Herbal medicines are defined as “finished, labeled medical products that contain as active components aerial or subterranean portions of plants, or other plant material, or mixtures thereof, whether in the crude condition or as plant preparations,” according to the World Health Organization. Juices, gums, fatty oils, essential oils, and other plant-derived compounds are all examples of plant material. Excipients, in addition to the active components, may be included in herbal remedies. Herbal medications are those that incorporate plant material in combination with chemically specified active ingredients, such as chemically defined, isolated components of plants. . Herbal medications are made up of a mixture of pharmacologically active plant elements that are said to interact together synergistically to generate an impact greater than the sum of the individual constituents’ effects [2,3,4,5]. The public has a misconception that herbal medications are safe since they are natural. This is, however, a dangerous oversimplification. Many diverse herb side effects have been documented and evaluated recently [6,7], including adverse events induced by herb-drug interactions.
Both conventional and herbal medications are frequently taken together35–37, which can result in clinically significant HDIs. 38 The HDI is a regular occurrence, and it can be helpful, detrimental, or even fatal. In most cases, the HDI has either positive or negative consequences. The latter may have negative consequences, including death. 39
Mechanism of herb-drug interaction
The same pharmacokinetic (changes in plasma drug concentration) and pharmacodynamic (drugs interacting at receptors on target organs) principles apply to herb-to-drug interactions.
The pharmacokinetic interactions that have been discovered so far all point to the possibility that a number of herbs, most notably St. John’s wort, can affect the blood concentration of various conventional medicines that are metabolised by cytochrome P450 (CYP, the most important phase I drug-metabolizing enzyme system) and/or transported by P-glycoprotein. (a glycoprotein which influences drug absorption and elimination by limiting the cellular transport from the intestinal lumen into epithelial cells and by enhancing the excretion of drugs from hepatocytes and renal tubules into the adjacent luminal space). Polymorphisms in the genes for CYP enzymes and P-glycoprotein may influence the interactions mediated through these pathways . Probe drugs used in pharmacokinetic trials include midazolam, alprazolam, nifedipine (CYP3A4), chlorzoxazone (CYP2E1), debrisoquine, dextromethorphan (CYP2D6), tolbutamide, diclofenac and flurbiprofen (CYP2C9), caffeine, tizanidine (CYP1A2) and omeprazole (CYP2C19). Fexofenadine, digoxin and talinolol have been extensively used in pharmacokinetic trials as P-glycoprotein substrates. Pharmacodynamic interactions are less well understood, although they can be additive (or synergetic), in which herbal medicines enhance the pharmacological/toxicological impact of synthetic medications, or antagonistic, in which herbal medicines diminish synthetic drug efficacy. Interactions between warfarin and other drugs are a typical example of pharmacodynamic interactions. When warfarin is taken with coumarin-containing herbs (certain plant coumarins have anticoagulant properties) or antiplatelet herbs, greater anticoagulant effects should be expected. Vitamin K-rich plants, on the other hand, can counteract the effects of warfarin.
Clinical instances of interactions between herbal and mainstream medicine:
Aloe vera is a kind of plant that has been used for centuries
In western nations, aloe vera (Family Liliaceae) is used as a laxative (A. vera latex, which includes anthraquinones) and for dermatologic diseases (A. vera gel, which contains mostly mucilages) [2,4]. A. vera is used to treat inflammatory disorders, diabetes, and hyperlipidemia in traditional Chinese medicine. A potential interaction between A. vera and the anesthetic sevoflurane has been observed to cause blood loss during surgery . Because both sevoflurane and A. vera components suppress platelet aggregation, an additive impact on platelet function has been proposed but not verified.
Cohosh (Black) (Cimicifuga racemosa)
Black cohosh (Cimicifuga racemosa rhizome and roots, Fam. Ranunculaceae) has been linked to significant safety issues, including hepatotoxicity, that need to be investigated further [3,4].
