Volume 52, Issue 6, June 2023

Interactions between complementary medicines and drugs used in primary care and oral COVID-19 antiviral drugs

Jennifer Hunter    Joanna E Harnett   
doi: 10.31128/AJGP-12-22-6631   |    Download article
Cite this article    BIBTEX    REFER    RIS


Patient harm resulting from drug interactions between conventional and traditional or complementary medicines (CM) are avoidable.


To provide a clinical overview of a selection of CM interactions with drugs commonly used in Australian general practice or in the management of COVID-19.


Many herb constituents are substrates for cytochrome P450 enzymes, and inducers and/or inhibitors of transporters such as P-glycoprotein. Hypericum perforatum (St John’s Wort), Hydrastis canadensis (golden seal), Ginkgo biloba (ginkgo) and Allium sativum (garlic) are reported to interact with many drugs. Simultaneous administration of certain anti-viral drugs with zinc compounds and several herbs should also be avoided.

Preventing and identifying unwanted CM–drug interactions in primary care requires vigilance, access to CM–drug interaction checkers and excellent communication skills. Potential risks from interactions should be balanced against the potential benefits of continuing the drug and/or CM and involve shared decision making.

Unwanted drug interactions with complementary medicines (CMs) can be avoided by being aware of the risks and discussing them with patients.1 CMs contain nutritional and herbal ingredients that are complex, multiconstituent compounds with demonstrable pharmacological actions.2 As such, the use of CMs is associated with potential benefits and harms, including harm from CM–drug interactions.3

Approximately 50% of adults living in Australia reportedly use CM products. Of these, 80% also use prescription and over-the-counter drugs, and 73% have chronic conditions that further increase their risk of unwanted drug interactions due to polypharmacy.4,5


This narrative review provides an overview of selected CM–drug interactions reported in human studies that may occur when CMs are used with drugs that are commonly prescribed in Australian general practice and reviews potential interactions between CMs marketed for respiratory tract infections or immune support in Australia and drugs used to treat COVID-19.


This review article summarises the findings from systematic reviews and comprehensive narrative reviews and other primary studies known to the authors. Interactions between CMs and medicines typically only prescribed in secondary care settings are not reported. Given the emerging evidence for interactions between CMs and drugs used to treat COVID-19, product information documents for drugs and reputable interaction checkers listed in Table 1 were also used to identify interactions. 

Table 1. Complementary medicine–drug interaction resources
Name Website Comments
Most comprehensive for CM–drug interactions
IMgatewayA,B Only CM–drug interaction checker
Search research database/monographs according to conditions, treatment options, nutrient depletion risk from drugs
Natural MedicinesA Only CM–drug interaction checker
Check for effectiveness, nutrient depletion from drugs, use during pregnancy and lactation, and adverse events
MedicinesComplete Stockley’s interactions checkerA,C Both CM–drug and drug–drug interaction checker
Herb interaction monographsD
Only some CM–drug interactions are listed
MIMS IntegratedA Interaction checker for all registered medicines and some listed CMs in Australia
Integrates with clinical practice software common in Australia
University of Liverpool drug–drug interaction resources Specific HIV, hepatitis, cancer and COVID-19 drug interactions checkers; includes some CM ingredients
DynaMed/MicromedexA Drug interaction checker, FDA-approved drugs, includes some CM ingredients and products available in the US, missing many known CM–drug interactions
ASubscription is required for access.
BAvailable as an eMIMS Australia add-on module.
CAvailable via John Murtagh Library for members of The Royal Australian College of General Practitioners.
DMonographs are in Stockley’s Herbal Medicines Interactions.
CM, complementary medicine; FDA, US Food and Drug Administration.

Mechanisms of drug interactions

Drug interactions can occur when two or more compounds taken within a certain period of time alter the pharmacokinetics or pharmacodynamics of either compound. Both are implicated in an increased or decreased clinical effect that is not observed when either compound is used alone.6

Pharmacokinetic interactions change the systemic concentration of a compound and/or its active metabolites by altering absorption, distribution, metabolism or excretion.6 Most CM–drug pharmacokinetic interactions are associated with the induction or inhibition of cytochrome P450 (CYP) enzymes or transporters such as P-glycoprotein and organic anion transporting polypeptides.4 Approximately 80% of drugs used in clinical practice are metabolised by CYP enzymes.7

Pharmacodynamic interactions occur when the compounds have negative, additive or synergistic effects on drug targets.8

Determining clinically important interactions

Preclinical studies, such as in vitro and animal studies, are useful for identifying potential CM–drug interactions and the mechanisms by which they occur. Human studies are still required to determine the clinical relevance of any such interactions.6 As such, for the purpose of the present narrative review, our focus is on human studies.

