-2 weeks to resolve after discontinuation.

Enzyme Inhibition:

Herbs can block CYP enzymes, slowing drug metabolism and causing drug accumulation to potentially toxic levels.

Grapefruit juice—The Most Studied Inhibitor:

Furanocoumarins (bergamottin, 6′,7′-dihydroxybergamottin) in grapefruit irreversibly inhibit intestinal CYP3A4.

Clinical consequences:

• Simvastatin/Atorvastatin: Increased blood levels → rhabdomyolysis (muscle breakdown) risk
• Felodipine/Amlodipine: Increased blood levels → excessive hypotension
• Cyclosporine: Increased blood levels → nephrotoxicity
• Buspirone: Increased blood levels → excessive sedation

Duration: Effect can last 24-72 hours from a single glass of grapefruit juice.

Other CYP inhibitors:

• Goldenseal (Hydrastis canadensis): Berberine inhibits CYP2D6, CYP3A4
• Echinacea: May inhibit CYP3A4 (conflicting evidence)

2. P-glycoprotein (P-gp) Transporter Modulation

P-glycoprotein is an efflux transporter in intestinal epithelium, blood-brain barrier, and kidneys. It pumps substrates back into gut lumen (reducing absorption) or into renal tubules (increasing excretion).

P-gp substrates include:

• Digoxin
• Dabigatran
• Fexofenadine
• Many chemotherapy agents

St. John’s Wort: Induces P-gp expression

• Digoxin: Reduced absorption and increased renal excretion → reduced blood levels → reduced cardiac efficacy

P-gp inhibitors:

• Black pepper (piperine): Inhibits P-gp → increases bioavailability of curcumin, many drugs
• Quercetin (found in many herbs): P-gp inhibitor in vitro

Clinical relevance: Co-administration of P-gp modulators with P-gp substrate drugs can significantly alter drug bioavailability.

3. Absorption Interactions

Chelation/Adsorption:

Herbs high in tannins, mucilage, or minerals can bind to drugs in the gut, reducing drug absorption.

Example: High-fibre herbs taken with levothyroxine (thyroid medication) can reduce thyroid hormone absorption. Solution: Take herbs 2-4 hours away from thyroid medication.

pH alteration:

Herbs affecting stomach pH can alter absorption of pH-dependent drugs.

Example: Bitter herbs stimulate gastric acid secretion, potentially affecting drugs that require specific pH for absorption or dissolution.

4. Pharmacodynamic Interactions

These occur when herbs and drugs have additive, synergistic, or antagonistic effects at the site of action.

Additive/Synergistic Effects:

Sedative herbs + sedative drugs:

• Valerian, hops, passionflower, kava + benzodiazepines, Z-drugs, barbiturates
• Effect: Excessive sedation, respiratory depression (in severe cases)
• Mechanism: Both act on GABA-A receptors or similar pathways

Anticoagulant herbs + anticoagulant drugs:

• High-dose garlic, ginger, ginkgo, feverfew + warfarin, aspirin, DOACs
• Effect: Increased bleeding risk
• Mechanism: Additive antiplatelet effects, fibrinolysis enhancement

Hypoglycemic herbs + diabetes medications:

• Cinnamon, fenugreek, gymnema + metformin, sulfonylureas, insulin
• Effect: Risk of hypoglycemia
• Mechanism: Additive blood glucose-lowering effects

Serotonergic Herbs + SSRIs/SNRIs:

St. John’s Wort has complex interactions with antidepressants:

• Pharmacokinetic: Induces metabolism → reduced antidepressant levels
• Pharmacodynamic: Serotonin reuptake inhibition → serotonin syndrome risk when combined with SSRIs

Serotonin syndrome: Life-threatening condition with symptoms including agitation, hyperthermia, tremor, hyperreflexia, clonus, autonomic instability. Requires immediate medical intervention.

