Mechanisms for herbal interactions with prescription drugs
A herb-drug interaction is defined as any pharmacological modification caused by a herbal substance(s) to another exogenous-chemical (a prescription medication) in the diagnostic, therapeutic or other action of a drug in or on the body.
- A herb can potentially mimic, increase, or reduce the effects of co-administered drugs and the consequences of these interactions can be beneficial, undesirable or harmful effects.
The underlying mechanisms for most reported drug interactions with herbal medicines are:
I. 1. Pharmacokinetic (PK) herb-drug interactions
PK interactions result from alteration of absorption, distribution, metabolism or elimination of a drug by a herbal product or a dietary supplement.
As known herbal components are chemicals and, like drugs, they are metabolized by phase I and phase II pathways.
I.1.A. Phase I pathway
Phase I processes include oxidation, reduction, hydrolysis and hydration resulting in the formation of functional groups (OH, SH, NH2 or COOH) that impart the metabolite with increased polarity compared to the parent compound.
1- In phase I processes, the cytochrome P450 (CYP) is responsible for the metabolism of a variety of xenobiotics and endobiotics.
2- The effect of phase I enzymes on the drug’s activity depends on the nature of the drug.
Some drugs (e.g., cyclophosphamide, ifosfamide) are introduced into the body as prodrugs, whose structure must be altered by phase I enzymes to become active.
3- Drugs that are introduced into the body in their active forms are de-activated by phase I enzymes as a part of the process of their clearance or removal from the body.
I.1.B. Phase II pathway
Phase II processes include sulfation, methylation, acetylation, glucuronidation, glutathione conjugation and fatty acid conjugation.
In conjugation, a new chemical entity is attached to a drug’s functional group to make the drug:
a- more polar,
b- facilitating its removal from the body.
Glucuronidation is catalyzed by uridine diphospho-glucuronosyl transferases (UGTs) and involves the transfer of the glucuronic acid residue from uridine 5--diphosphoglucuronic acid to a hydroxyl or a carboxylic acid group on the compound.
- As the case with CYPs, UGTs metabolize a broad range of endogenous and exogenous substances.
- Phase II enzymes are also considered to have a significant role in disabling and exporting chemical carcinogens.
- Not all drugs go through the phase II metabolizing enzymes; many are removed after metabolism by phase I cytochrome P450 enzymes.
I.2. Role of drug metabolizing enzymes and transporters in herbal-drug interaction
Herbal or even dietary phytochemicals can cause:
1- induction of drug metabolizing enzymes (DME’s: phase I and phase II) and
2- transporters via nuclear hormonal and non-hormonal receptors.
I.2.A. Role of CYP450 in herbal-drug interaction
☻The CYPs are a group of enzymes found primarily in the liver and the gut mucosa; and lower levels may be found in the lungs, the kidneys and brain.
☺82% of the drugs that interact with herbs are substrates for various cytochrome P450s (CYPs).
☺The enzymes catalyze phase I biotransformation of a variety of compounds including most drugs.
☻CYP3A is the most abundant isozyme in the human liver; representing approximately 30% of total hepatic CYP and more than 70% of intestinal CYP activity.
☺Moreover CYP3A is responsible for the metabolism of more than 50-70% of all prescribed drugs.
Xenobiotics, drugs, dietary or herbal constituents can interact in several ways with the CYP450 system resulting in altered drug clearance and effect.
1• A compound may be a substrate of one or several CYP isoforms. If the main isoform is saturated, it becomes a substrate for the secondary enzyme(s).
2• A compound can be an inducer of a CYP isoform, either of the one it is a substrate for, or may induce several different enzymes at the same time.
The process of induction increases the rate of metabolism of substrates of that enzyme.
3• A compound may be an inhibitor of CYP450 enzymes, and a compound may inhibit several isoforms including a substrate.
In humans, there is a wide range of variation in expression of CYP450 enzymes.
1- This accounts for the inter-individual variability in:
a- Responses to drugs,
b- The occurrence
c- Severity of adverse effects
d- Drug interactions.
2- Factors affecting individual variation in CYP450 expression are:
b- genetics including gender and race;
c- disease, including both general infection as well as specific hepatic conditions.
The expression of CYP3A4, CYP3A5, CYP2B6 and CYP2C8 is tightly regulated by the nuclear factor pregnane x receptor (PXR/NR112), which is activated by certain herbal components such as hyperforin from St John’s wort.