Many of the CM–drug interactions flagged by interaction checkers or in the drug product information or CM monographs are theoretical and based on knowledge of shared mechanisms of action and/or shared metabolism. Sometimes, they are inferred from the findings of studies evaluating other drugs with similar pharmacological properties or in vitro and animal studies.6 However, there are a growing number of case reports, case series and controlled trials reporting clinically important CM–drug interactions.9

Collectively, this evidence warrants attention, especially for drugs that have a narrow therapeutic index or when there are potentially serious consequences.6 These include drugs used for contraception, mental health, epilepsy, cancer, immunosuppression, infections, diabetes and cardiovascular conditions.6

However, not all CM–drug interactions are necessarily unwanted or undesirable, and some could improve clinical outcomes (eg by augmenting the clinical effects of the drug, increasing drug concentrations or reducing side effects).9

CM–drug interactions relevant to general practice

Table 2 summarises some of the clinical research on CM–drug interactions relevant to general practice. Notable in some reports, altered plasma or serum concentrations of a drug were not always associated with altered clinical effects. For example, Echinacea purpura was found to lower warfarin levels, yet there was no significant change in INR.10 

Table 2. Clinical interactionsA between ingredients of complementary medicines and primary care drugs available in Australia
CM ingredient (common name) RiskB Drug investigated PD and/or PK enzyme transporter involved Observed effects on drug concentrations and/or clinical effects
Ascorbic acid (vitamin C) × × Warfarin10,11 Unclear mechanism decreased anticoagulant effectD  Anticoagulant–warfarin resistance11
 ≤1,000 mg/day10
Allium sativum (garlic) ×× Metformin12,13 Additive PD effectD
Unclear PK mechanism
Improved glycaemic control
× Alprazolam14 CYP3A4  Alprazolam
× Dextromethorphan14 CYP3A4  Dextromethorphan
×× Ritonavir14,15 CYP3A4  Ritonavir
 (non-significant) Ritonavir concentrations
×× Warfarin10,16 Additive PD effectD  ADP-induced platelet aggregation
Aloe barbadensis Miller (aloe vera) ×× Glibenclamide12,13 Additive PD effectD Improved glycaemic control
Curcuma longa (turmeric) ×× Glibenclamide12 CYP3A4, CYP2C19  Glibenclamide
Improved glycaemic control
Crocus sativus (saffron) × Fluoxetine9 Unclear  Sexual dysfunction
Echinacea angustifolia and Echinacea purpurea ×× Warfarin9,14 CYP2C9  Warfarin
Echinacea purpurea × Ritonavir14 CYP3A4  Ritonavir
×× Warfarin10 CYP3A4  Warfarin
Eurycoma longifolia (longjack) ×× Propranolol9  Absorption  Propranolol
Folic acid ×× Warfarin10  Clearance of (S)-7-hydroxywarfarin  INR
(Unclear risk for >5 mg)
Ginkgo biloba ×× Alprazolam14 CYP3A4  Alprazolam
×× Atorvastatin14 Unclear ↓ Atorvastatin
×× Metformin12 Unclear  Metformin
 Glycaemic control
×× Simvastatin9,14 OATP1B1, CYP3A4, BCRP  Simvastatin
 On simvastatin acid (active metabolite)
×× Tolbutamide12 CYP2C9, CYP3A4 ↓ Tolbutamide
 Glycaemic control
× Bupropion14 CYP2B6  Bupropion
× Dextromethorphan14 CYP3A4  Dextromethorphan
× Diazepam14 CYP2C19  Diazepam
× Omeprazole14 CYP2C19  Omeprazole
×× Warfarin10,14 CYP2C9,
 Increased risk of bleeding in some patients
Camellia sinensis (green tea) ×× Simvastatin17 CYP3A4, P-gp  Simvastatin
×× Rosuvastatin17 OATP1A2, OATP2B1  Rosuvastatin
×× Sildenafil17 CYP3A  Sildenafil
Hydrastis canadensis (goldenseal) ×× Digoxin14,18 CYP3A Small  digoxin, may not be clinically important
×× Midazolam19 CYP3A ↑ Midazolam
Hypericum perforatum (St John’s wort) ×× Amitriptyline14 CYP3A5, P-gp  Amitriptyline
×× Digoxin9,20 CYP3A4, P-gp  Digoxin
×× Gliclazide14 CYP2C9  Gliclazide
×× Nifedipine14 CYP3A4  Nifedipine
×× Nortriptyline14 CYP3A5, P-gp  Nortriptyline
××× OCP: ethinyl oestradiol and norethindrone14,21 CYP3A4/5  Ethinyl oestradiol
 Breakthrough bleeding
↑ Ovarian follicles >30 cm
××× Omeprazole9,14 CYP2C19  Omeprazole
×× Oxycodone9,22 CYP3A  Oxycodone
×× Simvastatin14 CYP3A4  Simvastatin
×× Verapamil14 CYP3A4/5  Verapamil
××× Warfarin9,14 CYP1A2, CYP3A4  Warfarin
×× Zolpidem14 CYP3A4  Zolpidem
×× Metformin13,14  Renal clearance
 Insulin secretionD
 Glycaemic control
× Pravastatin14 CYP3A  Pravastatin
× Repaglinide13,14 CYP3A4  Repaglinide
 Glycaemic control
Momordica charantia (bitter gourd/melon, karela) ×× Glibenclamide12,13 Additive PD effect, CYP3A4D Improved glycaemic control
×× Metformin12,13 Additive PD effectD Improved glycaemic control
Panax ginseng (Korean ginseng) × Warfarin10 Additive PD effectD  INR
Panax quinquefolius (American ginseng) ××× Warfarin9,10  Additive PD effect  Warfarin
↑ TT
Omega-3 fatty acids (fish oil) ×× Warfarin10 Additive PD effect  Factor V
 Factor VII
 or  Anticoagulant effect (conflicting clinical results)
Psyllium hydrophilic mucilloid × Warfarin10  AbsorptionD  INR
Policosanol × Warfarin10 Additive PD effectD  INR
Rhodiola rosea ×× Losartan23 CYP2C9  Losartan
Salvia miltiorrhiza (danshen) ××× Warfarin10 Additive PD effectD  Anticoagulant effect
Silybum marianum (St Mary’s thistle, silymarin, milk thistle) ×× Losartan14 CYP2C9*1/*1 genotypeE  Losartan
× Losartan14 CYP2C9*1/*1 genotype E  Losartan
Scutellaria baicalensis ×× Rosuvastatin9  CYP2C9*1/*1 genotypes E  Rosuvastatin
Ubiquinone (coenzyme Q10) ××× Warfarin10,24,25 Unclear ↑ ↓Anticoagulation
Vaccinium macrocarpon (cranberry) ××× Warfarin9,10,26 CYP2C9, CYP3A4, BRCP ↑ ↓ Warfarin
Unstable INR (depending on timing of coadministration)
Vitamin E ××× Warfarin10 Additive PD effectD ↔ INR
 Risk of bleeding
Vitamin K ××× Warfarin10 Antagonistic PD effect  Anticoagulant effect
Yin Zhi Huang formulaC ×× Omeprazole9 CYP3A4, CYP2C19 ↓ Omeprazole
Zinc ×× Tetracycline antibiotics27  Absorption ↓ Tetracycline antibiotics if simultaneously coadministered
×× Quinolone antibiotics28  Absorption Quinolone antibiotics if simultaneously coadministered
AInteraction confirmed in at least one controlled trial involving humans with or without preclinical studies that was reported in one or more systematic or comprehensive narrative review.
BRisk is categorised as follows: (×), lower risk (of unwanted interaction or theoretical risk; monitor); (××), moderate risk (interaction probable; monitor, adjust dose or avoid); and (×××), higher risk (of serious adverse event from interaction; avoid).
CYin Zhi Huang formula: Artemisia scoparia, Gardeniae fructus, Scutellaria baicalensis Georgi and Lonicerae japonicae flos.
DThe mechanism of potential interaction is either yet to be confirmed and/or is only theoretical.
EThe interaction is likely to only occur in people with CYP2C9*1/*1 genotype.
aPTT, activated partial thromboplastin time; BCRP, breast cancer resistance protein; CMs, complementary medicine products; CYP, cytochrome P450; INR, international normalised ratio of prothrombin time; OATP, organic anion transporting polypeptide; OCP, oral contraceptive pill; PAF, platelet-activating factor; PD, pharmacodynamic; P-gp, P-glycoprotein transporter; PK, pharmacokinetic; TT, thrombin time.