Antagonistic Effects:

Immune-stimulating herbs + immunosuppressants:

• Echinacea, astragalus + cyclosporine, tacrolimus, methotrexate (for autoimmune conditions)
• Effect: May counteract immunosuppressive therapy
• Mechanism: Immune activation vs. immune suppression

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Special Population Safety

Pregnancy and Lactation

Pregnancy alters pharmacokinetics due to:

• Increased blood volume (dilutional effect on drug concentration)
• Increased cardiac output and renal blood flow (faster drug clearance)
• Hormonal changes affecting CYP enzyme activity
• Placental metabolism of drugs
• Transfer across placenta to fetus

Critical periods:

First trimester (weeks 1-12): Organogenesis—most sensitive period

• Neural tube formation (weeks 3-4)
• Heart development (weeks 3-8)
• Limb development (weeks 4-8)
• Teratogenic exposure during this period causes major malformations

Second/Third trimester: Fetal growth and functional development

• Some herbs can affect fetal organ function
• Risk of preterm labor from uterine stimulants

Mechanisms of herb-induced pregnancy complications:

Uterine stimulation:

• Herbs containing uterotonic compounds (prostaglandins, alkaloids)
• Examples: Blue cohosh (caulosaponin, N-methylcytisine), pennyroyal (pulegone), rue (rutacridone)
• Risk: Miscarriage, preterm labor

Hormonal effects:

• Phytoestrogenic herbs (red clover, soy, black cohosh in high doses)
• Risk: Potential interference with normal hormonal development

Hepatotoxicity:

• Pregnancy already stresses liver function
• Hepatotoxic herbs (comfrey, kava, greater celandine) pose higher risk

Case study: Pennyroyal

Pennyroyal (Mentha pulegium) contains pulegone, metabolized to menthofuran—a potent hepatotoxin.

Historical use: Abortifacient (to induce abortion)

Reality: Doses required for abortion are near-lethal. Multiple documented deaths from pennyroyal poisoning. Causes fulminant hepatic failure.

Never use during pregnancy (or at all, given extreme toxicity).

Generally Recognised as Safe in Pregnancy (culinary amounts):

Ginger (Zingiber officinale):

• Extensive research on pregnancy safety
• Multiple RCTs show 1g/day effective for nausea without adverse pregnancy outcomes
• Doses >4g/day not well-studied; avoid

Peppermint (Mentha × piperita):

• Tea in moderate amounts appears safe after first trimester
• May relax lower esophageal sphincter (avoid if heartburn)

Chamomile (Matricaria chamomilla):

• Weak tea occasionally appears safe
• Theoretical uterine stimulation at high doses (data limited)
• Avoid medicinal doses

Herbs to AVOID in pregnancy (non-exhaustive):

• Blue cohosh, black cohosh (high doses)
• Pennyroyal
• Tansy
• Rue
• Feverfew
• Dong quai (angelica)
• Kawakawa (medicinal doses—traditional rongoā practice has specific protocols)
• Many others—always verify

Lactation considerations:

Herbs can transfer into breast milk. Considerations:

• Lipophilicity: Fat-soluble compounds transfer more readily
• Molecular weight: Smaller molecules transfer more easily
• Protein binding: Highly protein-bound compounds transfer less
• Maternal dose and timing: Peak milk levels occur 1-3 hours post-dose

Galactagogues (milk-stimulating herbs):

• Fenugreek, blessed thistle, fennel, goat’s rue
• Evidence: Mixed; some studies show benefit, others don’t
• Safety: Generally appear safe in moderate amounts, but infant monitoring important

Herbs to avoid while breastfeeding:

• Sage (high doses—suppresses lactation)
• Peppermint oil (high doses—may reduce milk supply)
• Herbs with known toxicity that could transfer to infant

Pediatric Safety

Children are not small adults. Pharmacokinetic and pharmacodynamic differences include:

Absorption:

• Gastric pH less acidic in infants (affects absorption of weak acids/bases)
• Intestinal transit time different

Distribution:

• Higher total body water percentage (affects volume of distribution)
• Lower plasma protein (affects protein binding, free drug fraction)
• Immature blood-brain barrier in neonates (higher CNS penetration)

Metabolism:

• CYP enzyme activity develops gradually (some enzymes not fully functional until adolescence)
• Phase II conjugation (glucuronidation) limited in neonates
• Higher metabolic rate per kg body weight in children

Excretion:

• Renal function immature in infants (lower glomerular filtration rate)
• Reaches adult values around age 1-2 years

Dosing calculations:

Young’s Rule (for children 1-12 years):
Child dose = (Age ÷ [Age + 12]) × Adult dose

Clark’s Rule (weight-based):
Child dose = (Weight in kg ÷ 70 kg) × Adult dose

Better approach: Use published pediatric dosing guidelines from reliable sources when available. When unavailable, err on conservative side.

Special considerations for infants:

Peppermint oil: NEVER apply to or near face of infants

• Menthol can cause laryngospasm, apnea
• Life-threatening in infants under 30 months

Honey (herbal infusions in honey): Not for infants under 1 year

• Risk of infant botulism

Geriatric Considerations

Aging affects pharmacokinetics:

Absorption:

• Reduced gastric acid secretion
• Slower gastric emptying
• Reduced intestinal blood flow and motility

Distribution:

• Decreased total body water (higher plasma concentration for water-soluble drugs)
• Increased body fat (higher volume of distribution for lipophilic drugs)
• Reduced plasma proteins (more free drug)

Metabolism:

• Reduced liver mass and blood flow
• Decreased CYP enzyme activity (slowed drug metabolism)

Excretion:

• Progressive decline in renal function (GFR decreases ~1% per year after age 40)
• Reduced drug clearance

Clinical implications:

• Elderly may require lower doses
• Higher risk of drug accumulation and toxicity
• Increased sensitivity to sedative effects
• Polypharmacy common (higher drug interaction risk)

Herbs requiring extra caution in elderly:

• Sedatives (valerian, hops, kava—risk of falls)
• Diuretics (risk of dehydration, electrolyte imbalances)
• Herbs affecting blood pressure (orthostatic hypotension risk)

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Quality, Adulteration & Contamination

Heavy Metal Contamination

Sources:

• Growing in contaminated soil (industrial areas, lead-painted building runoff)
• Traditional processing methods (some Ayurvedic and Traditional Chinese Medicine preparations intentionally include metals)
• Contamination during processing

Metals of concern:

• Lead: Neurotoxin, accumulates in bones
• Arsenic: Carcinogen, multi-organ toxicity
• Cadmium: Nephrotoxin, carcinogen
• Mercury: Neurotoxin

Studies:
Multiple surveys of herbal products have found concerning levels of heavy metals in 10-30% of products tested, particularly in imported products.

Prevention:

• Buy from companies that test for heavy metals
• Look for certifications (USDA Organic reduces risk but doesn’t eliminate it)
• Avoid products from unknown sources

Pesticide and Herbicide Residues

Concerns:

• Organophosphates (neurotoxic)
• Carbamates (neurotoxic)
• Glyphosate (endocrine disruption concerns, carcinogenicity debated)
• Pyrethroids (neurotoxic at high levels)

High-risk herbs:

• Those cultivated with intensive agriculture
• Non-organic imports from countries with less strict regulations

Protection:

• Choose organic certified herbs
• Know your supplier’s growing practices
• When foraging, avoid areas known to be sprayed

Microbial Contamination

Bacteria:

• Salmonella, E. coli, Staphylococcus aureus
• Risk: Gastroenteritis, systemic infection in immunocompromised

Fungi:

• Aflatoxins (from Aspergillus mold): Potent hepatotoxic carcinogens
• Common in improperly stored herbs, particularly in humid conditions

Prevention:

• Proper drying (moisture content <10%)
• Storage in airtight containers
• Discard moldy herbs immediately
• Purchase from suppliers with microbial testing

Adulteration

Types:

Species substitution:

• Intentional: Substituting cheaper, similar-looking species
• Unintentional: Misidentification