The following herbal remedies as, in vitro, are inhibitors of the various CYP isozymes with IC50 values 20- 1000 mg/mL.
The herbs identified were:
1- Devil's claw root (Harpagophytum procumbens),
2-Feverfew herb (Tanacetum parthenium),
3- Fo-ti root (Polygonum multiflorum),
4- Kava-kava root (Piper methysticum),
5-Peppermint oil (Mentha piperita),
6- Eucalyptus oil (Eucalyptus globulus) and
7- Red clover blossom (Trifolium pratense).
I.2.B. Role of efflex proteins and transporters in drug-herbal interaction
29.4% of the drugs that interact with herbs have been identified as substrates for P-glycoprotein (P-gp) and multiple resistance proteins (MRPs).
P-gp and MRPs are members of the ATP binding cassette family (ABC), responsible for transporting compounds against a steep concentration gradient (efflux).
1- A drug transporter, P-gp, is found in the intestines, liver and kidneys. It plays important roles in the absorption, distribution or elimination of drugs from various tissues.
2- The multi-drug resistance-associated protein (MRP) is another famous ATP-binding cassette transporter involved in biliary, renal, and intestinal secretion of numerous organic anions, including:
1- Endogenous compounds such as bilirubin
2- Exogenous compounds such as drugs and toxic chemicals.
Evidence suggests that the transporter interacts directly with:
1- Non-polar substrates within the membrane environment of the cell and may act as drug flippest, facilitating the efflux of the drug from the enterocytes to the intestinal lumen.
As a result of such efflux,
- drug absorption is reduced and
- bioavailability of xenobiotics is decreased at the target organs.
CYPs, P-gp and MRPs can be induced and inhibited by several xenobiotics, including drugs and herbal medicines and is also regulated by PXR.
Several herbs and naturally occurring compounds are found to modulate P-gp, e.g.,
- Curcumin, ginsenosides, piperine, sylimarin and catechins are affect P-glycoprotein-mediated drug transport.
- Flavonoids may induce or inhibit P-gp, for example tangeretin inhibits P-gp, whereas quercitin and kaempferol are P-gp inducers.
I.2.C. Combined effects
23.5% of the reported drugs that interact with herbs are dual substrates for both CYP3A4 and intestinal efflux proteins, and therefore, they have a much higher potential for interaction with herbs that also modulate CYP3A4 and P-gp/MPRs.
Thus the modulation of intestinal and hepatic efflux proteins and CYP3A4 by herbal medicines represents a potentially important mechanism by which the bioavailability of co-administered drugs can be modulated.
Any inhibitory effect of herbs on efflux proteins and CYP3A4 may result in enhanced plasma and tissue concentrations leading to toxicity.
Any inductive effect may cause reduced drug concentration leading to decreased drug efficacy and treatment failure.
I.2.D. Some dietary phytochemical modulators of metabolizing enzymes
There are many non drug inducers and inhibitors of CYP450, among the best known are grapefruit juice which inhibits intestinal CYP3A4 activity.
A- Grapefruit constituents that appear to promote this effect are:
1- furanocoumarins (psoralens),
e.g., bergamottin and its derivative 6`,7`-dihydroxy- bergamottin, and its dimers.
B- Cruciferous vegetables, (e.g., cabbage family) induce CYP1A2 through its glucosilinated indole-3-carbinol contents and increase the activity of phase II enzymes; they are thus important as anticarcinogenic agents.
3- tea which is found to induce CYP1A2, CYP2B and also to stimulate the activity of some phase II conjugation enzymes.
II. Pharmacodynamic (PD) herb-drug interactions
PD interactions may occur when constituents of herbal products have either synergistic or antagonist activity in relation to a drug.
As a result,
1- Concentration-dependent activity of a therapeutic molecule is altered at the site of action at the drug-receptor level.
2- Displacement from plasma protein binding sites may increase the availability of drug to its active site.
3- Competition at receptor sites, by active agents in the herb, may interfere with the pharmacological response,
a- agents with similar actions are pharmacologically additive,
b- agents with opposite actions are pharmacologically antagonistic.
III. Other factors influencing drug-herb interactions
1- The interference of any laxative or bulk-forming herb with the absorption of any intestinally absorbed drug by speeding intestinal transit.