The impact of black cohosh extract on the activity of human CYP enzymes and P-glycoprotein has been studied in several clinical studies [14,15,16,17] utilising various probe agents including as caffeine, midazolam, chlorzoxazone, debrisoquin, and digoxin. The findings show that black cohosh has no effect on the pharmacokinetics of medications metabolised by CYP1A2, CYP3A4, CYP2E1, and CYP2D6 or that are P-glycoprotein substrates. Furthermore, an in vitro liver microsomal method revealed that seven distinct brands of commercial black cohosh supplements had no effect on human CYP . In people receiving traditional medication, black cohosh appears to offer relatively modest hazards.
The cat’s claws (Uncaria tomentosa)
The Amazon rainforest medicinal plant cat’s claw (Uncaria tomentosa, Fam. Rubiaceae) It has been used to treat diseases including rheumatoid arthritis and AIDS  due to its immunostimulant and antiviral properties. Atazanavir, ritonavir, and saquinavir, protease inhibitors, have been found to enhance plasma concentrations of cat’s claw . Cat’s claw has been demonstrated in vitro to inhibit CYP3A4, the enzyme that is responsible for the metabolism of protease inhibitors. To yet, no human data on the regulation of CYP enzymes by cats’ claw has been provided.
Chamomile is a flower that has been used for centuries (Matricaria recutita)
Chamomile flower heads (Matricaria recutita, Asteraceae) are used both topically (for skin and mucous membrane inflammations) and orally (for gastrointestinal spasms and inflammatory illness of the gastrointestinal system) [4,5]. Coumarins, a broad family of natural chemicals with over 1,300 components, are found in chamomile. Coumarin molecules may have anticoagulant properties in some cases, but not all .
Cranberry (Vaccinium macrocarpon)
Cranberry is the American name for the fruit of Vaccinium macrocarpon (Fam. Ericaceae), which has been used to prevent urinary tract infections for decades [3,4], usually in the form of an encapsulated standardised extract, a dilute juice, or a dried-juice capsule.
Serious concerns have been raised about a potential interaction with the anticoagulant warfarin, based on numerous reported instances (including two fatal interactions) showing elevated international normalised ratio (INR) and haemorrhage [21,22,23,24,25,26,27,28,29,30,31]. These cautions, on the other hand, might be due to erroneous conclusions .
A number of clinical trials have consistently shown that cranberry juice, even at high doses, did not cause any clinically relevant changes in warfarin pharmacokinetics and pharmacodynamics [34,35,36,37,38]. With the exception of one study, which found that capsules containing concentrated cranberry juice increased the area under the INR-time curve of warfarin by 30% , cranberry juice did not cause any clinically relevant changes in warfarin pharma Clinical data suggests that cranberry juice does not interact with some CYP isoenzymes required for warfarin metabolism, such as CYP2C9, CYP1A2, and CYP3A4 [36,37,38]. Finally, a clinical investigation discovered that the pharmacokinetics of cyclosporine were altered by pomelo juice but not cranberry juice.
Mint leaves (Mentha piperita)
Mentha piperita (Family Labiateae) leaves and oil have traditionally been used to treat digestive problems [3,4]. Irritable bowel syndrome symptoms may be relieved by enteric-coated peppermint oil, according to recent research . Peppermint may raise the levels of medications metabolised by CYP3A4, such as felodipine , according to some clinical evidence.
Rice with Red Yeast
The fungus Monascus purpureus ferments washed and cooked rice to generate red yeast rice, which is used to reduce blood cholesterol [3,4]. In a stable renal-transplant patient receiving cyclosporine therapy, red yeast rice was suspected of causing rhabdomyolysis . (see table 1 for further details). Even when given alone, red yeast rice has the potential to induce myopathy .