Given this review is not comprehensive, practitioners should also refer to interaction checker databases to identify other potentially important interactions (Table 1).

Table 2 lists numerous examples when a CM altered the plasma or serum concentrations of a drug, yet it is unknown whether these changes are clinically important. Clinical importance cannot be assumed; for example, Echinacea purpurea (with or without Echinacea angustifolia) lowered warfarin levels, yet this did not appear to affect the international normalised ratio of prothrombin time (INR).9,10,14 Similarly, it was unclear whether the small increase in digoxin levels from coadministration with Hydrastis canadensis (goldenseal) was clinically important.14,18

There were quite a few instances where the clinical outcomes from a CM–drug interaction could be favourable. Many of these interactions were due to the additive hypoglycaemic effects of the CM, which improved glycaemic control when coadministered with a hypoglycaemic drug.12.13 Depending on the clinical circumstances, close monitoring may still be advisable to reduce the risk of a hypoglycaemic event. Other examples include specific species and strains of probiotic bacteria that may improve vaccine efficacy and duration of protection.29

Coincidentally, except for Hypericum perforatum (St John’s wort), the common name for many of the CMs commonly implicated in clinically important drug interactions begins with the letter ‘G’: Allium sativum (garlic), Zingiber officinale (ginger), Ginkgo biloba (ginkgo), Hydrastis canadensis (goldenseal), Camellia sinensis (green tea), Gymnema sylvestre (gymnema), Panax quinquefolius (American panax ginseng), Panax notoginseng (Korean/Chinese ginseng) and Eleutherococcus senticosus (Siberian ginseng) and glucosamine. Clinically important drug interactions are summarised below.

Pharmacokinetic interactions

Interactions of P-glycoprotein and CYP enzymes with several herbs are relatively common. It is well established that Hypericum perforatum (St John’s Wort) and one of its bioactive constituents, hyperforin, are potent inducers of intestinal P-glycoprotein and several CYP enzymes, specifically cytochrome P450 family 3 subfamily A member 4 (CYP3A4), which is involved in the metabolism of over 50% of commonly prescribed drugs.30 Extracts with hyperforin doses over 0.3 mg have a substantially increased risk of a drug interaction.30,31 Consequently, some Hypericum perforatum (St John’s wort) products standardise both the hypericin and hyperforin content.

Clinical studies have confirmed that Hypericum perforatum (St John’s Wort) alters the expected pharmacokinetics of drugs commonly used for the prevention and treatment of cardiovascular disease, diabetes and contraception (Table 2).32 In addition, the product information for numerous other drugs often includes an interaction warning for Hypericum perforatum (St John’s wort) when it has been shown to dramatically alter the pharmacokinetics of another drug with similar pharmacokinetic properties.33

Allium sativum (garlic) is known to substantially increase the intestinal expression of P-glycoprotein and inhibits several CYP enzymes. Thus, there is a risk of pharmacokinetic interactions between garlic and numerous drugs (Table 2).34 The risks may be higher with Allium sativum (garlic) products that have a high allicin content (Table 2).35