The most popular stimulant laxative herbs are the antharnoid-containing plants including:
1- Senna (Cassia senna and C. angustifolia),
2- Cascara sagrada (Rhamnus purshiana) bark,
3- The dried exudate from the aloe vera (Aloe barbadensis) leaf,
4- Soluble fibers including guar gum.
Many of the drugs are interacting with herbal medicines, they have: Narrow therapeutic indices, thus a small change in their plasma concentration lead to a marked alteration in their therapeutic effect and/or toxicity. Warfarin, digoxin, theophylline and cyclosporine are examples of these drugs.
1- Drug metabolism enzymes
3- Food habits,
5- Health status
6- Genetic make up.
The use of multiple medications will significantly increases the risk of potential herb-drug interaction, especially in the elderly or certain groups of consumers, such as cancer patients.
The risk for potential interactions when consuming:
- two products is 6%,
- five products 50%;
- the risk increases to 100% when consuming eight or more products.
Clinical implication of drug-herbal interactions is persuaded by variety of factors such as
1. Herb type and species,
2. Timing of herbal intake,
3. Dose and dosing regimen,
4. Route of drug administration
5. Therapeutic range.
Popular herbal products and their interactions with therapeutic drugs
1. St. John's Wort
- St. John's Wort accounted for 9 million U.S. dollars in sales in 2005, making it the ninth highest selling botanical.
Hypericum perforatum L.
It is marketed as an extract of the dried flowering portion of the plant Hypericum perforatum.
It is presented in different forms (tea, tincture, tablet or capsule) alone or in combination products.
Has many trade names: e.g.
-St. john’s Wort High Potency,
-St. john’s Wort Preferred,
-St. john’s Wort Time Release.
1- Major constituents of pharmacological interest hyperforin, hypericin.
2- Other components such as pseudohypericin, adhyperforin, biapigenin, quercetin, quercitrin, isoquercitrin, hyperoside and rutin.
- Commercial preparations are often standardized to 0.3 mg per capsule hypericin.
1- Sedative, anxiolytic.
2- Relief of depression, anxiety.
3- It is applied topically for wounds, minor burns, inflammation.
- Several clinical studies have demonstrated the potential benefits of St. John's Wort compared with conventional therapy in the treatment of mild to moderate depression.
In vitro and in vivo studies on animals have shown that:
1- Hyperforin is a lipophilic compound, has a binding affinity for a variety of neurotransmitter receptors, (serotonin, g-aminobutyric acid, adenosine and other muscarinic receptors).
2- It is a potent inhibitor of synaptosomal uptake of 5-HT, norepinephrine and dopamine. So, its effective as tricyclic antidepressants in relieving the symptoms of mild to moderate depression but not in severe depression.
The mechanism by which SJW interacts with all these medications is:
A. SJW and CYP450 modulation
Hydroxylation mediated by CYP3A and CYP2B enzymes is the primary pathway of metabolism of hyperforin. The four major metabolites that had been detected in vitro using rat liver microsomes indicated hydroxyl groups in positions 19, 24, 29 and 34.
M1 : R2=R3=R4=CH3, R1=CH2OH
M2 : R1=R3=R4=CH4, R2=CH2OH
M3 : R1=R2=R4=CH3, R3=CH2OH
M4 : R1=R2=R3=CH3, R4=CH2OH
When plasma concentration of hyperforin in human reach a maximum of 0.17-0.5 mM, potential drug interactions with several CYP substrates.
In vitro study had showed the St John's Wort crude extract is competitively, inhibits CYP3A4, e.g., biapigenin being the most potent inhibitor of CYP3A4.
- long-term effect of SJW can elevate metabolism of xenobiotics, consequently reducing their bioavailability, - short-term SJW has inhibitory effect on CYP may actually raise drug levels.
B. SJW and efflex proteins modulation
In vivo studies, long-term (14 days) exposure to SJW 900 mg/day leads to higher expression of MDR1 and a significant increase in P-gp-mRNA expression in rat intestine.
The action of SJW is dose-and exposure dependent:
1- Short-term exposure of SJW with drugs like erythromycin, saquinavir and ritonavir, can enhance drug absorption due to competitive inhibition of P-gp/MRP-mediated efflux.
2- Chronic exposure induces intestinal P-gp resulting in reduced intestinal absorption possibly through enhanced drug efflux.
