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. 2023 Nov 15;11:e16149. doi: 10.7717/peerj.16149

Pharmacokinetic and pharmacodynamic herb-drug interactions—part I. Herbal medicines of the central nervous system

Szilvia Czigle 1,, Milan Nagy 1, Přemysl Mladěnka 2, Jaroslav Tóth 1,; the OEMONOM.
Editor: Fares Ali
PMCID: PMC10656908  PMID: 38025741

Abstract

Unlike conventional drug substances, herbal medicines are composed of a complex of biologically active compounds. Therefore, the potential occurrence of herb-drug interactions is even more probable than for drug-drug interactions. Interactions can occur on both the pharmacokinetic and pharmacodynamic level. Herbal medicines may affect the resulting efficacy of the concomitantly used (synthetic) drugs, mainly on the pharmacokinetic level, by changing their absorption, distribution, metabolism, and excretion. Studies on the pharmacodynamic interactions of herbal medicines and conventional drugs are still very limited. This interaction level is related to the mechanism of action of different plant constituents. Herb-drug interactions can cause changes in drug levels and activities and lead to therapeutic failure and/or side effects (sometimes toxicities, even fatal). This review aims to provide a summary of recent information on the potential drug interactions involving commonly used herbal medicines that affect the central nervous system (Camellia, Valeriana, Ginkgo, Hypericum, Humulus, Cannabis) and conventional drugs. The survey databases were used to identify primary scientific publications, case reports, and secondary databases on interactions were used later on as well. Search keywords were based on plant names (botanical genera), officinal herbal drugs, herbal drug preparations, herbal drug extracts.

Keywords: Herbal medicine-drug interaction, Pharmacokinetic, Pharmacodynamic, Camellia, Valeriana, Ginkgo, Hypericum, Humulus, Cannabis, Review

Introduction

Medicinal plants and herbal drugs were undoubtedly among the first successful treatment modality ever used by humanity—herbal drugs are currently defined as ‘mainly whole, fragmented or broken plants or parts of plants in an unprocessed state, usually in dried form but sometimes fresh’, (European Pharmacopoeia, 2023h). Even today, the majority of the world’s population still relies on traditional herbal medicines in the broadest sense, and a large part of currently clinically used drugs is of a natural origin or has been derived from it—this fact is also being systematically followed and highlighted, e.g., in a continuing series of reviews by Newman and Cragg, at least since 1997 (Newman & Cragg, 2020).

The focus on the issue of herb–drug interactions has been initiated several decades ago by a case report concerning Citrus (grapefruit) juice interactions with cardiovascular drugs (that shall be elaborated in the contemporaneously prepared Part II of this review series). Since that, many other herb-drug interaction have been revealed or suggested. Studying herb-drug interactions is complicated by the fact, that there are not only herbal medicines but also herbal food supplements on the world market (N. B.: food supplements—EU terminology, are legally called dietary supplements in the USA) (Czigle et al., 2018). For many popular medicinal plant extracts, the same particular (standardized) extract can be found in medicinal and food products at the same time on the same local market (Czigle et al., 2018). Even that food products should be marketed with lower doses of these extracts, as they must not be intended to treat human diseases. Regardless, even if the ingredients of supplements are labelled as part of the traditional human diet by manufacturers, and their effects claimed physiological, i.e., maintaining human health, such herbal materials (herbal drugs, botanicals, and extracts) certainly contain the same biologically active constituents, no matter if they are part of medicinal or food products. These active compounds can interact with other medications, herbal or synthetic, at different levels (Cordier & Steenkamp, 2011; Singh & Zhao, 2017).

In contrast to well-investigated novel drugs which must undergo long-term preclinical and clinical investigations with the aim of defining indications, mechanism of action, as well as their undesirable effects, contraindications, and possible interactions, many phytopharmaceuticals profit from their traditional status (European Medicines Agency, 2023). This means that detailed information including data from clinical studies is mostly missing. A quite dangerous subconscious assumption has evolved, that all what comes from nature is safe (Ng, 2021). The need for new data on herbal efficacy and safety has been highlighted by recent systematic regulatory approaches in the herbal medicines segment, most prominently represented by the works of the European Medicines Agency—Committee on Herbal Medicinal Products (EMA-HMPC). European Union herbal monographs typically also contain chapters on contraindications, undesirable effects, interactions with other medicinal products, warnings, etc. (European Medicines Agency, 2023). Contrary to indications and mechanisms of action, information on less frequent undesirable effects and interactions with other medicinal products is often gained in the clinical trials phase IV, i.e., in post-market surveillance studies and/or from less systematic and less predictable sources, e.g., individual case reports. The latter usually comes from a casual overdose incident. The prevalence of use of particular herbal medicines in the general population is so well reflected in the number of clinically important herb-drug interactions known and described so far for these herbal sources (Prely et al., 2022; TRC, 2023; Williamson, Driver & Baxter, 2009, 2018; Zhang et al., 2022; Ziemann et al., 2019).

Based on recently published information, this work aims to sum up the knowledge about interactions between conventional drugs and (traditional) herbal drugs that affect the central nervous system (psychopharmaceuticals) at the level of vigilance, affectivity, and psychical integrity. Vigilance is affected by psychostimulants—herbal caffeine sources (guarana—Guaranae semen/Paulliniae semen, green/black tea—Camelliae folium, cola—Colae semen, coffee—Coffeae semen, maté leaf—Mate folium, cocoa—Cacao semen), hypnotics (valerian root—Valerianae radix) and nootropics (Ginkgo leaf—Ginkgonis folium). The affectivity is impacted by antidepressants (St. John’s wort—Hyperici herba) and anxiolytics (hop strobile—Lupuli flos), and psychical integrity by hallucinogens (cannabis aerial part/marijuana—Cannabis herba, cannabis resin/hashish—Cannabis resina).

A drug interaction is said to occur when the effect of one drug is changed by the presence of another substance, including herbal medicines, foods (supplements), beverages, and environmental agents. The outcome can be harmful if the interaction causes an increase in the side effect and/or toxicity of the drug (Cordier & Steenkamp, 2011; Singh & Zhao, 2017). A reduction in efficacy due to an interaction can sometimes be just as harmful as an increase. Patients can apparently tolerate adverse interactions remarkably well and many interactions can be accommodated, so effects may not be consciously recognized as the result of an interaction. The mechanism of herbal interaction might not be easily tracked, as herbal sources differ from conventional drug substances in that they are complex mixtures of many biologically active compounds (Nagy, Mučaji & Grančai, 2017). The resulting pharmacological action is likely to arise often on the basis of synergism. Explaining so-called herb-drug interactions is therefore often more difficult. Furthermore, many drugs can interact by more than a single mechanism. Sometimes, more mechanisms are acting in concert. For clarity, most of the mechanisms that are dealt with in this review are as though they occur in isolation (Nagy, Mučaji & Grančai, 2017). For convenience, the mechanism of interactions can be divided into those that involve the pharmacokinetics of a drug, and those that are pharmacodynamic (Cordier & Steenkamp, 2011; Singh & Zhao, 2017; Williamson, Driver & Baxter, 2009).

Pharmacokinetic interactions are those that can affect the processes by which drugs are absorbed, distributed, metabolized, and eliminated (the so-called ADME interactions) (Cordier & Steenkamp, 2011; Singh & Zhao, 2017; Williamson, Driver & Baxter, 2009, 2013). The classical example of a target is the most well-investigated drug transporter efflux transporter P-glycoprotein (P-gp), also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) (Williamson, Driver & Baxter, 2009). Some well-known examples include ginkgo (maidenhair tree)—Ginkgo biloba (with active ginkgolides) is an inhibitor of P-gp and St. John’s wort—Hypericum perforatum is an inductor of P-gp (Czigle & Tóth, 2016). Other transporters that are involved in some drug interactions are organic cation transporters (OCTs) and organic anion-transporting polypeptides (OATPs) (Ali et al., 2020; Rodrigues et al., 2019). Although all of these mechanisms are undoubtedly relevant for interactions with herbal medicines, this review will focus mainly on cytochrome P450 and the P-gp drug transporter protein, as information on other transporters is currently limited or of unknown biological relevance. Some of the secondary metabolites are enzyme inductors or inhibitors (CYP isoenzymes) (Amaeze et al., 2021; Manikandan & Nagini, 2018; Pandian et al., 2020; Wanwimolruk & Prachayasittikul, 2014; Williamson, Driver & Baxter, 2009; Zhou et al., 2003). With the exception of prodrugs, inhibitors slow down drug metabolism, which often leads to a substantial increase in serum drug levels with significant risk of adverse or even toxic effects (Cordier & Steenkamp, 2011; Singh & Zhao, 2017). Inductors cause the opposite, increased drug metabolism. Again, with the exception of prodrugs, this consequently often leads to lower-than-expected serum drug levels with potential treatment failure (Williamson, Driver & Baxter, 2009). St. John’s wort—Hypericum perforatum is a well-known inductor of CYP isoenzymes (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009), inhibitors include ginkgo—Ginkgo biloba (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009), valerian—Valeriana officinalis (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009), hop—Humulus lupulus (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009), among others (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009). Finally, several other enzymes have been shown to play a role in herb-drug interactions, such as UDP-glucuronyltransferases (UGT) (Williamson, Driver & Baxter, 2009, 2018).

Pharmacodynamic interactions are those where the effects of one drug are changed by the presence of another drug at its site of action. Sometimes the drugs and the biologically active plant metabolites directly compete for a particular target (e.g., receptor, enzyme), but often the reaction is more indirect and involves interference with physiological mechanisms. If two drugs that have the same or similar pharmacological effect are given together, the effects can be additive and, in some cases, even potentiating (Nagy, Mučaji & Grančai, 2017). In contrast, there are some pairs of drugs with activities that are opposed to each other (antagonist) (Nagy, Mučaji & Grančai, 2017). For example, a particular additive effect is well known to occur between ginkgo—Ginkgo biloba and antithrombotic agents (Czigle & Tóth, 2016; European Medicines Agency, 2012d) and similarly between St. John’s wort—Hypericum perforatum and antidepressant drugs (Czigle & Tóth, 2016; European Medicines Agency, 2021). The exposures to drugs, for which knowledge of the potential adverse herb-drug interactions is lacking, might be a risk to patients’ safety (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009, 2018). On the contrary, some interactions may be therapeutically beneficial (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009, 2018) and might be used to develop new therapeutic strategies in the future.