Hydrastis canadensis (goldenseal) and its main bioactive constituents berberine and hydrastine inhibit cytochrome P450 family 2 subfamily D member 6 (CYP2D6), CYP3A and P-glycoprotein.14,36 The clinical importance of this is uncertain given the results of one clinical trial in which digoxin concentrations were only slightly increased by goldenseal (Table 2).18

Interactions between Camellia sinensis (green tea/green tea supplements) and cardiovascular drugs that are metabolised by CYP3A or transported by P-glycoprotein, organic anion transporting polypeptide (OATP) 1A1 or OATP1A2 are another potential risk, although the clinical significance of some of these interactions is yet to be determined (Table 2).17

Zinc is a common ingredient in CM used to support immune function and reduce the symptoms and duration of the common cold and flu.37 Of clinical importance to general practitioners prescribing tetracycline and quinolone antibiotics is the potential for zinc to reduce the intestinal absorption of these antibiotics.27,28

Pharmacodynamic interactions

Along with pharmacokinetic interactions, there is also the potential risk of serotonin syndrome when Hypercium perforatum (St John’s wort) is combined with another drug that has a serotonergic effect.38 It is therefore recommended that this combination is avoided.39

Interactions that increase the risk of bleeding from antithrombotic or non-steroidal anti-inflammatory drugs are predominantly due to the additive anticoagulant and/or platelet aggregation inhibitory effects of CMs and/or an increase in the plasma concentrations of the drugs. The commonly used herbs, Allium sativum (garlic), Zingiber officinalis (ginger) and Ginkgo biloba (ginkgo) all have antiplatelet and anticoagulant properties.40 Consequently, despite the inconsistent clinical evidence of an increased risk (Table 1), coadministration of these herbs with antithrombotic drugs is generally not recommended.10 Glucosamine supplements should also be avoided in patients taking warfarin. A case series reported an increased INR associated with the concurrent use of glucosamine supplements and warfarin, in which 17 of 21 cases resolved after discontinuation of the glucosamine supplements.41 Coadministration of P. quinquefolius (American ginseng) and warfarin can lower INR levels. Changes in the dose, batch or brand of ginseng may destabilise a patient’s INR and increase the risk of bleeding or clotting.9,10

Interactions can also occur between antihypertensive drugs and several CMs, most notably with Allium sativum (garlic). Garlic formulations containing higher amounts of the bioactive sulfur compound allicin have demonstrated additive hypotensive effects.42

Interactions between glycaemic drugs and Allium sativum (garlic),43 Ginkgo biloba (ginkgo),44 P. quinquefolius (American ginseng),45 Hydrastis canadensis (goldenseal)46 and Gymnema sylvestre (gymnema)12 could also occur. Clinical monitoring is recommended because of potential additive hypoglycaemic effects or unstable glycaemic control due to pharmacodynamic and/or pharmacokinetic interactions.12,13,43–45,47

Interactions between CMs and oral COVID-19 antiviral drugs

Of the three oral COVID-19 antiviral drugs provisionally registered by the Therapeutic Goods Administration in Australia, only ritonavir plus nirmatrelvir has an interaction warning for a CM (St John’s wort). However, there are other CMs that could potentially interact with drugs that patients might be taking to prevent or treat COVID-19 infections (Table 3).

Table 3. Interactions between oral COVID-19 antiviral drugs and complementary medicines marketed for respiratory tract infections or immune supportA
Interaction risk Complementary medicine COVID-19 antiviral drug Mechanism and effect on plasma concentrations of antiviral drug
Clinically important interaction possible Zinc sulfateB Paxlovid® (ritonavir + nirmatrelvir) Lower plasma concentration from zinc chelation of ritonavir in the gut (one RCT)48
Interaction possible, clinical risk uncertain Zinc compoundsB
Althaea officinalisB (marshmallow)
Paxlovid® (ritonavir + nirmatrelvir)
Veklury® (remdesivir)
Lagevrio® (molnupiravir)
Lower plasma level from zinc chelation in the gut (human studies of other drugs)
Lower plasma level from marshmallow reducing absorption in gut (theoretical risk)
Allium sativum (garlic)
Echinacea purpurea
Veklury® (remdesivir) Lower plasma level from CYP3A induction (conflicting results from human studies of other drugs)
Allium sativum (garlic), with high allicin content Paxlovid® (ritonavir + nirmatrelvir) Gastrointestinal adverse effects from complex interaction of CYP enzymes induction/inhibition and/or P-glycoprotein induction (two case reports)49
Glycyrrhiza uralensis and Glycyrrhiza glabra (licorice, gan cao)
Schizonepeta tenuifolia (jing jie)
Paxlovid® (ritonavir + nirmatrelvir)
Veklury® (remdesivir)
Lower plasma concentration from CYP3A induction (conflicting results from human studies of other drugs, or only preclinical studies)
Schisandra chinensis (wu wei zi) Paxlovid® (ritonavir + nirmatrelvir)
Veklury® (remdesivir)
Higher plasma concentration from CYP3A4 inhibition (human studies of other drugs)
Eucalyptus oil Paxlovid® (ritonavir + nirmatrelvir)
Veklury® (remdesivir)
Higher plasma concentration from CYP3A4 inhibition (preclinical studies)
Interaction unlikely Allium sativum (garlic), with low allicin content Paxlovid® (ritonavir + nirmatrelvir) Non-significant lower ritonavir plasma concentration from CYP enzymes and/or P-glycoprotein induction (one RCT)50
Echinacea purpurea Paxlovid® (ritonavir + nirmatrelvir) No effect on plasma concentration despite potential CYP3A induction (one RCT)51
No interactions expected based on PK and PD data Andrographis paniculata
Armoracia rusticana (horseradish)
Astragalus membranaceus (huang qi)
Codonopsis pilosula
Eleutherococcus senticosus (Siberian ginseng, ci wu jia)
Forsythia suspensa (lian qiao)
Ganoderma lucidum (reishi mushroom, ling zhi)
Hedera helix (ivy leaf)
Inula helenium (xuan fu hua)
Isatis tinctoria (banlangen)
Ligustrum lucidum (privet, mi zhen zi)
Lonicera japonica (honeysuckle, ren dong teng)
Magnolia liliiflora (xin yi hua)
Olea europaea (olive leaf)
Platycodon grandiflorus (balloon flower, jie geng)
Salvia officinalis (sage)
Sambucus nigra (elderberry)
Thymus vulgaris (thyme)
Trigonella foenum-graecum (fenugreek)
Verbascum thapsus (mullein)
Vitamin C
Vitamin D3
ACommon ingredients in Therapeutic Goods Administration Listed Medicines58 that are marketed for respiratory tract infection or immune support.
BEither avoid coadministration or administer the antiviral drugs at least two hours before or six hours after ingesting the complementary medicine.33
CYP, cytochrome P450; PD, pharmacodynamic; PK, pharmacokinetic; RCT, randomised controlled trial.
Sources: Natural Medicines (, University of Liverpool drug–drug interaction resources ( or IMgateway interaction database.