Famous case: Aristolochia fangchi (toxic) substituted for Stephania tetrandra in weight-loss formulas → multiple cases of severe kidney failure and urothelial cancer

Pharmaceutical adulteration:

• Addition of undeclared pharmaceutical drugs to increase efficacy
• Common in “natural” products for erectile dysfunction (sildenafil), weight loss (sibutramine), diabetes (glibenclamide)

Testing reveals: 10-20% of “herbal” products tested contain undeclared pharmaceuticals in some surveys

Fillers:

• Addition of inert substances to increase weight/volume
• Rice powder, starch, talc
• Reduces potency, may cause reactions in sensitive individuals

Protection:

• Buy from reputable suppliers only
• Look for third-party testing (USP, NSF, ConsumerLab certifications)
• Be skeptical of products with “too good to be true” effects
• In NZ: Look for products with Medsafe approval numbers

Sourcing Quality Herbs in NZ:

For practitioners and serious students requiring pharmaceutical-grade or quality-controlled herbs:

• Go Native NZ (go-native.co.nz) – GMP-certified NZ supplier
• Lotus Oils NZ (lotusoils.co.nz) – Organic certified suppliers
• Professional suppliers: Contact NZAMH for practitioner-only supplier lists
• Import considerations: Medsafe requirements for importing therapeutic-grade herbs

Look for:

• Batch testing certificates (heavy metals, pesticides, microbiology)
• Certificate of Analysis (COA) with constituent quantification
• GMP (Good Manufacturing Practice) certification
• Proper botanical identification (voucher specimens)

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Allergenicity & Immunological Reactions

IgE-Mediated (Type I) Hypersensitivity

Classic allergic reactions:

Mechanism:

1. First exposure: Sensitization—IgE antibodies produced against plant proteins
2. Re-exposure: IgE-antigen binding on mast cells/basophils
3. Degranulation: Release of histamine, leukotrienes, prostaglandins
4. Symptoms: Urticaria, angioedema, rhinitis, asthma, anaphylaxis

Cross-reactivity:

Asteraceae (Compositae) family: Chamomile, calendula, echinacea, dandelion, yarrow

• Share sesquiterpene lactone allergens
• Ragweed allergy: High cross-reactivity (up to 50% of ragweed-allergic individuals react to chamomile)

Apiaceae family: Fennel, anise, coriander, parsley

• Share similar protein structures
• Cross-reactive with celery, carrot allergies

Profilin-mediated cross-reactivity:

• Profilin is a ubiquitous plant protein
• Individuals with birch pollen allergy may react to: apple, hazelnut, chamomile, fennel
• Oral Allergy Syndrome: Itching/tingling of lips, mouth, throat after eating/drinking cross-reactive foods/herbs

Contact Dermatitis (Type IV Hypersensitivity)

Mechanism: Cell-mediated (T-cell) response to plant chemicals absorbed through skin

Common botanical allergens:

• Urushiol: Poison ivy, poison oak (not in NZ, but related compounds in some NZ natives)
• Sesquiterpene lactones: Asteraceae family (chamomile, calendula, yarrow, arnica)
• Essential oils: Many can cause sensitization with repeated use

Presentation: Delayed reaction (12-72 hours post-exposure), eczematous rash at contact site

Prevention:

• Patch test new topical herbs (apply to inner forearm, cover, wait 48 hours)
• Dilute essential oils (never use “neat” on skin repeatedly)
• Rotate herbs rather than using same one continuously

Anaphylaxis

Life-threatening systemic reaction:

Symptoms:

• Airway: Swelling of tongue, throat, difficulty breathing
• Cardiovascular: Rapid pulse, drop in blood pressure, shock
• Skin: Widespread urticaria, flushing
• GI: Severe cramping, vomiting, diarrhea

Common herbal triggers:

• Chamomile (in highly allergic individuals)
• Royal jelly/bee pollen/propolis (in bee-allergic individuals)
• Echinacea (rare but documented)