Survey methodology

This work aims to summarize the knowledge about interactions between conventional drugs and (traditional) herbal drugs; and, as part of an intended series on this topic, concentrates on principal herbal drugs that affect psychopharmaceuticals. Subheads include herbal drugs that affect the central nervous system at the level of vigilance, affectivity, and psychical integrity. The given topic has been comprehensively summarized from the current scientific view on herbal medicines and has been currently (re-)evaluated by the Evidence Based Medicine approach (factor—risk/benefit ratio; the beneficial effects of an herbal medicine can outweigh the side effect). The minimum acceptance criteria were similar to the guidelines for authors of reviews by Munn et al. (2018). The survey databases used were SciFinder, PubMed, which identified primary scientific publications (e.g., case reports), and several secondary databases on interactions were used later on as well (Therapeutic Research Center—Natural Medicines database (TRC, 2023), Stockley’s Herbal Medicines Interactions (Williamson, Driver & Baxter, 2009, 2013, 2018), and other databases). The search was focused on officinal herbal drugs (European Pharmacopoeia, 2023h), herbal drug preparations (European Pharmacopoeia, 2023g), and herbal drug extracts (European Pharmacopoeia, 2023f). Keywords for search are listed here: herbal medicine-drug interaction, pharmacokinetic and pharmacodynamic interaction, selected botanical genera: Camellia, Coffea, Paullinia, Ilex, Cola, Theobroma, Valeriana, Ginkgo, Hypericum, Humulus, Cannabis. Subsequently, the names of the particular herbal drugs were included in the search, as Camelliae folium non fermentatum/fermentatum, Coffeae semen, Guaranae semen, Mate folium, Colae semen, Cacao semen, Valerianae radix, Ginkgonis folium, Hyperici herba, Humuli flos, Cannabis flos/herba/resina. Some botanical synonyms and related terms. We compiled information about pharmacokinetic and pharmacodynamic interactions with biologically active metabolites of these plants or herbal drugs. The criteria for the inclusion or exclusion of specific literature sources were interaction results, the conclusions of case report evaluations, clinical relevance of particular interactions or their absence, and the exhaustiveness of the description of the interaction. The same herbal medicines are often used in multiple indications, in different individual diagnoses; on the other hand, the mechanism of action of particular secondary metabolites is related to several diagnoses by EU herbal monographs (European Medicines Agency, 2023). Our objective was to explain the biological mechanisms of pharmacological activities for particular secondary metabolites in individual indications. The resulting pharmacological effect often is due to the synergism of the individual secondary metabolites. As for legislative aspects, the European Medicines Agency (EMA) applies the same criteria on all herbal drugs and on all diseases/health problems in its given methodological procedures. We summarize, synthesize, paraphrase data, and give an overview of the main points out of each source and combine them into a coherent whole. We analyze and interpret (clinically relevant) herb-drug interactions in the tables in the next sections with clarification, notes after analyses of theoretical or practical information. The Anatomical Therapeutic Chemical (ATC) classification system of the World Health Organization (WHO) Collaborating Centre for Drug Statistics Methodology (World Health Organization, 2023) is used to order and organize drug molecules in tables to highlight links in therapeutic and pharmacological/chemical subgroups. Further criteria reflected in this article include the availability of information about the potential of interaction of the particular drug, about interactions prevention measures, as well as practical recommendations after the manifestation of the interaction.

Drug interactions of herbal drugs containing caffeine (Guaranae semen, Camelliae folium, Colae semen, Coffeae semen, Mate folium, Cacao semen)

The most common herbal drugs used as sources of caffeine include green and black tea—Camelliae folium non fermentatum/fermentatum (Theae folium), coffee—Coffeae semen, guarana—Guaranae semen (Paulliniae semen, Guarana, Pasta guarana), maté leaf—Mate folium, cola—Colae semen, and cocoa—Cacao semen. Significantly, in addition to their use in herbal medicinal products, all of these herbal sources are commonly present in foods and beverages, as well (tea, coffee, cola drinks, and energy drinks) (Czigle & Tóth, 2010b). The caffeine content in the named herbal drugs decreases in the following order: Guarana (3.6–6%) > Camelliae folium (2–4%) > Colae semen (1–2.5%) > Coffeae semen (1–2%) > Mate folium (0.5–0.8%) > Cacao semen (0.07–0.4%) (Czigle & Tóth, 2010b). Camelliae folium and Colae semen additionally contain appreciable amounts of tannins, for Colae semen and Coffeae semen the presence of chlorogenic acids, and for Cacao semen the content of fatty acids is substantial (Czigle & Tóth, 2010b; Nagy, Mučaji & Grančai, 2017).

The European Pharmacopoeia lists officinal monographs for: green tea (Camelliae sinensis non fermentata folia) (European Pharmacopoeia, 2023d), guarana (Guaranae semen) (European Pharmacopoeia, 2023e), cola (Colae semen) (European Pharmacopoeia, 2023a), and maté leaf (Mate folium) (European Pharmacopoeia, 2023j). Coffee (Coffeae semen, Coffea L. spp., Rubiaceae) and cocoa (Cacao semen, Theobroma cacao L., Malvaceae) are not officinal in the European Pharmacopoeia.

The plant species Camellia sinensis (L.) Kuntze (Theaceae), with the botanical synonym Thea sinensis L., is known as the source of green tea (Camelliae folium non fermentatum), black tea (Camelliae folium fermentatum) and oolong (Camelliae folium semifermentatum) (The World Flora Online, 2022). There is a wide array of indications, well supported by in-depth studies on a number of defined chemical constituents of Camellia sinensis (L.) Kuntze. The main biologically active compounds are xanthine derivatives, such as caffeine (2–4%), theobromine (0.05%) and theophylline (traces); polyphenols (up to 30%), including gallotannins, (-)-epigallocatechin-3-O-gallate (EGCG, up to 12%), (-)-epicatechin-3-O-gallate (ECG), catechin tannins, other flavonoids, ellagitannins, phenolic carboxylic acids; theanine (amino acid), ascorbic acid, triterpene saponins, and minerals (Nagy, Mučaji & Grančai, 2017).

The dried seed of Paullinia cupana Kunth (syn. Paullinia sorbilis Mart.) (Sapindaceae), guarana, is also known as a food product, often available in the form of candy lozenges with Pasta guarana (guarana extract) (Czigle & Tóth, 2010b).

The dried leaf of Ilex paraguariensis A.St.-Hil. (Aquifoliaceae) is known as maté tea. After harvesting, the leaf is rapidly desiccated by heating, and cut (Czigle & Tóth, 2016).

Cola is produced from the plant species Cola nitida (Vent.) Schott et Endl. (syn. C. vera K. Schum.) and its varieties, as well as from Cola acuminata (P. Beauv.) Schott et Endl. (syn. Sterculia acuminata P. Beauv.) (Malvaceae); the herbal drug consists of whole or fragmented dried seeds, which were freed from the testa. Cola drinks contain extracts of this herbal drug (Czigle & Tóth, 2016).

Caffeine-containing herbal drugs with psychostimulant effects are used medicinally ‘for the relief of symptoms of (temporary) fatigue and sensation of weakness’, (European Medicines Agency, 2023). Based on a large amount of verified scientific data, several of these herbal drugs have been classified as traditional herbal medicinal products with the above cited indication: Camelliae folium non fermentatum (whole dried leaf, comminuted and powdered herbal substance) (European Medicines Agency, 2012c), Guaranae semen (guarana seed in solid dosage forms for oral use) (European Medicines Agency, 2011b), Colae semen (as a powdered herbal substance in solid dosage forms or as a herbal tea for oral use, as liquid extract or tincture) (European Medicines Agency, 2010b), Mate folium (as a comminuted herbal substance such as herbal tea for oral use) (European Medicines Agency, 2008b). In addition to this general therapeutic indication, maté leaf was also classified as a traditional herbal medicinal product ‘to increase the amount of urine to achieve flushing of the urinary tract as an adjuvant in minor urinary complaints’, (European Medicines Agency, 2008b).

Caffeine itself is a CYP1A2 inhibitor (Guo et al., 2021; Kot & Daniel, 2008; Williamson, Driver & Baxter, 2013). Caffeine metabolites are paraxanthine (84%), theobromine (12%), and theophylline (4%) (Faber, Jetter & Fuhr, 2005). In commonly achievable plasma concentrations, caffeine is an antagonist at adenosine A1 and A2-receptors (Cauli & Morelli, 2005; Nehlig, 2018). In higher concentrations, it acts as well as a phosphodiesterase inhibitor (PDE1, PDE4, PDE5) (Boswell-Smith, Spina & Page, 2006); γ-aminobutyric acid receptor (GABAA) antagonist (Isokawa, 2016; Lopez et al., 1989); ryanodine receptor (RYR) agonist (Kong et al., 2008); and it also affects the nervus vagus (Hibino et al., 1997). Caffeine and paraxanthine have similar sympathomimetic actions (Benowitz et al., 1995).

This review presents and summarizes relevant and more recent data on the interaction potential of caffeine and caffeine-containing herbal drugs that are, notably, not included in the European Union herbal monographs and their related assessment reports (European Medicines Agency, 2008a, 2010a, 2011a, 2012a, 2020a, 2022).