The gastrointestinal absorption of the three oral antiviral COVID-19 drugs may be reduced by zinc compounds or Althaea officinalis (Marshmallow root). Zinc sulfate has been shown to lower plasma concentrations of ritonavir through chelation in the gut.48 It is possible that other zinc compounds could also have chelating properties. However, it should be noted that at the time of writing this review, the University of Liverpool’s COVID-19 drug interaction checker ( does not mention the study of Moyle et al48 and only considers whether zinc is likely to affect the metabolism of ritonavir. Coadministration of marshmallow (A. officinalis) root may also reduce the absorption of any three oral antiviral COVID-19 drugs due to the mucilage content of marshmallow root. As a precaution, patients should avoid CMs with either ingredient, or take the antiviral drugs at least two hours before or six hours after ingestion of the CM.48

CMs that induce or inhibit CYP3A4 and/or P-glycoprotein can potentially interact with remdesivir, ritonavir or nirmatrelvir. Pharmacokinetic interactions with molnupiravir are unlikely because it is not metabolised by CYP enzymes or renally excreted.52

Taking Hypericum perforatum (St John’s wort) with ritonavir plus nirmatrelvir should be avoided because there is a theoretical risk that the CM may reduce the plasma concentrations of either drug because of its induction of CYP3A4 and P-glycoprotein, an effect that may take up to two weeks to wear off. Based on this theoretical risk, there is also the potential for a weak interaction between Hypericum perforatum (St John’s wort) and remdesivir. According to the University of Liverpool’s COVID-19 drug interaction checker, strong inducers of CYP3A4 are likely to have a clinically unimportant effect on remdesivir concentrations (~15–30% reduction) and, as such, dose adjustments are not recommended. However, other interaction checkers such as Natural Medicines ( take a more cautious approach and recommend against coadministration. Given the limited evidence for molnupiravir,53 it may still be preferable to prescribe remdesivir despite the theoretical risk of reduced efficacy and, of course, stop Hypericum perforatum (St John’s wort), at least temporarily.

A controlled trial evaluated the effects of two weeks of Echinacea purpurea51 on ritonavir and another study evaluated the effects of four days of a Allium sativum (garlic) product with a low allicin content.50 Neither of the CMs reduced ritonavir plasma concentrations.35,36 This might be attributed to ritonavir’s potent inhibition of CYP3A4 and P-glycoprotein, which potentially counteracted any induction effects from the CMs.51

A pharmacokinetic study of a Allium sativum (garlic) product with a high allicin content revealed reduced plasma concentrations of saquinavir, another protease inhibitor,35 and another case study reported that approximately six stir-fried garlic cloves three times per week reduced serum concentrations of atazanavir, as well as its clinical effectiveness.54

Most patients using prescription drugs for COVID-19 are at a high risk of complications. Ensuring optimum drug concentrations is likely to be a priority for these patients, including those who are strong proponents of CM. Therefore, the potential interactions between CMs and drugs prescribed for COVID-19 listed in Table 3 should be discussed with all patients.

Reducing the risk of CM–drug interactions

There is a real opportunity for healthcare professionals to engage in informed conversations that promote the safe and appropriate use of CMs (Table 4).