St. John’s Wort & interactions:
Clinical studies show that:
1- SJW is lowering plasma concentrations of variety of drugs such as:
- Sedatives and antidepressants (amitriptyline)
- Immunosuppressants (cyclosporine),
- Anticoagulants (phenprocoumon, warfarin)
- Cardiovascular (digoxin),
- Antihistamines (fexofenadine),
- Anti-HIV agents (indanavir),
- Analgesics (methadone),
- Cholesterol lowering drugs (simvastatin),
- Asthma medication (theophylline),
- Oral contraceptives.
Echinacea plant (Family: Compositae).
It is used as antiseptic and analgesic.
It was the second most popular herb in the United States with about 68 million U.S. dollars in sales.
E. angustifolia E. purpurea E. pallida roots
Marketed Echinacea is prepared from the alcoholic extract of three species.
Echinacea is available in numerous forms, including teas, capsules, prepared beverages, and chewing gum marketed under various trade names by many companies. It is combined frequently with conventional over-the-counter cold medications such as dextromethorphan (Benylin®).
Root parts have more:
1- Volatile oils (such as caryophyllene and humulene).
2- Pyrrolizidine alkaloids (such as tussilagine and isotussilagine) and
than the above-ground parts.
The active components of the upper plant are:
1- Caffeic and ferulic acid derivatives (such as cichoric acid and echinacoside).
2- Complex polysaccharides.
1- Internally, for treating common cold, cough, bronchitis, and inflammation of the mouth and pharynx.
2- Topically, to treat snake bites and for poorly healing wounds.
Main alkaloids of Echinacea roots
Some of the hydrophilic components of E. purpurea extract.
Some volatile constituents of Echinacea roots
1- Echinacea may be best known as an immunostimulant. Echinacea has ability to shorten the duration and lessen the symptoms of an illness by
-boosting the phagocytic immune cell response,
- stimulation of tumor necrosis factor.
2- Chronic ingestion of Echinacea may potentially do more harm than good. Increased reactivity of the phagocytic system may result in the potential generation of free radicals that cause damage to the host.
3- Cichoric acid has phagocytosis stimulatory activity, Cichoric acid has also recently been shown to inhibit hyaluronidase and to protect collagen type III from free radical induced degradation,
4- Echinacoside has antibacterial and antiviral activity.
5- The lipophilic alkamide, and polysaccharides have immunomodulatory activity.
Alkamides have been also shown to posses anti-inflammatory activity, attributed to their ability to inhibit both cyclooxygenase (COX-1 and COX-2) enzymes.
Echinacea & interactions
Echinacea & CYPs: A potential interactions with substrates of cytochrome P450 CYP3A4 and CYP1A2.
Echinacea & immunosuppressives:
1- Interference with immunosuppressive therapy. Exacerbation of autoimmune disorders such as systemic lupus erythematosus. Echinacea not be taken by patients receiving immunosuppressive medications or patients with autoimmune conditions or HIV infection.
Echinacea & hepatotoxic drugs:
long term use (>8 weeks) of Echinacea has been associated with hepatotoxicity, many studies warn of concomitant use of Echinacea and other hepatotoxic drugs such as methotrexate and anabolic steroids.
- Gingko biloba L. (Family Ginkogoaceae) indigenous to China, Japan and Korea .
- It is the most sold medicinal plants in the world with estimates of the annual sales of over 1 billion dollars.
- Most of the sales concern special standardized extracts from the leaves.
Ginkgo fruits, leaves and stem
3.1. Preparations, contents and uses
Ginkgo biloba is available in different liquid or solid pharmaceutical forms for:
1- Oral intake
2- Parenterally for homeopathic use.
G. biloba special extract EGb 761® is registered in Germany for the treatment of dementia disorders.
Clinical trials showed the effectiveness of EGb 761 in managing mild-to-moderate dementia of the Alzheimer’s disease patients.
Chemical analysis of the standardized products found in the market revealed the presence of:
1- Terpene trilactones (6.0%),
2- Flavonol glycosides (24.0%), (quercetin, kaempferol, isorhamnetin)
3- The biflavone, Ginkgetin, is a powerful antiinflammatory compound.
4- Proanthocyanidins (7.0%).
5- Diterpene trilactones (ginkgolides A, B, C).
6- Alkylphenol compounds (ginkgolic acids, ginkgols and bilobols) are found to posses cytotoxic, mutagenic and slight neurotoxic properties and their presence is undesirable in Ginkgo marketed extracts.
Ginkgo biloba is approved in Germany for the treatment of cerebral circulatory disturbances.