Clinically significant pharmacokinetic and pharmacodynamic interactions are summarized in Table 1. In relation of pharmacodynamic interactions, it is important to emphasize that preparations containing caffeine reduce the sedative action and increase the side effects caused by sympathomimetic drugs (European Medicines Agency, 2008b, 2010b, 2011b, 2012c). Patients taking monoamine oxidase (MAO) inhibitors should be cautious when concomitantly using Paulliniae semen (European Medicines Agency, 2011b), Mate folium (European Medicines Agency, 2008b), and/or Colae semen (European Medicines Agency, 2010b). However, there are, also some important pharmacokinetic interactions based either on the inhibition of CYP1A2 metabolism of other drugs by caffeine (e.g., melatonin) (European Medicines Agency, 2008b, 2010b, 2011b, 2012c) or by inhibition of the same cytochrome by other drugs resulting in potential caffein toxicity (e.g., fluvoxamine, ciprofloxacine) (European Medicines Agency, 2008b, 2010b, 2011b, 2012c).

Table 1. Drug interactions of caffeine and herbal drugs containing caffeine.

ATC therapeutic subgroup ATC pharmacological/chemical subgroup Drugs Pharmacokinetic basis of interaction Pharmacodynamic basis of interaction Manifestation of interaction
Stomatological preparations (A01) Vasoconstrictors Epinephrine (Adrenaline) CYP1A2 Caffeine is a competitive adenosine antagonist and releases endogenous catecholamines. additive (psychostimulant) effect
adverse reactions (hypertension, myocardial infarction, stroke, seizures)
! reduce/restrict caffeine intake
Van Soeren et al. (1996)
CYP3A4
Antihemorrhagics (B02) Local hemostatics
Cardiac therapy (C01) Adrenergic agents
Nasal preparations (R01) Decongestants and other nasal preparations for topical use
Sympathomimetics, plain
Drugs for obstructive airway diseases (R03) Adrenergic inhalants, alpha- and beta-adrenoreceptor agonists
Ophtalmologicals (S01) Sympathomimetics in glaucoma therapy
Stomatological preparation, in dentistry (A01) Salicylic acid and derivatives Acetylsalicylic acid CYP1A2
CYP2C9
CYP3A4
bioavailability
analgetic effect
Diener et al. (2005)
Antithrombotic agents (B01)
Analgetics (N02)
Drugs for acid related disorders (A02) H2-receptor antagonists Cimetidine CYP2C9 caffeine plasma level
caffeine clearance (31–42%)
caffeine adverse reactions
! reduce/restrict caffeine intake
Broughton & Rogers (1981)
Proton pump inhibitors Omeprazol CYP2C9 caffeine plasma level
caffeine clearance
caffeine adverse reactions
! reduce/restrict caffeine intake
Andersson et al. (1998)
Antiobesity preparations, excl. diet products (A08) Centrally acting antiobesity products Amfepramone Phentermine CYP1A2
CYP3A4
Caffeine is a competitive adenosine antagonist and releases endogenous catecholamines. additive (psychostimulant) effect
adverse reactions (hypertension, myocardial infarction, stroke, seizures)
! reduce/restrict caffeine intake
Solimini et al. (2017)
Antiobesity preparations, excl. diet products (A08) Centrally acting antiobesity products Ephedrine (orally) CYP1A2
CYP3A4
Caffeine is a competitive adenosine antagonist and releases endogenous catecholamines. additive effect
! life-threatening risk (hypertension, myocardial infarction, stroke, seizures, even death)
! reduce/restrict caffeine intake
Astrup et al. (1992)
Cardiac therapy (C01) Adrenergic and dopaminergic agents
Nasal preparations (R01) Decongestants and other nasal preparations for topical use; sympathomimetics, plain
Sympathomimetics, combinations excl. corticosteroids
Drugs for obstructive airway diseases (R03) Alpha- and beta-adrenoreceptor agonists
Ophthalmologicals (S01) Sympathomimetics excl. antiglaucoma preparations
Drugs used in diabetes (A10) Blood glucose lowering drugs, excl. insuline, sulfonylureas Glibornuride
Glimepiride
CYP2C9 Glucose tolerance affected. glucose level affected
! monitor glucose level(s)
Czigle & Tóth (2016), Williamson, Driver & Baxter (2018)
Blood glucose lowering drugs, excl. insuline, thiazolidinedione Pioglitazone
Rosiglitazone
CYP2C9 Glucose tolerance affected. glucose level affected
! monitor glucose level(s)
Czigle & Tóth (2016), Williamson, Driver & Baxter (2018)
Antithrombotic agents (B01) Platelet aggregation inhibitors excl. heparin Clopidogrel
Dipyridamole
Ticlopidine
CYP1A2
CYP2D6
Caffeine is a competitive adenosine antagonist. bioavailability
antithrombotic effect
! bleeding risk
! do not use combination (24 h interval)
Birnbaum et al. (2015)
Vitamin K antagonists Warfarin CYP1A2
CYP2C9
anticoagulant effect
! bleeding risk
! reduce/restrict caffeine intake
Anthony et al. (2009)
Heparin group Ardeparin
Dalteparin
Enoxaparin
Heparin
CYP1A2
CYP2C9
anticoagulant effect
! bleeding risk
! reduce/restrict caffeine intake
Ardeparin was recalled from circulation for reasons unrelated to safety or efficacy
Anthony et al. (2009)
Cardiac therapy (C01) Antiarrhythmics, class Ib Lidocaine
Mexiletine
Tocainide
CYP1A2
CYP2D6
Caffeine is a competitive adenosine antagonist. caffeine plasma level
caffeine adverse reactions
! reduce/restrict caffeine intake
Amjad et al. (2017), Czigle & Tóth (2016)
Antiarrhythmics, class Ic Flecainide CYP2D6 Caffeine is a competitive adenosine antagonist. caffeine plasma level
caffeine adverse reactions
! reduce/restrict caffeine intake
Hwang et al. (2019)
Antifungals for dermatological use (D01) Antifungals for systemic use/allylamine antifungals Terbinafine CYP1A2
CYP3A4
caffeine plasma level
caffeine clearance (19%)
caffeine effect prolongation
! reduce/restrict caffeine intake
Trépanier, Nafziger & Amsden (1998)
Sex hormones and modulators of the genital system (G03) Hormonal contraceptives for systemic use Ethinylestradiol (EE),
Estradiol + progestogens
CYP1A2
CYP2C9
CYP3A4
Estrogens are inhibitors of caffeine metabolism. caffeine plasma level
caffeine clearance (40–65%)
! reduce/restrict caffeine intake
Fantoli (1981), Patwardhan et al. (1980)
Antibacterials for systemic use (J01) Quinolone antibacterials Ciprofloxacin
Clinafloxacin
Enoxacin
Gatifloxacin
Grepafloxacin
Levofloxacin
Lomefloxacin
Moxifloxacin
Norfloxacin
Ofloxacin
Pipemidic acid
Rufloxacin
Sparfloxacin
Trovafloxacin
CYP1A2
CYP3A4
caffeine plasma level
caffeine metabolism (N-demethylation)
caffeine clearance
adverse reactions
! reduce/restrict caffeine intake
Czigle & Tóth (2010b), Woziwodzka et al. (2022)
Antimycotics for systemic use (J02) Triazole and tetrazole derivatives—antimycotics Fluconazol CYP1A2
CYP3A4
caffeine clearance (25%)
! reduce/restrict caffeine intake
Czigle & Tóth (2010b)
Drugs for treatment of bone diseases (M05) Drugs affecting bone structure and mineralization, bisphosphonates Alendronic acid CYP1A2
CYP3A4
bioavailability
! reduce/restrict caffeine intake (2 h interval)
Czigle & Tóth (2010b)
Analgesics (N02) Other analgesics and antipyretics, anilides Paracetamol CYP1A2
CYP3A4
CYP2E1
bioavailability
analgetic effect
Diener et al. (2005), Granados-Soto & Castañeda-Hernández (1999), Zhang (2001)
Antimigraine preparations, ergot alkaloids Ergotamine CYP1A2
CYP3A4
Caffeine vigilance increased. absorbance
! reduce/restrict caffeine intake
Granados-Soto & Castañeda-Hernández (1999)
Antiepileptics (N03) Antiepileptics, barbiturates and derivatives Phenobarbital CYP2C9 Caffeine vigilance increased. plasma level
anticonvulsive effect
! reduce/restrict caffeine intake
Chrościńska-Krawczyk et al. (2014), Jankiewicz et al. (2007)
Antiepileptics, hydantoin derivatives Phenytoin CYP1A2
CYP3A4
Caffeine vigilance increased. plasma level
anticonvulsive effect
! reduce/restrict caffeine intake
Chrościńska-Krawczyk et al. (2014), Nomani et al. (2019)
Antiepileptics, benzodiazepine derivatives Clonazepam CYP1A2
CYP3A4
Caffeine vigilance increased. plasma level
anticonvulsive effect
! reduce/restrict caffeine intake
Chrościńska-Krawczyk et al. (2014), Nomani et al. (2019)
Antiepileptics, carboxamide derivatives Carbamazepine CYP3A4
CYP2C8
Caffeine vigilance increased. plasma level
anticonvulsive effect
! reduce/restrict caffeine intake
Chrościńska-Krawczyk et al. (2014), Jankiewicz et al. (2007), Nomani et al. (2019)
Antiepileptics, fatty acid derivatives Valproic acid CYP2C9
CYP2A6
Caffeine vigilance increased. plasma level
anticonvulsive effect
! reduce/restrict caffeine intake
Chrościńska-Krawczyk et al. (2014), Nomani et al. (2019)
Psycholeptics (N05) Antipsychotics Clozapine
Fluphenazine
Haloperidol
Chlorpromazine
Lithium
Prochlorperazine
Thioridazine
Triflupromazine
CYP1A2
CYP2D6
Caffeine vigilance increased. clozapine plasma level
clozapine toxicity (400–1,000 mg caffeine per day)
lithium plasma level (tremor possible after abrupt caffeine withdrawal)
! exacerbation of psychotic symptoms (possible)
! reduce/restrict caffeine intake
! patient monitoring necessary
Carrillo & Benitez (2000)
Anxiolytics, benzodiazepine derivatives Alprazolam
Diazepam
CYP1A2
CYP3A4
Caffeine vigilance increased. plasma level
anxiolytic effect
! reduce/restrict caffeine intake
Loke, Hinrichs & Ghoneim (1985), Roache & Griffiths (1987)
Hypnotics and sedatives Pentobarbital
Triazolam
Zolpidem
Zopiclon
CYP2C2 Caffeine vigilance increased. hypnotic effect
! reduce/restrict caffeine intake
Batéjat et al. (2006), Walsh, Muehlbach & Schweitzer (1995)
Melatonin receptor agonists Melatonin Harpsøe et al. (2015), Härtter et al. (2006)
Psychoanaleptics (N06) Antidepressants, non-selective monoamine reuptake inhibitors Amitriptyline
Imipramine
CYP1A2
CYP2C19
Caffeine vigilance increased. caffeine plasma level
adverse reactions
! reduce/restrict caffeine intake
Sawynok (2011)
Antidepressants, selective serotonin reuptake inhibitors Fluvoxamine CYP1A2
CYP2C19
Caffeine vigilance increased. caffeine plasma level
adverse reactions
! reduce/restrict caffeine intake
Carrillo & Benitez (2000)
Other nervous system drugs (N07) Drugs used in nicotine dependence Nicotine
(transdermally)
CYP2C9 of caffeine plasma level
caffeine clearance
! exclude caffeine (intoxication risk)
Kroon (2007)
Drugs used in alcohol dependence Disulfiram CYP1A2
CYP3A4
caffeine plasma level
caffeine clearance
! exclude caffeine (intoxication risk)
Beach et al. (1986)
Other nervous system drugs, multiple sclerosis treatment Riluzole CYP1A2 Caffeine vigilance increased. caffeine and riluzole plasma level
! reduce/restrict caffeine intake
van Kan et al. (2005)
Nasal preparations (R01) Sympathomimetics Phenylpropanolamine
Pseudoephedrine
CYP1A2 Caffeine vigilance increased. caffeine plasma level
adverse reaction (hypertension)
! dosage adjustment
Jones (2008), Pentel (1984)
Drugs for obstructive airway diseases (R03) Non-selective beta-adrenoreceptor agonists) Isoprenaline (Isoproterenol)
Orciprenaline (Metaproterenol)
CYP1A2 positive inotropic effect of β-sympathomimetics
! reduce/restrict caffeine intake
Czigle & Tóth (2010b)
Selective beta-2-adrenoreceptor agonists Salbutamol
(Albuterol)
Terbutaline
CYP1A2 positive inotropic effect of β-sympathomimetics
! reduce/restrict caffeine intake
Czigle & Tóth (2010b)
Other systemic drugs for obstructive airway diseases, xanthines Theophylline CYP1A2 plasma level (23–29%)
adverse reactions
! reduce/restrict caffeine intake
Carrillo & Benitez (2000), Chrościńska-Krawczyk et al. (2014)
All other therapeutic products (V03) Nerve depressants Ethanol CYP2D6 caffeine plasma level
! reduce/restrict caffeine intake
Mohamed et al. (2011), Striley & Khan (2014)