Management:

1. Call 111 immediately
2. Administer epinephrine (EpiPen) if available
3. Position supine with legs elevated (unless breathing difficulty)
4. Monitor airway and breathing
5. Be prepared for CPR

Prevention in at-risk individuals:

• Avoid herbs from families known to cause cross-reactions
• Start with extremely small amounts
• Have EpiPen available if history of anaphylaxis
• Never use herbs alone in remote locations if high-risk

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Organ-Specific Safety Considerations

Hepatotoxicity

The liver is vulnerable to herb-induced injury because:

• High blood flow from GI tract (first-pass effect)
• Site of metabolism—toxic metabolites formed locally
• Hepatocytes have limited regenerative capacity after severe damage

Hepatotoxic mechanisms:

Direct toxicity:

• Pyrrolizidine alkaloids (comfrey, coltsfoot) → hepatocyte necrosis, veno-occlusive disease
• Pulegone (pennyroyal) → metabolized to menthofuran → fulminant hepatic necrosis

Idiosyncratic hepatotoxicity:

• Kava (Piper methysticum): Rare but severe hepatotoxicity in some individuals
• Mechanism unclear: Possible genetic polymorphisms in kava metabolism
• Led to bans/restrictions in multiple countries

Drug-induced hepatotoxicity potentiation:

• Green tea extracts (EGCG) can potentiate acetaminophen hepatotoxicity
• St. John’s Wort induces CYP enzymes → increased production of toxic metabolites from some drugs

Monitoring:
For long-term use of herbs with hepatotoxic potential:

• Baseline liver function tests (ALT, AST, ALP, bilirubin)
• Repeat testing every 3-6 months
• Discontinue if enzymes elevate >2x upper normal limit

Nephrotoxicity

Aristolochic acid nephropathy:

• Aristolochia species → progressive interstitial fibrosis → renal failure
• Also causes urothelial cancer
• Prevention: Never use Aristolochia; verify absence in Chinese herbal formulas

Oxalate nephropathy:

• Excessive consumption of high-oxalate herbs (rhubarb, sorrel)
• Calcium oxalate crystal deposition in renal tubules

NSAID (Non-Steroidal Anti-Inflammatory) like effects:

• Willow bark (salicylates) in excessive doses
• Can cause acute interstitial nephritis, analgesic nephropathy (chronic use)

Protection:

• Adequate hydration when using diuretic herbs
• Avoid excessive use of high-oxalate herbs
• Monitor kidney function in individuals with pre-existing renal impairment

Cardiotoxicity

Cardiac glycosides:

• Foxglove, lily of the valley, oleander
• Mechanism: Na+/K+-ATPase inhibition → increased intracellular Ca2+
• Effects: Positive inotropy (therapeutic) but also arrhythmias (toxic)
• Narrow therapeutic index: Easy to overdose

Arrhythmogenic herbs:

• Ephedra (banned in many countries): Sympathomimetic → tachycardia, hypertension
• Aconite (extremely toxic): Interferes with sodium channels → ventricular arrhythmias

QT prolongation:

• Some herbs can prolong cardiac repolarization
• Risk of torsades de pointes (life-threatening arrhythmia)
• Examples: Bitter orange (synephrine), liquorice (via electrolyte disturbances)

Neurotoxicity

Seizure risk:

• Ginkgo seeds (contain ginkgotoxin—blocks GABA synthesis)
• Essential oils in excessive doses (camphor, eucalyptus, pennyroyal, sage oil)
• Mechanism: GABAergic inhibition or cholinergic toxicity

Peripheral neuropathy:

• Long-term, excessive pyridoxine (vitamin B6) use with certain herbs

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Evidence-Based Risk Assessment

Hierarchy of Evidence for Herbal Safety

Level 1: Systematic reviews and meta-analyses of RCTs (randmonised Clinical trials)

• Gold standard but rare for herbal safety
• Example: Ginger safety in pregnancy—multiple systematic reviews available