Palmetto (Serenoa repens)
Serenoa repens (Fam. Arecaceae) preparations are well accepted by the majority of users and are not linked to significant side effects [2,3,4]. There has been no documented evidence of saw palmetto medication interactions. In healthy volunteers, saw palmetto had no impact on CYP1A2, CYP2D6, CYP2E1, or CYP3A4 [50,134]. The most often used herbal formulations for the treatment of benign prostatic hyperplasia are extracts from S. repens berries [2,3,4,5,200]. Curbicin contains saw palmetto, pumpkin, and vitamin E, and is intended to treat symptoms of benign prostatic hyperplasia. The most common herbal remedies for treating benign prostatic hyperplasia are extracts from S. repens berries [2,3,4,5,200]. Curbicin is a herbal preparation that contains saw palmetto, pumpkin, and vitamin E. It is intended to treat symptoms of benign prostatic hyperplasia.
Phytoestrogens, non-steroidal plant-derived chemicals with a mild oestrogenic action, are abundant in soy beans, which are produced from Glycine max (Fabaceae). Soy phytoestrogens are said to help with menopausal symptoms, heart disease, and cancer prevention [2,4]. A patient using warfarin was found to have a lower INR . In contrast, a clinical trial in 18 healthy Chinese female volunteers found that a 14-day therapy with soy extract had no effect on the pharmacokinetics of losartan and its active metabolite E-3174 .
A significant portion of the data on herb-drug interactions presented in this article is based on case reports, which are frequently fragmentary and do not allow for inference of a causative link. It’s worth noting that even well-documented case reports can’t prove a link between drug administration and an adverse event; additionally, the evidence for many of the interactions listed in table 1 isn’t conclusive because only one case report was used in some cases, and in others, a poorly documented case report was published. A 5-point grading system was used to classify the degree of evidence in this article. When an adverse event mentioned in a case report was verified by a clinical pharmacokinetic study, the highest level of clinical evidence (i.e. level of evidence: 5) was used. Many unfavourable events, on the other hand, are backed up by sloppy case reports (level of evidence 1, see table 1 for further details). The degree of evidence was characterised as ‘not relevant’ when pharmacokinetic trials did not confirm the adverse effect anticipated based on published case report(s) (e.g. interactions between warfarin and cranberry or ginkgo), or when contradicting pharmacokinetic data was published. In many cases, clinical publications do not specify the extract type, standardisation of the extract, plant portion utilised, or scientific (Latin) name of the plant. This is a significant oversight since preparations derived from the same plant might have varied chemical compositions and, as a result, biological effects. Because herbal medicines are not subject to the same restrictions as prescription medications, the active ingredient amount may differ across producers, possibly resulting in a wide range of efficacy and safety [247,248].
Another safety concern is herbal medication quality, which is frequently unregulated. Adulteration of herbal medications, particularly adulteration with synthetic pharmaceuticals, is a common occurrence that might result in drug interactions [2,3]. To put it another way, it’s impossible to rule out the potential that medication interactions are caused by a contaminant/adulterant rather than a herbal component. People who take herbal medications are more likely to keep their usage hidden from their doctors or pharmacists, as previously stated. This finding, along with the fact that many nations lack central reporting systems for herb-to-drug interactions, makes identifying most herb-to-drug interactions difficult.
Herbal medications have been shown to interact with conventional pharmaceuticals in clinical studies. While the majority of these interactions are unlikely to have a clinical impact, a few might represent a severe hazard to public health. Combining St. John’s wort with antiviral, immunosuppressive, or anticancer drugs that are metabolised by CYP enzymes and/or are P-glycoprotein substrates, for example, might result in medication failure. Patients who use herbal remedies before surgery may have serious health issues. There have been reports of delayed emergence, cardiovascular collapse, and blood loss. According to a recent retrospective analysis of surgery patients who presented to the University of Kansas Hospital’s Anesthesia Preoperative Evaluation Clinic, almost one-fourth of patients stated that they used natural products prior to surgery . Clinicians must thus check patients for usage of these supplements before to surgery.
Finally, herbal medicines may be utilised by patients who are taking conventional medications at the same time, which might lead to significant side effects. Healthcare providers must be well-versed in the expanding body of clinical information about herb-drug interactions.