It is used to treat peripheral arterial circulatory disturbance, high altitude sickness and equilibrium disorders like tinnitus of vertigo.
Flavone glycosides posses:
2- Platelet aggregation-inhibiting properties,
3- Reduce capillary fragility
Gingko & interactions
Gingko & CYPs:
140 mg G. biloba extract twice daily for 12 consecutive days. A 67.5% decrease on the ratio of omeprazole to 5-OH-omeprazole concentrations and a decrease in urinary excretion of 5-hydroxyomeprazole.
G. biloba extract induced CYP2C19 mediated hydroxylation of omeprazole, and concomitantly reduced urinary excretion of 5-hydroxyomeprazole.
Gingko & anticoagulants/NSAI:
40 mg of G. biloba with aspirin, ibuprofen, and warfarin leading to bleeding that cause eye hemorrhage, cerebral hemorrhage and coma.
The interaction is due to the presence of ginkgolide B, has been shown to decrease platelet aggregation and displace platelet-activating factor from its binding sites, thus potentially decreasing blood coagulation.
These data suggest that ginkgo should not be taken with oral anticoagulants, preparations containing non-steroidal anti-inflammatory drugs
Caution also should be used when ginkgo is taken in conjunction with other agents that could compromise hemostasis, such as vitamin E or oils containing omega III fatty acids.
Gingko & antidepressants: A case report of a patient, who lapsed into reversed coma after taking 20 mg trazodone (an antidepressant drug) twice daily with the addition of 80 mg G. biloba daily.
G. biloba is act as an antagonist of gamma-aminobutyric acid (GABA) activity at benzodiazepine binding sites resulting in increased sedation effect.
Phytoestrogens containing herbs
Phytoestrogens are secondary plant metabolites with estrogenic properties.
Black cohosh Red clover Chaparral
(Cimicifuga racemosa) (Trifolium pratense) (Larrea tridentata)
Alfalfa Dong quai plant & prepatation
(Medicago sativa) (Angelica sinensis)
Preparations, contents and uses
Phytoestrogens are present in both:
1- Foodstuffs (e.g., cereal grains, soy milk and protein and vegetables or fruits) and
2- Herbal remedies (e.g., alfalfa, black cohosh, red clover, chaparral, dong quai, fenugreek, licorice)
Most of these herbs extracts are available in market as nutritional supplements (nutriceuticals) in different forms and names.
The major isoflavones are genistein and daidzein.
Lignans are present in whole grains, flax seed.
Coumestans are found in bean sprouts in clover and alfalfa sprouts.
1- Phytoestrogens (particularly genistein) are able to inhibit tyrosine kinases and DNA topoisomerases, that promote cell differentiation that leading to inhibit cancer cell proliferation.
2- Phytoestrogens (particularly genistein and daidzein) can act as antioxidants and are affect cell signaling depending on phosphorylation pathways.
Phytoestrogens exert estrogenic effects in a manner similar to endogenous estrogen, mainly through activation of the estrogen receptors (ER).
The six plants with the highest ER-binding characteristics were soy, licorice, red clover, thyme, tumeric, hops.
Phytoestrogens & interactions
Isoflavones & levothyroxine: A case report:
Concurrent administration of levothyroxine with soy proteins resulted in decreased therapeutic concentration of levothyroxine and the need for higher dose to attain therapeutic serum thyroid hormone level.
Isoflavones & tamoxifen: It was found that high intake of the soy isoflavone, genistein, interfered with the ability of tamoxifen to inhibit the growth of ER+ breast cancer cells implanted in mice.
This was explained by the ability of isoflavones to stimulate the growth of estrogen receptor positive (ER+) breast cancer cells.
Some experts think that, women with a history of breast cancer, particularly ER+ breast cancer, should not increase their consumption of phytoestrogens, including soy isoflavones.
Medicinal use of garlic (Allium sativum Linne., Fam. Liliaceae).
Preparations, contents and uses
Garlic is available in many forms, including
Most commercially available products, for medicinal purposes, are composed of dried garlic powder standardized for allicin content, in doses of about 650 mg/day.
Garlic is characterized by a high content of organosulfur.
In the bulb, the sulfur is primarily
1- -glutamyl peptides,
2- allylcysteine sulfoxides.
When the bulb is cut, chopped or squeezed, alliin, the main allylcysteine sulfoxide, is metabolized to allicin through the action of alliinase.