Note:

ATC, Anatomical Therapeutic Chemical Classification System (World Health Organization, 2023); ↑, increase (of); ↓, decrease (of); !, warning; excl., excluding.

Drug interactions of Ginkgonis folium

Ginkgo biloba L. (Ginkgoaceae), commonly also known as ginkgo or the maidenhair tree, is a species of dioecious tree native to China (Bensky, Gamble & Bensky, 1986; Czigle et al., 2018; van Beek, 2000).

The European Pharmacopoeia lists a monograph for the dried leaf of Ginkgo biloba L. (Ginkgonis folium) (European Pharmacopoeia, 2023c) and requires the content of not less than 0.5% flavonoids, expressed as flavone glycosides (Mr 757). The pharmacopoeial monograph for the refined and quantified dry extract produced from Ginkgo leaf (Ginkgonis extractum siccum raffinatum et quantificatum) (European Pharmacopoeia, 2023b) contains three positive criteria on active constituents: 22.0–27.0% flavone glycosides (Mr 756.7), 2.8–3.4% ginkgolides (A, B and C), and 2.6–3.2% bilobalide. The fourth criterion requires that the content of ginkgolic acids is less than 5 ppm (European Pharmacopoeia, 2023b).

Products prepared from Ginkgo leaf and from its refined and quantified dry extract, often marketed as EGb 761, are top-selling herbal medicinal products, especially in Europe, as well as important major botanical food supplements on the world market. The quality of these food supplements on the European market is often dubious and prone to adulteration (Czigle et al., 2018). In western allopathic medicine, Ginkgo biloba medications underwent strict evaluations of their clinical therapeutic use, for example, by the European Medicines Agency (EMA), with the following results: the Ginkgo leaf herbal medicinal dry extract is indicated in the well-established medicinal use category ‘for the improvement of (age-associated) cognitive impairment and of quality of life in mild dementia’, (European Medicines Agency, 2012d), ATC code: N06DX02 (World Health Organization, 2023), and the powdered Ginkgo leaf herbal substance is beneficial as a traditional herbal medicinal product ‘for the relief of heaviness of legs and the sensation of cold hands and feet associated with minor circulatory disorders’ (European Medicines Agency, 2012d). The European Union herbal monograph is accompanied by a detailed assessment report (European Medicines Agency, 2012b).

The indications for G. biloba leaf are well supported by in-depth studies on a number of defined chemical constituents. The best known are flavonoids (flavonols, e.g., quercetin, kaempferol, isorhamnetin and their mono-, di-, and triglycosides; biflavonoids, e.g., amentoflavone, ginkgetin, bilobetin, sciadopitysin) (Hasler et al., 1992; Hasler & Meier, 1993; Meier, Hasler & Sticher, 1992) and terpene lactones (several diterpenes, e.g., ginkgolides A, B, C, D, K, L, M, N, P, Q, and the pentanorditerpene bilobalide) (van Beek, 2005; van Beek & Lelyveld, 1992; van Beek & Montoro, 2009), but they also include hypersensitive (ginkgolic acid) (Fuzzati, Pace & Villa, 2003; van Beek & Wintermans, 2001) and neurotoxic compounds (ginkgotoxin) (Leistner & Drewke, 2010).

Ginkgolides are inhibitors of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 (Czigle & Tóth, 2009a, 2016; Williamson, Driver & Baxter, 2009, 2013) and of the P-gp (causing decreased absorption and increased elimination) (Czigle & Tóth, 2009a, 2016; Williamson, Driver & Baxter, 2009, 2013). Ginkgolides are also antagonists of the platelet-activating factor (PAF); (Czigle & Tóth, 2009a, 2016; Czigle et al., 2018; Oberpichler et al., 1990; Smith, Maclennan & Darlington, 1996), Ginkgo flavonoids affect hemorheology (Czigle & Tóth, 2016; Chen et al., 2019a; Witte, Anadere & Walitza, 1992) and vasopressin level (Czigle & Tóth, 2016; Kubota et al., 2006). The EGb 761 extract increases the synaptosomal uptake of 5-hydroxytryptamine (Czigle & Tóth, 2016; Ramassamy et al., 1992), acts as an GABAA antagonist (Czigle & Tóth, 2016; Ivic et al., 2003), and has a neuroprotective effect (Ahlemeyer & Krieglstein, 2003). Biflavones (ginkgetin, isoginkgetin, bilobetin, and amentoflavone), and some flavonoids (apigenin, quercetin, isorhamnetin, luteolin, and kaempferol) inhibit thrombin activity (Chen et al., 2019c).

This review presents and summarizes relevant and more recent data on the drug interaction potential of Ginkgo leaf and its active metabolites. Interactions can occur at both the pharmacokinetic and pharmacodynamic levels (Table 2). Ginkgo biloba can increase the effects of anticoagulants, such as coumarin derivatives (European Medicines Agency, 2012d); patients with concomitant anticoagulant (e.g., warfarin, phenprocoumon) and antiplatelet treatment (e.g., clopidogrel, acetylsalicylic acid, and other non-steroidal anti-inflammatory drugs (NSAIDs)) should only use Ginkgo medicinal products after consultation with a physician (European Medicines Agency, 2012d). Concomitant use of Ginkgo biloba preparations and efavirenz (a non-nucleoside reverse transcriptase inhibitor) is not recommended, as plasma concentrations of efavirenz can be decreased due to induction of CYP3A4 (European Medicines Agency, 2012d). An interaction study with talinolol (a selective beta-blocking agent) indicates that Ginkgo biloba may inhibit P-gp (European Medicines Agency, 2012d). This can cause increased exposure of drugs markedly affected by the P-gp in the intestine, such as dabigatran etexilate (a direct thrombin inhibitor); caution is advised for the combination of Ginkgo biloba with dabigatran (European Medicines Agency, 2012d). A study of interaction has indicated that the Cmax of nifedipine (a calcium channel blocker) increased by up to 100% in some individuals that resulted in dizziness and an increased severity of hot flashes (European Medicines Agency, 2012d).

Table 2. Drug interactions of Ginkgonis folium.