Table 4. Identifying and discussing complementary medicine–drug interactions in the context of shared decision making
  • Take a full medication history for prescription, over-the-counter and complementary medicines
    Tip: Use non-technical terms that are culturally appropriate and non-judgemental. Explain why you need this information; for example, ‘People often use natural therapies, vitamins, herbs, teas, super-foods, and traditional remedies and report benefits. Some can interfere with your medicines, so it’s important we talk about them’
  • Suspect interactions when there is polypharmacy or the clinical presentation correlates with known pharmacological effects or toxicities of the drug or CM
    Tip: Ask about CM brand changes or starting a new bottle. Explain that herbal constituents can differ between brands and batches
  • Use an interaction checker to screen for potential CM–drug interactions
    Tip: Only trust a ‘no interaction risk’ when searching a comprehensive CM database (Table 1)
  • Explain potential risks or benefits from the interaction and whether they are theoretical or proven. Provide consumer information
    Tip: Patients can be sceptical about medical doctors’ CM expertise. Be clear about uncertainties, including your information sources. Offer to do more research or follow‑up with an expert
  • Ask and actively listen to understand reasons for CM/drug choices, preferences/values, risk thresholds
    Tip: Use open-ended questions, be respectful, find out what matters the most and what information sources and opinions influence decisions
  • Engage in shared decision making: affirm there are choices, discuss the options (eg stop/adjust drug or CM, use an alternative, monitor), discuss the pros and cons, check understanding, elicit preferences, allow time for deliberation, remain respectful of patient preferences and decisions
    Tip: When making recommendations, acknowledge whether these align with the patient’s preferences and any perceived or observed benefits from using the CM. When relevant, involve caregivers (or other key people) in the decision-making process
  • Document the discussion, any recommendations and decisions made, and plans to monitor and follow-up
    Tip: Provide written information about key facts, print a copy or excerpt of the consultation notes
CM, complementary medicine.

A CM–drug interaction should be suspected when the clinical presentation correlates with the drug’s clinical effects or a known adverse effect. Polypharmacy (five or more medicines) also increases the risk of drug interactions.5 People living with chronic health conditions are more likely to use CMs alongside multiple over-the-counter and prescription drugs.4

Pharmacodynamic interactions are easier to predict because they correlate with the anticipated clinical effects of the compounds. Although the scientific evidence of clinical efficacy is limited for many CMs, these types of interactions should still be considered, even though some may be welcomed, such as improved glycaemic control (Table 3), which may still require the monitoring of blood glucose.

Predicting pharmacokinetic interactions is more difficult. Clinically important interactions with drugs are more likely when there is a narrow therapeutic index and with CMs that are known perpetrators. The risks are also higher with larger doses of constituents known to cause CM–drug interactions. However, the formulation or minimum dose required for an interaction to occur are not always clear from the available research.

Identifying CM–drug interactions is further complicated by the wide variations in CM quality (especially for raw herbs and products purchased outside of Australia) and their different constituent profiles, formulations and doses.6 CM products, especially herbs when used in a traditional context, often have multiple ingredients that may also interact with each other.55 Therefore, a CM–drug interaction may be triggered by changing the CM product batch or brand. Unclear labelling and low health literacy can exacerbate these risks; for example, the American, Korean/Chinese and Siberian ginsengs vary in their pharmacological effects and interaction risks. Patients may not realise this and unwittingly switch between CM products containing ‘ginseng’, and therefore tell their healthcare practitioner that there have been no changes in their CM use.

Close monitoring of CM use or avoidance is warranted when the drug has a narrow therapeutic index or the consequences of an interaction are serious.56 However, there will be other instances when the benefits of a CM warrant its continuation and other management options should be implemented, such as monitoring clinical outcomes or prescribing another drug with equivalent effectiveness that is unlikely to interact with the CM. Decisions about medicine use, dose adjustments and cessation must also consider patient preferences, including any observed or perceived benefits that are motivators for ongoing use.37 Shared decision making may improve treatment compliance (Table 4).57


Vigilance, an understanding of clinical pharmacology and the nuances of CMs, and effective communication skills are required to prevent and identify unwanted CM–drug interactions.