Allicin is a self-reactive constituent and it is converted readily to more stable compounds such as polysulfides
Garlic derivatives and preparations are frequently used for antiplatelet, antioxidant, fibrinolytic effects and in treatment of common cold.
plant extract is used as an antimicrobial, antifungal and antiviral agent this attributed to its main constituent, allicin, and molecules pass through cell membranes and react biologically at the low level of thiol bonds in amino acids.
Garlic is believed to inhibit cholesterol biosynthesis at several enzymatic steps. It was able to lower the levels of free and esterified cholesterol in cultured human cells and to decrease fatty streak development in rabbits.
The results were consistent across analyses: garlic modestly reduces lipids 15 to 25 mg/dl (5% to 15%).
Inhibition of lipid peroxidation was another effect observed for garlic in clinical trials performed on subjects with atherosclerotic conditions.
In vitro studies suggest garlic to reduce blood pressure by inhibiting platelet nitric oxide synthase. Clinical trials, evaluating hypertensive subjects, reported a modest systolic reduction of 7.7 mm Hg and diastolic reduction of 5.0 mm Hg.
Garlic is known to have blood-thinning properties, attributed to enhanced fibrinolytic and antiplatelet activity.
It was suggested that diallyl disulfide and diallyl trisulfide inhibit thromboxane synthesis, possibly by inhibiting phospholipase-A and mobilizing arachidonic acid.
Recently, epidemiological studies have proved that high consumption of garlic is associated with reduced cancer risk in humans, primarily stomach and colon cancer.
Experimental studies have demonstrated the ability of garlic to reduce chemical carcinogenesis in several tissues of different animal models and against a broad range of carcinogens.
Garlic & interactions
Garlic & CYPs/P-gp:
Several in vitro and in vivo studies of organosulfur constituents of garlic, as well as garlic extracts, showed simultaneous inhibitory and inducing effect on several CYP enzymes (1A, 2B, 2C, 2E and 3A subfamilies) in the liver, as well as the efflux transporter P-gylcoproptein (Pgp) in the intestinal mucosa.
In vivo, a single dose of garlic oil, administered to rats, significantly decreased hepatic CYP activity. However, daily administration for 5 days significantly increased hepatic CYP activity.
In conclusion, studies suggest that garlic can act as an enzyme inhibitor during acute dosing and an enzyme inducer during chronic dosing.
Garlic & protease inhibitors: Ritonavir, a protease inhibitor, used in AIDs management is mainly metabolized by CYP3A4 and has a high binding affinity to P-glycoprotein. At the same time, it inhibits and induces CYP3A4 and predominantly induces other drug-metabolizing enzymes. Therefore, a possible interaction between ritonavir and garlic, also a CYP3A4 modulator, is highly probable.
A report, discussing two cases of HIV patients who developed GI toxicity after concomitant use of garlic supplement and ritonavir, concluded that toxicity could have resulted from either ritonavir effect on CYP3A4 leading to toxic concentration of compounds derived from garlic, or the latter inhibiting the CYP-mediated metabolism or P-glycoprotein-mediated transport of ritonavir leading to elevated levels of the drug.
In another study, on healthy volunteers, a 3-week administration of a garlic supplement decreased plasma concentrations of the protease inhibitor saquinavir by about 50%.
Garlic & acetaminophen/chlorzoxazone: CYP2E1 is one of the isosymes inhibited by garlic. CYP2E1 is also involved in the metabolism of acetaminophen (Panadol, Tylenol, etc.) and the muscle relaxant chlorzoxazone (Parafon Forte®). These drugs could possibly linger longer in people who are taking or eating garlic.
Garlic & hypoglycemic agents: Animal and clinical studies imply hypoglycemic effects of garlic which could explain the fall in glucose levels reported in several cases regarding patients concomitantly taking dietary garlic supplement with diabetic medication such as chlorpropamide.
The idea that herbal drugs are safe and free from side effects is false.
Plants contain hundreds of constituents and some of them are very toxic, such digitalis and the pyrrolizidine alkaloids, etc.
Herb-drug interactions are a reality and can present a serious threat to human health.
The trend in the domestication, production and biotechnological studies and genetic improvement of medicinal plants, instead of the use of plants harvested in the wild, will offer great advantages, it will be possible to obtain uniform and high quality raw materials which are fundamental to the efficacy and safety of herbal drugs.