ATC therapeutic subgroup ATC pharmacological/chemical subgroup Drugs Pharmacokinetic basis of interaction Pharmacodynamic basis of interaction Manifestation of interaction
Stomatological preparation, in dentistry (A01) Salicylic acid and derivatives Acetylsalicylic acid CYP1A2
CYP2C9
CYP3A4
EGb 761 is a PAF antagonist. synergistic effect
antiplatelet effect
! bleeding risk (hyphema)
Ke et al. (2021)
Antithrombotic agents (B01)
Analgetics (N02)
Drugs for acid related disorders (A02) H2-receptor antagonists Cimetidine CYP2C9 EGb 761 has a mucoprotective effect. mucoprotective effect Wang, Zhao & Ma (2000)
Drugs used in diabetes (A10) Insulins and analogues Insulin EGb 761 increases the function of Langerhans islets β cells. additive effect
! patient monitoring necessary
Banin et al. (2014)
Antithrombotic agents (B01) Platelet aggregation inhibitors excl. heparin Clopidogrel
Dipyridamol
Ticlopidine
CYP1A2
CYP2D6
P-gp
EGb 761 is a PAF antagonist. synergistic effect
antithrombotic effect
! bleeding risk (hyphema)
Williamson, Driver & Baxter (2013, 2018)
Direct thrombin inhibitors Dabigatran etexilate EGb 761 is a PAF antagonist. additive effect
! bleeding risk
Williamson, Driver & Baxter (2013, 2018)
Vitamin K antagonists Warfarin CYP1A2
CYP2C9
EGb 761 affects hemorheology. additive effect
! bleeding risk
Stoddard et al. (2015)
Heparin group Dalteparin
Enoxaparin
Heparin
CYP1A2
CYP2D6
CYP3A4
EGb 761 affects hemorheology. additive effect
! bleeding risk
Williamson, Driver & Baxter (2009, 2018).
Cardiac therapy (C01) Cardiac glycosides Digoxin CYP3A4 plasma level
! hypokalemia
Mauro et al. (2003)
Diuretics (C03) Low-ceiling diuretics, thiazides/sulfonamides Hydrochlorothiazide
Chlorothiazide
Indapamide
EGb 761 affects vasopressin level. diuretic effect
! hypertension risk
Williamson, Driver & Baxter (2013, 2018)
Calcium channel blockers (C08) Selective calcium channel blockers with mainly vascular effects, or with direct cardiac effects Nicardipine
Nifedipine
Verapamil
CYP3A4
CYP1A2
plasma level
! do not use combination
Williamson, Driver & Baxter (2013, 2018)
Immunosuppressants (L04) Calcineurin inhibitors Ciclosporin CYP3A4
P-gp
plasma level Williamson, Driver & Baxter (2013, 2018)
Anti-inflammatory and antirheumatic products (M01) Anti-inflammatory and antirheumatic products, non-steroids Celecoxib
Diclofenac
Ibuprofen
Indometacin
Naproxen
Piroxicam
CYP2C9 EGb 761 is a PAF antagonist. ! gastric bleeding risk Williamson, Driver & Baxter (2009, 2018)
Antiepileptics (N03) Antiepileptics, carboxamide derivatives Carbamazepine CYP3A4
CYP2C8
Neurotoxic ginkgotoxin (mainly in seeds). anticonvulsive effect Williamson, Driver & Baxter (2013, 2018)
Antiepileptics, fatty acid derivatives Valproic acid CYP2C9
CYP2A6
Neurotoxic ginkgotoxin (mainly in seeds). anticonvulsive effect Williamson, Driver & Baxter (2009, 2013, 2018)
Antiepileptics, barbiturates and derivatives Phenobarbital CYP2C9 Neurotoxic ginkgotoxin (mainly in seeds). anticonvulsive effect Czigle & Tóth (2016), Williamson, Driver & Baxter (2013, 2018)
Antiepileptics, hydantoin derivatives Primidone
Phenytoin
Gabapentin
Neurotoxic ginkgotoxin (mainly in seeds). anticonvulsive effect Williamson, Driver & Baxter (2009, 2018)
Psycholeptics (N05) Antipsychotics Haloperidol CYP2D6 antipsychotic effect Zhang et al. (2001)
Anxiolytics, benzodiazepine derivatives Alprazolam
Diazepam
Absorption
CYP2C9
CYP3A4
anxiolytic effect Williamson, Driver & Baxter (2009, 2018), Zuo et al. (2010)
Anxiolytic drugs, azaspirodecanedione derivatives Buspirone absorption absorption
anxiolytic effect
Spinella & Eaton (2002)
Hypnotics and sedatives, benzodiazepine derivatives Midazolam Williamson, Driver & Baxter (2009, 2018)
Psychoanaleptics (N06) Antidepressants;
monoamine oxidase inhibitors, non-selective; selective serotonin reuptake inhibitors; other antidepressants
Tranylcypromin
Trazodon
Fluoxetine
CYP3A4
CYP2C19
CYP2D6
EGb 761 is a serotonin inhibitor; and GABAA-agonist. antidepressant/sedative effect
adverse reaction (coma risk)
Czigle & Tóth (2016)
Psychostimulants, agents used for ADHD and nootropics Caffeine CYP1A2 psychostimulant effect Czigle & Tóth (2016)

Note:

ATC, Anatomical Therapeutic Chemical Classification System (WHO, 2023); ↑, increase (of); ↓, decrease (of); !, warning; EGb 761, refined and quantified dry extract produced from Ginkgo leaf; GABA, γ-aminobutyric acid; PAF, platelet-activating factor; P-gp, P-glycoprotein.

Drug interactions of Valerianae radix

Valerian is an old favorite in European phytotherapy. The monograph of valerian root (Valerianae radix) in the European Pharmacopoeia describes the dried, whole or fragmented underground parts of Valeriana officinalis L. s. l. (Valerianaceae), including the rhizome surrounded by the roots and stolons (European Pharmacopoeia, 2023o). The pharmacopoeia also lists further monographs with pharmaceutical quality used in human medicine: valerian root, cut for the purpose of being used in herbal teas (Valerianae radix minutata) (European Pharmacopoeia, 2023p), valerian dry hydroalcoholic extract (Valerianae extractum hydroalcoholicum siccum) (European Pharmacopoeia, 2023n), valerian dry aqueous extract (Valerianae extractum aquosum siccum) (European Pharmacopoeia, 2023m), and valerian tincture (Valerianae tinctura) (European Pharmacopoeia, 2023q).

Recently, Valeriana officinalis medications underwent evaluations of their clinical therapeutic use, e.g., by the European Medicines Agency, with the following results: the dry extract of Valerianae radix is indicated in the category of well-established medicinal use for the ‘relief of mild nervous tension and sleep disorders’, (European Medicines Agency, 2015c), ATC code: N05CM09 (World Health Organization, 2023), and as a traditional medicinal product Valerianae radix and its dry extracts, tinctures, and expressed juice (from fresh root), are beneficial for the ‘relief of mild symptoms of mental stress and to aid sleep’, (European Medicines Agency, 2015c). The valerian essential oil (Valerianae aetheroleum), as a traditional herbal medicinal product is beneficial for the ‘relief of mild symptoms of mental stress and to aid sleep’, (European Medicines Agency, 2015b). This review article only presents relevant and more recent data that are not part of these herbal monographs or related assessment reports (European Medicines Agency, 2015a).

The combination of valerian root and hop strobile (Valerianae radix and Lupuli flos) is indicated in the category of well-established medicinal use for the ‘relief of sleep disorders’, and in the category of traditional use for the ‘relief of mild symptoms of mental stress’, and ‘to aid sleep’, (European Medicines Agency, 2017b).

Sedative herbal tea combinations (Species sedativae) shall contain 2, 3 or 4 herbal substances out of hop strobile—Lupuli flos (Humulus lupulus L., Cannabaceae), lavender flower—Lavandulae flos (Lavandula angustifolia Mill., Lamiaceae), Melissa leaf—Melissae folium (Melissa officinalis L., Lamiaceae), passionflower herb—Passiflorae herba (Passiflora incarnata L., Passifloraceae), and valerian root—Valerianae radix (Valeriana officinalis L., Valerianaceae). Depending on the chosen herbal substances, the percentage of Valerianae radix in combination is 15–57% or 33–57%. This herbal tea is beneficial as a traditional herbal medicinal product for the ‘relief of mild symptoms of mental stress and to aid sleep’, (European Medicines Agency, 2017a).

The major biologically active compounds of Valerianae radix are flavonoids, iridoids, lignans, volatile compounds, such as monoterpenes (borneol, bornyl acetate), and sesquiterpenes (valerenone, valerenic and acetoxyvalerenic acids) (Czigle & Tóth, 2010a, 2016; Orhan, 2021).

A possible mechanism, by which Valerianae radix may cause sedation, is by increasing the synaptic amount of γ-aminobutyric acid (GABA) (Johnston et al., 2006; Orhan, 2021; Savage et al., 2018). Flavonoids (Wasowski & Marder, 2012) and monoterpenes (bornyl acetate) (Wang & Heinbockel, 2018) have GABA agonistic properties, and flavonoids also act as MAO inhibitors (Dhiman et al., 2019). Valerenic acid could attenuate increases in serum corticosterone levels in a mouse model of stress, the extract could modulate serotonin (5-HT) and norepinephrine (NE) turnover in the hippocampus and amygdala region (Jung et al., 2015). Valerenic acid is a selective positive allosteric modulator of the GABAA receptor (Khom et al., 2007), an agonist at the metabotropic glutamate receptor mGlu I, but an antagonist at the mGlu II (Del Valle-Mojica & Ortíz, 2012; Feinberg et al., 2005); a partial agonist at the 5-HT5A receptor (Dietz et al., 2005), it also has antidepressant potential. Isovaltrate (a valepotriate) is an inverse agonist at the adenosine A1 receptor (Sichardt et al., 2007), and it presents antidepressant-like activity, mediated by dopaminergic, noradrenergic, serotonergic neurotransmissions (Dietz et al., 2005; Jayaraj et al., 2020; Orhan, 2021; Ortiz, Nieves-Natal & Chavez, 1999). It also has inhibitory activity towards the Na+/K+-ATPase (Müller et al., 2015). Some lignans, for example 1-hydroxypinoresinol, are GABAA receptor agonists; and 4′-O-β-d-glucosyl-9-O-(6″-deoxysaccharosyl)olivil is a partial agonist at adenosine A1 receptors (Cavadas et al., 1995; Savage et al., 2018; Schumacher et al., 2002).