Level 2: Individual RCTs

• Controlled trials assessing safety outcomes
• Limited for most herbs due to cost, ethical considerations

Level 3: Cohort studies

• Prospective or retrospective observational studies
• Example: Pregnancy registries tracking herb exposure and outcomes

Level 4: Case-control studies

• Comparing herb exposure in cases vs. controls

Level 5: Case reports and case series

• Majority of herb-drug interaction and toxicity data
• Limitation: Cannot establish causation, only association
• Value: Hypothesis-generating, signal detection for rare events

Level 6: Traditional use and expert opinion

• Centuries of use provide empirical safety data
• But lack rigorous scientific validation
• Culture-specific practices may not translate universally

Integrating evidence:

Responsible herbalists integrate multiple evidence levels:

• Traditional use: Provides safety track record over time
• Mechanistic plausibility: Phytochemical and pharmacological data
• Clinical evidence: RCTs, observational studies, case reports
• Personal clinical experience: Pattern recognition from practice

Example: Chamomile safety assessment

• Traditional use: Thousands of years, multiple cultures, generally safe reputation
• Mechanistic: Apigenin binds benzodiazepine receptors (mild sedation plausible, generally safe)
• Clinical trials: Multiple studies show good safety profile in adults
• Case reports: Rare allergic reactions in Asteraceae-sensitive individuals
• Conclusion: Generally safe with caution in allergic individuals

Causality Assessment in Adverse Events

When an adverse event occurs during herb use, assessing whether the herb caused it requires systematic evaluation.

Naranjo Algorithm (modified for herbs):

Questions (scored +2, +1, 0, -1):

1. Are there previous conclusive reports of this reaction?
2. Did the adverse event appear after the herb was given?
3. Did the reaction improve when herb was discontinued or antagonist given?
4. Did the reaction reappear when herb re-administered?
5. Are there alternative causes?
6. Did the reaction reappear when placebo given?
7. Was herb detected in body fluids at toxic levels?
8. Was reaction more severe when dose increased or less severe when decreased?
9. Did patient have similar reaction to same or similar herb previously?
10. Was adverse event confirmed by objective evidence?

Score interpretation:

• ≥9: Definite
• 5-8: Probable
• 1-4: Possible
• ≤0: Doubtful

This framework prevents over-attribution of unrelated events to herbs while identifying true causal relationships.

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Clinical Decision-Making Framework

Assessing Benefit-Risk Ratio

For every herbal intervention, evaluate:

Benefits:

• Magnitude of therapeutic effect (from evidence)
• Likelihood of achieving desired outcome
• Quality of life improvements
• Patient preference and values

Risks:

• Probability of adverse effects
• Severity of potential adverse effects
• Reversibility of adverse effects
• Drug interaction potential

Alternative options:

• Lifestyle interventions
• Other herbs with better safety profile
• Conventional medical treatment
• Combination approaches

Example: Kava for anxiety

Benefits:

• Moderate evidence for anxiolytic effects
• May reduce benzodiazepine use

Risks:

• Rare but severe hepatotoxicity
• Potential for dependency
• CNS depression

Assessment:

• In region where kava is safe (traditional use, proper preparation): Benefit may outweigh risk
• In Western context with supplements of unclear quality: Risk may outweigh benefit
• Alternatives: Lemon balm, passionflower, lavender (safer anxiety herbs)

Decision: Most practitioners now avoid kava or use only traditionally-prepared forms with close monitoring.