Key points

  • Most Australians who use CMs are also using prescription and over-the-counter medicines.
  • Pharmacokinetic CM–drug interactions can alter the absorption, distribution, metabolism and elimination of a drug.
  • Pharmacodynamic CM–drug interactions can negate or add to a drug’s clinical effects.
  • Clinically important CM–drug interactions are more likely when there is a narrow therapeutic index, polypharmacy or changes in CM brands and batches.
  • The quality use of medicines includes asking patients about CM use and engaging in informed discussions about CM–drug interactions.
Competing interests: Both authors have separately received payments for providing expert advice about traditional, complementary and integrative medicine, including nutraceuticals, to industry, government bodies and non-government organisations, and have spoken at workshops, seminars and conferences for which registration, travel and/or accommodation has been paid for by the organisers. JH has received funding from industry to conduct clinical research into the potential role of the microbiome, probiotics and prebiotics in specific conditions.
Provenance and peer review: Commissioned, externally peer reviewed.
Funding: None.
Correspondence to:
The authors thank Keiran Cooley and Jocelin Chan for their expert advice, and UnityHealth Pty Ltd for providing access to the Integrative Medicine Gateway during the preparation of this manuscript.
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  1. World Health Organization (WHO). Key technical issues of herbal medicines with reference to interaction with other medicines. Geneva, WHO, 2021. Available at [Accessed 23 March 2023]. Search PubMed
  2. Barnes J. Quality, efficacy and safety of complementary medicines: Fashions, facts and the future. Efficacy and Safety. Perspectives on complementary and alternative medicine. Routledge, 2019; p. 306–18. Search PubMed
  3. Parvez MK, Rishi V. Herb-drug interactions and hepatotoxicity. Curr Drug Metab 2019;20(4):275–82. doi: 10.2174/1389200220666190325141422. Search PubMed
  4. Harnett JE, McIntyre E, Steel A, Foley H, Sibbritt D, Adams J. Use of complementary medicine products: A nationally representative cross-sectional survey of 2019 Australian adults. BMJ Open 2019;9(7):e024198. Search PubMed
  5. Li Y, Zhang X, Yang L, et al. Association between polypharmacy and mortality in the older adults: A systematic review and meta-analysis. Arch Gerontol Geriatr 2022;100:104630. Search PubMed
  6. Coxeter P, McLachlan AJ, Duke C, Roufogalis B. Herb–drug interactions: An evidence based approach. Curr Med Chem 2004;11(11):1513–25. Search PubMed
  7. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138(1):103–41. Search PubMed
  8. Niu J, Straubinger RM, Mager DE. Pharmacodynamic drug-drug interactions. Clin Pharmacol Ther 2019;105(6):1395–1406. doi: 10.1002/cpt.1434. Search PubMed
  9. Zhang XL, Chen M, Zhu LL, Zhou Q. Therapeutic risk and benefits of concomitantly using herbal medicines and conventional medicines: From the perspectives of evidence based on randomized controlled trials and clinical risk management. Evid Based Complement Alternat Med 2017;2017:9296404. Search PubMed
  10. Tan CSS, Lee SWH. Warfarin and food, herbal or dietary supplement interactions: A systematic review. Br J Clin Pharmacol 2021;87(2):352–74. Search PubMed
  11. Sattar A, Willman JE, Kolluri R. Possible warfarin resistance due to interaction with ascorbic acid: Case report and literature review. Am J Health Syst Pharm 2013;70(9):782–86. Search PubMed
  12. Thikekar AK, Thomas AB, Chitlange SS. Herb–drug interactions in diabetes mellitus: A review based on pre-clinical and clinical data. Phytother Res 2021;35(9):4763–81. Search PubMed
  13. Gupta RC, Chang D, Nammi S, Bensoussan A, Bilinski K, Roufogalis BD. Interactions between antidiabetic drugs and herbs: An overview of mechanisms of action and clinical implications. Diabetol Metab Syndr 2017;9:59. Search PubMed
  14. Rombolà L, Scuteri D, Marilisa S, et al. Pharmacokinetic interactions between herbal medicines and drugs: Their mechanisms and clinical relevance. Life (Basel) 2020;10(7):106. Search PubMed
  15. Gallicano K, Foster B, Choudhri S. Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers. Br J Clin Pharmacol 2003;55(2):199–202. Search PubMed
  16. Rahman K, Billington D. Dietary supplementation with aged garlic extract inhibits ADP-induced platelet aggregation in humans. J Nutr 2000;130(11):2662–65. Search PubMed
  17. Werba JP, Misaka S, Giroli MG, et al. Update of green tea interactions with cardiovascular drugs and putative mechanisms. J Food Drug Anal 2018;26 Suppl 2:S72–77. Search PubMed
  18. Gurley BJ, Swain A, Barone GW, et al. Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos 2007;35(2):240–45. Search PubMed
  19. Gurley BJ, Swain A, Hubbard MA, et al. Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo. Clin Pharmacol Ther 2008;83(1):61–69. Search PubMed
  20. Johne A, Brockmöller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66(4):338–45. Search PubMed
  21. Berry-Bibee EN, Kim MJ, Tepper NK, Riley HE, Curtis KM. Co-administration of St. John’s wort and hormonal contraceptives: A systematic review. Contraception 2016;94(6):668–77. Search PubMed
  22. Nieminen TH, Hagelberg NM, Saari TI, et al. St John’s wort greatly reduces the concentrations of oral oxycodone. Eur J Pain 2010;14(8):854–59. Search PubMed
  23. Thu OK, Spigset O, Nilsen OG, Hellum B. Effect of commercial Rhodiola rosea on CYP enzyme activity in humans. Eur J Clin Pharmacol 2016;72(3):295–300. Search PubMed
  24. Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet 1994;344(8933):1372–73. Search PubMed
  25. Shalansky S, Lynd L, Richardson K, Ingaszewski A, Kerr C. Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: A longitudinal analysis. Pharmacotherapy 2007;27(9):1237–47. Search PubMed
  26. Yu C-P, Yang M-S, Hsu P-W, Lin S-P, Hou Y-C. Bidirectional influences of cranberry on the pharmacokinetics and pharmacodynamics of warfarin with mechanism elucidation. Nutrients 2021;13(9):3219. Search PubMed