Interactions occur at the pharmacokinetic and pharmacodynamic levels (Table 3). Different preparations of valerian root have been proven to inhibit the cytochrome P450 isoenzyme CYP3A4. In contrast, Valeriana does not affect other cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 (Bogacz et al., 2014; Czigle & Tóth, 2010a, 2016; Williamson, Driver & Baxter, 2009, 2013, 2018). Pharmacodynamic interactions are related to the mechanism of action of secondary metabolites. Valeriana does not affect the pharmacokinetics of caffeine, alprazolam, or midazolam to a clinically relevant extent (European Medicines Agency, 2015c). The stimulant effect of caffeine may oppose the hypnotic effects of valerian (European Medicines Agency, 2015c). However, additive anxiolytic effects are possible with benzodiazepines (European Medicines Agency, 2015c).

Table 3. Drug interactions of Valerianae radix.

ATC therapeutic subgroup ATC pharmacological/chemical subgroup Drugs Pharmacokinetic basis of interaction Pharmacodynamic basis of interaction Manifestation of interaction
Antidiarrheals, intestinal anti-inflammatory/antiinfective agents (A07) Antipropulsives Loperamide CYP3A4 Valeriana is a GABAA agonist, mGlu I agonist, mGlu II antagonist, MAO inhibitor, 5-HT5A agonist, A1 agonist. additive effect
adverse reaction
Czigle & Tóth (2016), Kelber, Nieber & Kraft, 2014)
Lipid modifying agents (C10) HMG CoA reductase inhibitors Lovastatin CYP3A4
P-gp
plasma level
adverse reaction (rabdomyolysis)
Czigle & Tóth (2016)
Antifungals for dermatological use (D01) Antifungals for topical use, imidazole and triazole derivatives Ketoconazole CYP3A4 plasma level
adverse reactions
Czigle & Tóth (2016), Hellum & Nilsen (2008)
Antimycotics for systemic use (J02) Triazole and tetrazole derivatives Itraconazole CYP3A4 plasma level
adverse reactions
Czigle & Tóth (2016), Hellum & Nilsen (2008)
Antineoplastic agents (L01) Plant alkaloids and other natural products Etoposide
Paclitaxel
Vinblastine
Vincristine
Vindesine
CYP3A4 plasma level
adverse reactions
Czigle & Tóth (2016), Mooiman et al. (2014)
Anesthetics (N01) Anesthetics, general Propofol
Thiopental
Valeriana is a GABAA agonist, mGlu I agonist, mGlu II antagonist, MAO inhibitor, 5-HT5A agonist, A1 agonist. additive effect
adverse reactions
! do not use combination
Czigle & Tóth (2016)
Analgesics (N02) Opioids Fentanyl
Morphine
Valeriana is a GABAA agonist, mGlu I agonist, mGlu II antagonist, MAO inhibitor, 5-HT5A agonist, A1 agonist. additive effect
adverse reactions
! do not use combination
Czigle & Tóth (2016)
Antiepileptics (N03) Antiepileptics, barbiturates Phenobarbital CYP2C9 Valeriana is a GABAA agonist, mGlu I agonist, mGlu II antagonist, MAO inhibitor, 5-HT5A agonist, A1 agonist. additive effect
adverse reactions
! do not use combination
Czigle & Tóth (2016), Dietz et al. (2005)
Antiepileptics, benzodiazepine derivatives Clonazepam CYP1A2
CYP3A4
Valeriana is a GABAA agonist, mGlu I agonist, mGlu II antagonist, MAO inhibitor, 5-HT5A agonist, A1 agonist. additive effect
adverse reaction
! do not use combination
Dietz et al. (2005), Kelber, Nieber & Kraft (2014)
Psycholeptics drugs (N05) Anxiolytic drugs, benzodiazepine derivatives, azaspirodecanedione derivatives Alprazolam
Diazepam
Lorazepam
Buspirone
CYP2C9
CYP3A4
Valeriana is a GABAA agonist, mGlu I agonist, mGlu II antagonist, MAO inhibitor, 5-HT5A agonist, A1 agonist. alprazolam plasma level (19%)
anxiolytic effect
! do not use combination
Cavadas et al. (1995), Dietz et al. (2005), Kelber, Nieber & Kraft (2014)
Hypnotics and sedatives, barbiturates Pentobarbital
Secobarbital
CYP2C9 Valeriana is a GABAA agonist, mGlu I agonist, mGlu II antagonist, MAO inhibitor, 5-HT5A agonist, A1 agonist. additive effect
adverse reaction (hypotension)
! do not use combination
Cavadas et al. (1995), Czigle & Tóth (2016), Dietz et al. (2005)
Hypnotics, benzodiazepine derivatives Midazolam
Temazepam
Triazolam
CYP2C19
CYP3A4
Valeriana is a GABAA agonist, mGlu I agonist, mGlu II antagonist, MAO inhibitor, 5-HT5A agonist, A1 agonist. plasma level
anxiolytic effect
! do not use combination
Cavadas et al. (1995), Czigle & Tóth (2016), Dietz et al. (2005), Mooiman et al. (2014)
Antihistamines for systemic use (R06) Selective peripheral H1 blocker Fexofenadine CYP3A4
Pgp
OATP
Valeriana is a GABAA agonist, mGlu I agonist, mGlu II antagonist, MAO inhibitor, 5-HT5A agonist, A1 agonist. plasma level
adverse reactions (sedative/hypnotic effect)
Czigle & Tóth (2016), Dietz et al. (2005)

Note:

ATC, Anatomical Therapeutic Chemical Classification System (WHO, 2023); ↑, increase (of); !, warning; A1 receptor, adenosine receptor, subtype A1; GABA, γ-aminobutyric acid; mGlu I, mGlu II receptors, metabotropic glutamate receptors subtype I a II; 5-HT5A receptor, 5-hydroxytryptamine (serotonin) 5A subtype receptor; MAO, monoamine oxidase; H, histamine; OATP, organic anion transporters; P-gp, P-glycoprotein.

Drug interactions of Hyperici herba

The herbal drug Hyperici herba consists of whole or fragmented, dried flowering tops of St. John’s wort (Hypericum perforatum L., Hypericaceae), harvested during flowering time (European Pharmacopoeia, 2023l). The Pharmacopoeia also lists a monograph for the St. John’s wort dry extract, quantified (Hyperici herbae extractum siccum quantificatum) (European Pharmacopoeia, 2023k) with pharmaceutical quality used in human medicine. In Western allopathic medicine, Hypericum perforatum medications were subjected to strict evaluations of their clinical therapeutic use, e.g., by the European Medicines Agency, with the following results: the Hypericum dry extract is indicated in the category of well-established medicinal use for the ‘treatment of mild to moderate depressive episodes, and for the short term treatment of symptoms in mild depressive disorders’, (European Medicines Agency, 2021), ATC code: N06AX25 (World Health Organization, 2023), and as a traditional medicinal product the Hyperici herba dry and liquid extracts, tinctures, expressed juice (from the fresh herb), and the comminuted herbal substance are beneficial for the ‘relief of temporary mental exhaustion, for the symptomatic treatment of minor inflammations of the skin (such as sunburn) and as an aid in healing of minor wounds, as well as for the symptomatic relief of mild gastrointestinal discomfort’, (European Medicines Agency, 2021). This review article presents relevant and more recent data that are not part of the European Union herbal monograph or the related assessment report (European Medicines Agency, 2016a).

The final antidepressant effect arises on the basis of the synergy of different biologically active compounds (Czigle & Tóth, 2009b; Nagy, Mučaji & Grančai, 2017). The phloroglucinol derivatives hyperforin and adhyperforin are re-uptake inhibitors of serotonin, dopamine, and norepinephrine (Tian et al., 2014). Hyperforin is a transient receptor potential channels (TRPC6) activator as well, and it induces the release of calcium and zinc from mitochondria (Tu, Gibon & Bouron, 2010). Recent data showed that the increase in the intracellular concentration of calcium ions is mediated by the activation of the mentioned TRPC6, a diacylglycerol-sensitive C-class of transient receptor potential channels, and without the activation of other isoforms (TRPC1, TRPC3, TRPC4, TRPC5, and TRPC7) (Nagy, Mučaji & Grančai, 2017; Tu, Gibon & Bouron, 2010). Hyperforin is also a GABA reuptake inhibitor (Zanoli, 2004). Flavonoids and proanthocyanins have a GABA agonistic effect (Hanrahan, Chebib & Johnston, 2011). The naphthodianthrone derivative hypericin is a MAO-A and MAO-B inhibitor (Butterweck, 2003), and dopamine β-hydroxylase inhibitor (Kleber et al., 1999), leading to increased dopamine levels, although thus possibly decreasing norepinephrine and epinephrine. It also affects 5-HT1A (Teufel-Mayer & Gleitz, 1997) and D3 receptors (McClatchey et al., 2009), and is a β-sympathomimetic (Nagy, Mučaji & Grančai, 2017).

Interactions occur at both the pharmacokinetic and pharmacodynamic levels. The Hypericum dry extract induces the expression of CYP3A4, CYP2C9, CYP2C19 (Czigle & Tóth, 2009b, 2016; Williamson, Driver & Baxter, 2009, 2013, 2018), which results in increased drug metabolism; it also inhibits the P-glycoprotein (causing decreased oral absorption and increased elimination) (Czigle & Tóth, 2009b, 2016; Dürr et al., 2000; Williamson, Driver & Baxter, 2013). Special care should be taken in the case of concomitant use of all drug substances whose kinetics are influenced by CYP3A4, CYP2C9, CYP2C19, or P-gp (e.g., digoxin, simvastatin, methadone, benzodiazepine derivatives, amitriptyline, finasteride, fexofenadine), because a reduction in plasma concentrations of these drugs is possible (Table 4). Concomitant use of immunosuppressive drugs for systemic use (cyclosporine/ciclosporin, tacrolimus) (Alscher & Klotz, 2003; Czigle & Tóth, 2016), antivirals for systemic use (protease inhibitors, such as amprenavir, indinavir, and others), several antineoplastic agents, such as topoisomerase 1 inhibitors (irinotecan), and anticoagulants, vitamin K antagonists (warfarin) is contraindicated (Table 4). A reduction in plasma concentrations of hormonal contraceptives for systemic use can lead to increased intermenstrual (breakthrough) bleeding and to a failure of the contraceptive effect. Women who use oral contraceptives should take alternate or additional contraceptive measures (Table 4) (Czigle & Tóth, 2016; European Medicines Agency, 2021; Hall et al., 2003).