Informed Consent in Herbal Practice

Ethical herbal practice requires patients/clients understand:

1. What herb is being recommended (botanical name, part used, dosage)
2. Why it’s being recommended (expected benefits, strength of evidence)
3. Potential risks and side effects (common and serious)
4. Drug interactions if applicable
5. Alternatives (including doing nothing)
6. When to stop and seek medical help
7. That herbs are not FDA/Medsafe-approved for specific conditions (in most cases)

Documentation:

• Record patient informed consent
• Document herb recommendations
• Note contraindications assessed
• Record adverse event reporting

When to Refer to Conventional Medicine

Herbs are NOT appropriate for:

Emergencies:

• Acute myocardial infarction, stroke
• Severe infections (sepsis, meningitis)
• Acute surgical conditions (appendicitis, ectopic pregnancy)
• Severe allergic reactions
• Diabetic ketoacidosis

Conditions requiring monitoring:

• Poorly controlled diabetes
• Heart failure
• Arrhythmias
• Severe hypertension
• Kidney failure
• Liver failure

Mental health crises:

• Suicidal ideation
• Acute psychosis
• Severe depression

Diagnostic uncertainty:

• Unexplained weight loss
• Unexplained fever >2 weeks
• New neurological symptoms
• Suspicion of cancer

The herbalist’s role: Complementary support, not primary treatment for serious acute/chronic illness.

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NZ Regulatory Context

Medsafe and Natural Health Products

Current regulation (as of 2024):

Natural health products in New Zealand fall under:

• Medicines Act 1981 (if making therapeutic claims)
• Dietary Supplements Regulations 1985 (if minimal/no therapeutic claims)

Medsafe responsibilities:

• Pre-market assessment of medicines (including some herbal products)
• Post-market surveillance
• Adverse reaction reporting (CARM—Centre for Adverse Reactions Monitoring)

Product classification:

Complementary medicines: Natural health products making therapeutic claims

• May require approval or notification depending on risk level
• Label must include indication, dose, warnings

Dietary supplements: General health support claims only

• Less stringent requirements
• Cannot claim to treat diseases

For practitioners and consumers:

• Look for products with NZFR (New Zealand Full Registration) or NZCP (New Zealand Complementary Product) numbers
• These indicate Medsafe assessment

Adverse Event Reporting

CARM (Centre for Adverse Reactions Monitoring):

Healthcare practitioners and consumers can report adverse reactions to natural health products:

• Website: https://nzphvc.otago.ac.nz/carm/
• Purpose: Post-market surveillance, signal detection

What to report:

• Serious reactions (hospitalization, significant disability, life-threatening)
• Unexpected reactions not listed on label
• Herb-drug interactions

Reporting strengthens safety knowledge for all users.

Professional Registration

Medical Herbalists in NZ:

• NZ Association of Medical Herbalists (NZAMH)
• Members have completed recognized training
• Follow professional code of ethics and practice standards

Naturopaths:

• NZ Naturopathic Council
• Training includes extensive herbal medicine

When seeking professional herbalist:

• Verify membership in professional organization
• Check training/qualifications
• Ensure appropriate insurance/professional indemnity

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Conclusion: Integrating Safety into Practice

Herbal safety is not about fear or restriction—it’s about knowledge-based confidence.

Key principles to integrate:

1. Respect phytocomplexity: Herbs are multi-compound mixtures requiring different thinking than pharmaceutical drugs
2. Understand mechanisms: Know how herbs work at molecular, cellular, and organ levels—this informs prediction of interactions and side effects
3. Assess individual risk: Age, health status, medications, genetics all affect how someone responds to herbs
4. Apply evidence hierarchically: Integrate traditional knowledge, mechanistic understanding, and clinical research
5. Practice informed consent: Patients/clients deserve full information to make autonomous decisions
6. Monitor and document: Track outcomes, adverse events, efficacy—contribute to collective knowledge
7. Know your limits: Recognize when conventional medicine is needed; practice complementary integration

The future of herbal safety:

• Pharmacogenomics may predict individual herb responses based on genetic profiles
• Better quality control and standardization of products
• More rigorous clinical trials on herb-drug interactions
• Integration of traditional knowledge with modern science

For practitioners and serious students:

Safety knowledge is never complete—commit to ongoing learning, staying current with research, participating in professional development, and contributing to the evidence base through careful observation and documentation.

Herbs are powerful allies. Used with knowledge, respect, and appropriate caution, they offer safe, effective support for health across the lifespan.