  27. Penttilä O, Hurme H, Neuvonen P. Effect of zinc sulphate on the absorption of tetracycline and doxycycline in man. Eur Clin Pharmacol 1975;9:131–34. Search PubMed
  28. Campbell NR, Kara M, Hasinoff BB, Haddara WM, McKay DW. Norfloxacin interaction with antacids and minerals. Br J Clin Pharmacol 1992;33(1):115–16. Search PubMed
  29. Zimmermann P, Curtis N. The influence of probiotics on vaccine responses – a systematic review. Vaccine 2018;36(2):207–13. Search PubMed
  30. Chrubasik-Hausmann S, Vlachojannis J, McLachlan AJ. Understanding drug interactions with St John’s wort (Hypericum perforatum L.): Impact of hyperforin content. J Pharm Pharmacol 2019;71(1):129–38. Search PubMed
  31. Mueller SC, Uehleke B, Woehling H, et al. Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxin. Clin Pharmacol Ther 2004;75(6):546–57. Search PubMed
  32. Nicolussi S, Drewe J, Butterweck V, Meyer zu Schwabedissen HE. Clinical relevance of St. John’s wort drug interactions revisited. Br J Clin Pharmacol 2020;177(6):1212–26. Search PubMed
  33. Adiwidjaja J, Boddy AV, McLachlan AJ. Physiologically based pharmacokinetic modelling of hyperforin to predict drug interactions with St John’s Wort. Clin Pharmacokinet 2019;58(7):911–26. doi: 10.1007/s40262-019-00736-6. Search PubMed
  34. Foster BC, Foster MS, Vandenhoek S, et al. An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic. J Pharm Pharm Sci 2001;4(2):176–84. Search PubMed
  35. Piscitelli SC, Burstein AH, Welden N, Gallicano KD, Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis 2002;34(2):234–38. Search PubMed
  36. Asher GN, Corbett AH, Hawke RL. Common herbal dietary supplement–drug interactions. Am Fam Physician 2017;96(2):101–7. Search PubMed
  37. Arentz S, Hunter J, Deed G. Integrating traditional and complementary medicine recommendations into clinical practice guidelines for people with diabetes in need of palliative and end-of-life care: A scoping review. J Altern Complement Med 2020;26(7):571–91. Search PubMed
  38. Bonetto N, Santelli L, Battistin L, Cagnin A. Serotonin syndrome and rhabdomyolysis induced by concomitant use of triptans, fluoxetine and hypericum. Cephalalgia 2007;27(12):1421–23. Search PubMed
  39. Canenguez Benitez JS, Hernandez TE, Sundararajan R, et al. Advantages and disadvantages of using St. John’s Wort as a treatment for depression. Cureus 2022;14(9):e29468. doi: 10.7759/cureus.29468. Search PubMed
  40. Lippert A, Renner B. Herb–drug interaction in inflammatory diseases: Review of phytomedicine and herbal supplements. J Clin Med 2022;11(6):1567. Search PubMed
  41. Knudsen JF, Sokol GH. Potential glucosamine–warfarin interaction resulting in increased international normalized ratio: Case report and review of the literature and MedWatch database. Pharmacotherapy 2008;28(4):540–48. Search PubMed
  42. Chan W-JJ, McLachlan AJ, Luca EJ, Harnett JE. Garlic (Allium sativum L.) in the management of hypertension and dyslipidemia – a systematic review. J Herb Med 2020;19:100292. Search PubMed
  43. Han D-G, Cho S-S, Kwak J-H, Yoon I-S. Medicinal plants and phytochemicals for diabetes mellitus: Pharmacokinetic characteristics and herb–drug interactions. J Pharm Investig 2019;49(6):603–12. Search PubMed
  44. Kudolo GB. The effect of 3-month ingestion of Ginkgo biloba extract (EGb 761) on pancreatic βcell function in response to glucose loading in individuals with non-insulin-dependent diabetes mellitus. J Clin Pharmacol 2001;41(6):600–11. Search PubMed
  45. Vuksan V, Stavro MP, Sievenpiper JL, et al. Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes. Diabetes Care 2000;23(9):1221–26. Search PubMed
  46. Nguyen JT, Tian D-D, Tanna RS, et al. Assessing transporter-mediated natural product–drug interactions via in vitro–in vivo extrapolation: Clinical evaluation with a probe cocktail. Clin Pharmacol Ther 2021;109(5):1342–52. Search PubMed
  47. Devangan S, Varghese B, Johny E, Gurram S, Adela R. The effect of Gymnema sylvestre supplementation on glycemic control in type 2 diabetes patients: A systematic review and meta-analysis. Phytother Res 2021;35(12):6802–12. Search PubMed
  48. Moyle G, Else L, Jackson A, et al. Coadministration of atazanavir–ritonavir and zinc sulfate: Impact on hyperbilirubinemia and pharmacokinetics. Antimicrob Agents Chemother 2013;57(8):3640–44. Search PubMed
  49. Laroche M, Choudhri S, Gallicano K, Foster B. Severe gastrointestinal toxicity with concomitant ingestion of ritonavir and garlic. Can J Infect Dis 1998;9 Suppl A:471P. Search PubMed
  50. Gallicano K, Foster B, Choudhri S. Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers. Br J Clin Pharmacol 2003;55(2):199–202. Search PubMed
  51. Penzak SR, Robertson SM, Hunt JD, et al. Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir–ritonavir exposure in healthy subjects. Pharmacotherapy 2010;30(8):797–805. Search PubMed
  52. Atmar RL, Finch N. New perspectives on antimicrobial agents: Molnupiravir and nirmatrelvir/ritonavir for treatment of COVID-19. Antimicrob Agents Chemother 2022;66(8):e0240421. doi: 10.1128/aac.02404-21. Search PubMed
  53. Focosi D. Molnupiravir: From hope to epic fail? Viruses 2022;14(11):2560. Search PubMed
  54. Duncan A, Mills J. An unusual case of HIV virologic failure during treatment with boosted atazanavir. AIDS 2013; 27(8):1361–62. Search PubMed
  55. Gurley BJ, Tonsing-Carter A, Thomas SL, Fifer EK. Clinically relevant herb–micronutrient interactions: When botanicals, minerals, and vitamins collide. Adv Nutr 2018;9(4):524s–32s. Search PubMed
  56. Cohen M, Hunter J. Complementary medicine products: Interpreting the evidence base. Intern Med J 2017;47(9):992–98. Search PubMed
  57. Deniz S, Akbolat M, Çimen M, Ünal Ö. The mediating role of shared decision-making in the effect of the patient–physician relationship on compliance with treatment. J Patient Exp 2021;8:23743735211018066. Search PubMed
  58. Australian Department of Health. Australian Register of Therapeutic Goods. 2023. Available at [Accessed 31 Search PubMed

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