Table 4. Drug interactions of Hyperici herba.

ATC therapeutic subgroup ATC pharmacological/chemical subgroup Drugs Pharmacokinetic basis of interaction Pharmacodynamic basis of interaction Manifestation of interaction
Drugs for acid related disorders (A02) Proton pump inhibitors Omeprazole CYP2C19
CYP3A4
plasma level Borrelli & Izzo (2009)
Antithrombotic agents (B01) Platelet aggregation inhibitors excl. heparin Clopidogrel CYP1A2
CYP2D6
active metabolites plasma level
antithrombotic effect
! adverse reaction (bleeding)
Lau et al. (2011)
Vitamin K antagonists Warfarin
Phenprocoumon
CYP1A2
CYP2C9
CYP3A4
CYP2C19
INR
PT
anticoagulant effect
Borrelli & Izzo (2009)
Cardiac therapy (C01) Cardiac glycosides Digoxin CYP3A4
Pgp
plasma level Borrelli & Izzo (2009)
Antihypertensives (C02) Antiadrenergic agents, centrally acting (Rauvolfia alkaloids) Reserpine CYP1A2
CYP2C6
CYP2D1
CYP2D2
CYP2E1
CYP3A4
Hypericum is a serotonin reuptake and MAO inhibitor. antagonistic effect Nicolussi et al. (2020)
Calcium channel blockers (C08) Selective calcium channel blockers with direct cardiac effects Verapamil CYP3A4
CYP1A2
plasma level Tannergren et al. (2004)
Lipid modifying agents (C10) HMG CoA reductase inhibitors Simvastatin
Pravastatin
Fluvastatin
Atorvastatin
Lovastatin
CYP3A4
P-gp
plasma level Eggertsen, Andreasson & Andrén (2007)
Sex hormones and modulators of the genital system (G03) Hormonal contraceptives for systemic use Ethinylestradiol (EE),
Estradiol + Progestogens
CYP1A2
CYP2C9
CYP3A4
estrogen (EE) plasma level (13–15%)
! breakthrough bleeding
! contraceptive failure
! alternate methods of contraception are advised.
Borrelli & Izzo (2009), Hall et al. (2003)
Urologicals (G04) Testosterone-5α reductase inhibitors Finasteride CYP3A4
P-gp
plasma level Lundahl et al. (2009)
Antivirals for systemic use (J05) Protease inhibitors Amprenavir
Indinavir
Nelfinavir
Ritonavir
Saquinavir
CYP3A4
P-gp
plasma level
AUC (57%)
elimination
Borrelli & Izzo (2009), James (2000)
Non-nucleoside reverse-transcriptase inhibitors Nevirapine
Delavirdine
Efavirenz
CYP3A4
P-gp
plasma level Borrelli & Izzo (2009)
Antineoplastic agents (L01) BCR-ABL tyrosine kinase inhibitors Imatinib CYP3A4 plasma level Smith et al. (2004)
Topoisomerase 1 inhibitors Irinotecan CYP3A4 plasma level
AUC (42%)
Mathijssen et al. (2002)
Sensitizers used in photodynamic/radiation therapy Aminolevulinic acid up-regulation of CYP activity Hypericin is phototoxic. light-induced toxicity (15%)
! Synergistic photensitivity reaction between aminolevulinic acid and hypericin.
Boiy, Roelandts & de Witte (2011), Ladner et al. (2001), Ritz et al. (2012), Schneider-Yin et al. (2009)
Endocrine therapy (L02) Anti-estrogens Tamoxifen CYP2C9 plasma level Hansten (2018)
Immunosuppressants drugs (L04) Calcineurin inhibitors Cyclosporine
Tacrolimus
CYP3A4
P-gp
cyclosporine (30–70%), and tacrolimus plasma level
! transplant rejection risk
Alscher & Klotz (2003), Borrelli & Izzo (2009), Hebert et al. (2004)
Analgesics (N02) Opioids, benzomorphan derivatives Pentazocine CYP3A4 Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist additive serotonergic effect
! risk: serotonin syndrome or Call-Fleming syndrome
Drugs (2023)
Other opioids Tramadol CYP1A2
CYP3A4
Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist. additive serotonergic effect
! risk: serotonin syndrome or Call-Fleming syndrome
Sansone & Sansone (2009)
Drugs used in opioid dependence
Opioids, diphenylpropylamine derivatives
Methadone CYP3A4
CYP2C19
CYP2D6
Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist. methadone effect
adverse reactions
! coma risk
Borrelli & Izzo (2009)
Other analgesics and antipyretics, anilides Paracetamol CYP1A2
CYP3A4
CYP2E1
analgetic effect Jiang et al. (2022)
Antimigraine preparations, selective serotonin (5-HT1) agonists Frovatriptan
Naratriptan
Rizatriptan
Sumatriptan
Zomitriptan
CYP1A2
CYP3A4
CYP2D6
MAO-A
P-gp
Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist. additive serotonergic effect
! risk: serotonin syndrome or Call-Fleming syndrome
Bonetto et al. (2007)
Antiepileptics (N03) Antiepileptics, barbiturates and derivatives Phenobarbital
Pentobarbital
Secobarbital
CYP2C9 anticonvulsive effect
! dosage adjustment
Nicolussi et al. (2020)
Antiepileptics, hydantoin derivatives Phenytoin CYP2C9
CYP2C19
anticonvulsive effect
! dosage adjustment
Borrelli & Izzo (2009)
Antiepileptics, carboxamide derivatives Carbamazepine CYP3A4 anticonvulsive effect
! dosage adjustment
Borrelli & Izzo (2009)
Psycholeptics (N05) Anxiolytics, benzodiazepine derivatives Alprazolam
Diazepam
CYP2C19
CYP3A4
anxiolytic effect Borrelli & Izzo (2009)
Hypnotics and sedatives, benzodiazepine derivatives Midazolam CYP2C19
CYP3A4
hypnotic effect Borrelli & Izzo (2009)
Psychoanaleptics (N06) Antidepressants, non-selective monoamine reuptake inhibitors Amitriptylin
Nortriptylin
CYP3A4
CYP2C9
CYP2D6
P-gp
Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist. plasma level of amitriptylin (22%) and its metabolite nortriptylin (42%)
antidepressant effect
Borrelli & Izzo (2009)
Antidepressants, MAO inhibitors, non-selective Tranylcypromine MAO additive effect
adverse reaction
! 14 days interval
Sacher et al. (2011)
Antidepressants, selective serotonin reuptake inhibitors Paroxetine
Sertraline
CYP2D6
CYP3A4
additive serotonergic effect
! risk: serotonin syndrome or Call-Fleming syndrome
Cui & Zheng (2016)
Antidepressants, other antidepressants Nefazodone CYP2D6
CYP3A4
additive serotonergic effect
! risk: serotonin syndrome or Call-Fleming syndrome
Borrelli & Izzo (2009)
Drugs for obstructive airway diseases (R03) Other systemic drugs for obstructive airway diseases, xanthines Aminophylline
Theophylline
CYP1A2 plasma level Morimoto et al. (2004)
Cough and cold preparations (R05) Cough suppressants, excl. combinations with expectorants Dextromethorphan CYP3A4
CYP2D6
Hypericum is a serotonin reuptake and MAO inhibitor, GABA agonist. additive serotonergic effect
! risk: serotonin syndrome or Call-Fleming syndrome
Markowitz et al. (2000)
Antihistamines for systemic use (R06) Other antihistamines for systemic use Fexofenadine CYP3A4
P-gp
OATP
plasma level
adverse reactions
Wang et al. (2002)

Note:

ATC, Anatomical Therapeutic Chemical Classification System (WHO, 2023); ↑, increase (of); ↓, decrease (of); !, warning; excl., excluding; AUC, area under the curve; GABA, γ-aminobutyric acid; INR, international normalized ratio; MAO, monoamine oxidase; OATP, organic anion transporters; P-gp, P-glycoprotein; PT, prothrombin time.

The outcome of the pharmacodynamic interaction is the risk of serotonin syndrome (Czigle & Tóth, 2016; Spadaro et al., 2022; Volpi-Abadie, Kaye & Kaye, 2013) or Call-Fleming syndrome (Czigle & Tóth, 2016; Skandhan, Ramakrishnan & Anand, 2013). The reason is that the Hypericum dry extract increases serotonergic effects when combined with antidepressants affecting serotonin, such as selective serotonin reuptake inhibitors (e.g., sertraline, paroxetine, nefazodone), tricyclic antidepressants, selective serotonin (5-HT1A) agonists employed in anxiety treatment (buspirone), or selective serotonin (5-HT1BD) agonists used for acute migraine attacks (triptans) (Table 4). The serotonin syndrome (Volpi-Abadie, Kaye & Kaye, 2013) is a potentially life-threatening condition based on the overactivation of both the central postsynaptic and peripheral 5HT1A, and most notably the 5HT2A receptors. Symptoms include a combination of altered cognitive functions (cephalgia, agitation, hypomania, confusion, hallucination, coma), autonomic hyperactivity (tremor, diaphoresis, hypertension, tachycardia, nausea, vomitus), neuromuscular hyperactivity (rigidity, tremor, myoclonus, hyperreflexia) and hyperthermia (Spadaro et al., 2022; Volpi-Abadie, Kaye & Kaye, 2013). Symptoms usually begin within 24 h of an increased dose of a serotonergic drug/agent, the addition of another serotonergic agent to a drug regimen, or overdosing. Most patients will seek help in a hospital in 6 h; however, patients with mild symptoms may have a more subacute or chronic presentation (Volpi-Abadie, Kaye & Kaye, 2013). The Call-Fleming syndrome (Skandhan, Ramakrishnan & Anand, 2013), also called reversible cerebral vasoconstriction syndrome (RCVS), is characterized by thunderclap headache and reversible vasoconstriction of the cerebral arteries.