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Sources & Further Reading

Comprehensive Texts:

• Mills, S., & Bone, K. (2005). The Essential Guide to Herbal Safety. Churchill Livingstone.
• Bone, K., & Mills, S. (2013). Principles and Practice of Phytotherapy: Modern Herbal Medicine (2nd ed.). Churchill Livingstone.
• Williamson, E. M., Driver, S., & Baxter, K. (Eds.). (2013). Stockley’s Herbal Medicines Interactions. Pharmaceutical Press.

Pharmacokinetics & Drug Interactions:

• Foley, H., et al. (2020). Pharmacokinetic interactions between herbal medicines and drugs: Their mechanisms and clinical relevance. Life, 10(7), 106. https://doi.org/10.3390/life10070106
• Chen, X. W., et al. (2012). Herb-drug interactions and mechanistic and clinical considerations. Current Drug Metabolism, 13(5), 640-651. https://doi.org/10.2174/1389200211209050640
• Zhou, S., et al. (2007). Mechanisms of herb-drug interactions and their clinical relevance. Clinical Pharmacokinetics, 46(1), 1-63.

Pregnancy & Lactation:

• Kennedy, D. A., et al. (2016). Safety classification of herbal medicines used in pregnancy in a multinational study. BMC Complementary and Alternative Medicine, 16, 102.
• Forinash, A. B., et al. (2012). Systematic review of breastfeeding and herbs. Breastfeeding Medicine, 7(6), 489-503.
• Romm, A. (2018). Botanical Medicine for Women’s Health (2nd ed.). Churchill Livingstone.

Toxicology:

• Izzo, A. A., et al. (2016). A critical approach to evaluating clinical efficacy, adverse events and drug interactions of herbal remedies. Phytotherapy Research, 30(5), 691-700.
• Teschke, R., & Eickhoff, A. (2015). Herbal hepatotoxicity in traditional and modern medicine. International Journal of Molecular Sciences, 16(11), 26087-26124.

Quality & Adulteration:

• Newmaster, S. G., et al. (2013). DNA barcoding detects contamination and substitution in North American herbal products. BMC Medicine, 11, 222.
• Ernst, E. (2002). Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. Journal of Internal Medicine, 252(2), 107-113.

Pediatric Herbal Medicine:

• Gardiner, P., & Kemper, K. J. (2005). Herbs in pediatric and adolescent medicine. Pediatrics in Review, 21(2), 44-57.

NZ-Specific:

• Medsafe NZ: https://www.medsafe.govt.nz/
• CARM (Centre for Adverse Reactions Monitoring): https://nzphvc.otago.ac.nz/carm/
• NZ Association of Medical Herbalists: https://nzamh.org.nz/

Systematic Reviews & Meta-Analyses:

• Posadzki, P., et al. (2013). Herb-drug interactions: An overview of systematic reviews. British Journal of Clinical Pharmacology, 75(3), 603-618.

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Disclaimer: This guide is for educational purposes only and is not medical advice. Herbal safety is complex and individualised. Always consult qualified healthcare practitioners before using herbs, especially if pregnant, nursing, trying to conceive, taking medications, or having diagnosed medical conditions. This guide covers Western herbalism safety principles and is not a substitute for traditional indigenous knowledge systems including rongoā Māori. For traditional Māori healing approaches, consult qualified rongoā practitioners. The mechanisms, interactions, and toxicology described represent current scientific understanding based on available research, but individual responses vary due to genetic polymorphisms, health status, and other factors. Not all herb-drug interactions have been studied in controlled trials – absence of evidence is not evidence of absence. Practitioners should maintain professional liability insurance, follow all applicable Medsafe regulations, participate in ongoing professional development, and report adverse events to CARM. This guide assumes professional-level knowledge and is not intended for lay self-treatment of serious conditions. Children under 2 years should not receive herbal preparations without specialist paediatric herbalist guidance. The author and publisher assume no liability for adverse reactions, drug interactions, or clinical decisions made based on this information.