During the treatment with Hypericum extracts, intense UV exposure should be avoided. Hypericin (a red pigment) ( G=(V,E) 595 nm) (Skalkos et al., 2006) is phototoxic (Schempp et al., 2000, 2001, 2003). A synergistic photosensitivity reaction has been observed between aminolevulinic acid (photodynamic therapy) (Boiy, Roelandts & de Witte, 2011; Ritz et al., 2012; Schneider-Yin et al., 2009) and hypericin (Table 4).

Drug interactions of Lupuli flos

The pharmacopoeial herbal drug hop strobile (Lupuli flos), having pharmaceutical quality and used in human medicine, is described as the dried, generally whole, female inflorescence (strobile) of hop (Humulus lupulus L., Cannabaceae) (European Pharmacopoeia, 2023i). Hops (hop strobiles) are also commonly used culinarily as a bittering and flavoring agent in the production of beer. In allopathic medicine, Humulus lupulus medications underwent strict evaluations of their clinical therapeutic use, e.g., by the EMA with the following results: Lupuli flos dry and liquid extracts (ethanolic or sweet wine extract), tincture, as well as the comminuted or powdered herbal substance are indicated in the category of traditional herbal medicinal products that are beneficial for the ‘relief of mild symptoms of mental stress and to aid sleep’, (European Medicines Agency, 2013). This review article presents relevant and more recent data that are not included in the European Union herbal monograph on hop strobile and the related assessment report (European Medicines Agency, 2005).

The medicinal use of valerian root and hop strobile as a combination (Valerianae radix et Lupuli flos) is indicated in the category of well-established medicinal use for the ‘relief of sleep disorders’, and in the category of traditional use for the ‘relief of mild symptoms of mental stress and to aid sleep’, (European Medicines Agency, 2017b).

Sedative herbal tea combinations (Species sedativae) shall contain 2, 3 or 4 herbal substances out of hop strobile—Lupuli flos (Humulus lupulus L., Cannabaceae), lavender flower—Lavandulae flos (Lavandula angustifolia Mill., Lamiaceae), Melissa leaf—Melissa folium (Melissa officinalis L., Lamiaceae), passionflower herb—Passiflorae herba (Passiflora incarnata L., Passifloraceae), and valerian root—Valerianae radix (Valeriana officinalis L., Valerianaceae). Depending on the chosen herbal substances, the percentage of Lupuli flos in combination is 15–40%, 15–43%, or 21–36%. This herbal tea is beneficial as a traditional herbal medicinal product for the ‘relief of mild symptoms of mental stress and to aid sleep’, (European Medicines Agency, 2017a).

The final anxiolytic/hypnotic effect of hop strobile is based on the synergy of different biologically active compounds. Lupuli flos contains resins with phloroglucinols (α-acids (humulone and its derivates), β-acids (lupulone and its derivates), and their degradation product 2-methyl-3-buten-2-ol), flavonoids (xanthohumol), and terpenes (β-myrcene, β-caryophyllene) (Nagy, Mučaji & Grančai, 2017).

Some Lupuli flos components, including those contained in beer (non-alcoholic), are believed to act in the CNS by influencing GABA, adenosine, serotonin, and melatonin neurotransmission with an effective sedative action that both modulates the circadian rhythms and the sleep-wake cycle and is beneficial for the induction of sleep (Abourashed, Koetter & Brattström, 2004; Brattström, 2007; Butterweck et al., 2007; Dietz et al., 2005; Franco et al., 2012; Savage et al., 2018). Humulone is a positive allosteric modulator of GABAA receptors (Benkherouf et al., 2020). Some components of hop resin (including the degradation product 2-methyl-3-buten-2-ol) increase GABA activity by modulating GABAA receptors (Franco et al., 2012). The Lupuli flos extract is an agonist of the melatonin receptor MT1 but α- and β-acids do not affect melatonin receptors (Grundmann et al., 2006). Melatonin secretion has a circadian character, its receptors (MT1 and MT2) are localized in the suprachiasmatic nucleus; melatonin regulates circadian rhythms and hence the sleep-wake cycle in humans. Humulus active compounds have an α2-agonistic effect (β-myrcene) (Surendran et al., 2021), they affect the cannabinoid CB2 receptor (β-caryophyllene) (Alberti et al., 2017; Klauke et al., 2014) and opioid receptors (Park et al., 2012). Lupuli flos also contains several compounds with estrogenic activity, such as the prenylated flavonoid 6-prenylnaringenin (Carbone & Gervasi, 2022; Dietz et al., 2017; Hemachandra et al., 2012; Tan et al., 2014; Yoshimaru et al., 2014). Prenylflavonoids (xanthohumol, isoxanthohumol and 8-prenylnaringenin) are capable of modulating aromatase activity, decreasing estrogen synthesis (Monteiro et al., 2006).

Interactions occur at both the pharmacokinetic and pharmacodynamic levels. Lupuli extract is a CYP1A2, CYP2C8, CYP2C9, CYP2C19 inhibitor (Czigle & Tóth, 2016; Foster et al., 2011; TRC, 2023; Williamson, Driver & Baxter, 2013; Yuan et al., 2014). 8-Prenylnaringenin is an inhibitor of multidrug resistance-associated transporters, P-glycoprotein and MRP1 (Wesołowska et al., 2010). Abundant Phase II conjugates of the prenylated flavonoids were observed, including monoglucuronides, diglucuronides, monosulfates and sulfate-glucuronic acid deconjugates (van Breemen et al., 2020). No clinically significant interactions are reported in the European Union herbal monograph (European Medicines Agency, 2013). The interactions between Humulus and other drugs are based mainly on experimental evidence (European Medicines Agency, 2013; Williamson, Driver & Baxter, 2009, 2013, 2018) (Table 5).

Table 5. Drug interactions of Lupuli flos.

ATC therapeutic subgroup ATC pharmacological/chemical subgroup Drugs Pharmacokinetic basis of interaction Pharmacodynamic basis of interaction Manifestation of interaction
Endocrine therapy (L02) Anti-estrogens Tamoxifen CYP2C9 Humulus has estrogenic effects (prenylated flavonoids). antagonistic effect Harrigan et al. (2021), Yoshimaru et al. (2014)
Analgesics (N02) Other analgesics and antipyretics, anilides Paracetamol CYP1A2
CYP3A4
CYP2E1
β-Caryophyllene affects CB2 receptor analgetic effect Horvat et al. (2007), Jakovljevic et al. (2009)
Antiepileptics (N03) Antiepileptics, barbiturates and derivatives Phenobarbital CYP3A4
CYP2C9
Humulus has an α2-agonistic effect (β-myrcene), affects CB2 (β-caryophyllene) and opioid receptors.
Humulone is a positive allosteric modulator of GABAA receptors.
additive effect
adverse reactions
Raskovic et al. (2007), Raskovic et al. (2016)
Psycholeptics (N05) Anxiolytics, benzodiazepine derivatives Diazepam CYP1A2
CYP2C19
CYP3A4
Humulus has an α2-agonistic effect (β-myrcene), affects CB2 (β-caryophyllene) and opioid receptors.
Humulone is a positive allosteric modulator of GABAA receptors.
additive effect
adverse reactions
Raskovic et al. (2007, 2016)

Note:

ATC, Anatomical Therapeutic Chemical Classification System (WHO, 2023); ↑, increase (of); ↓, decrease (of); !, warning; CB2, cannabinoid receptor type 2; GABAA, γ-aminobutyric acid A receptor.

Drug interactions of cannabinoids-containing herbal drugs (Cannabis flos, Cannabis herba, Cannabis resina)

Observing the impact of marijuana (Cannabis herba) or hashish (Cannabis resina) on the human body opened the way for the medical use of some cannabinoid receptor substrates in the therapy of certain diseases (e.g., as analgesics, antiemetics, antiepileptics) (Czigle & Tóth, 2016; Hill et al., 2017; NIH, 2023; Stasiłowicz et al., 2021). It took a long time to finally discover human cannabinoid receptors for in the 1980s; there are two subtypes: CB1 and CB2 (Kendall & Yudowski, 2017; Stasiłowicz et al., 2021; Svízenská, Dubový & Sulcová, 2008). Subsequently, the importance of the endocannabinoid system was clarified and endogenous ligands of the cannabinoid receptors—metabolites of arachidonic acid—were discovered. They include anandamide (AEA), 2-arachidonoylglycerol (2-AG), and palmitoylethanolamide. Less well-established endocannabinoids are virodhamin, noladin, and N-arachidonoyl dopamine (Mouslech & Valla, 2009). The main substances of marijuana or hashish are phytocannabinoids, e.g., Δ9-tetrahydrocannabinol (Δ9-THC, dronabinol, (-)-THC), Δ8-tetrahydrocannabinol (Δ8-THC), cannabidiol (CBD) and cannabinol (CBN). A total of almost 70 isolated cannabinoids are known (European Medicines Agency, 2020b; Gülck & Lindberg Møller, 2020). Currently, there is information on the therapeutic application of the above-mentioned herbal drugs, their extracts and/or individual active metabolites, as well as on some analogues with slight chemical structural modifications. Cannabis flos and Cannabis herba (European Medicines Agency, 2020b) of pharmaceutical quality (Cannabis sativa L., Cannabaceae) are used as analgesics in oncology and to treat neuropathic pain (oral use in the form of a water infusion, i.e., herbal tea, or as inhalation therapy) (Fitzcharles et al., 2021; Giacoppo, Bramanti & Mazzon, 2017; Hill et al., 2017; NIH, 2023; Stasiłowicz et al., 2021; Vulfsons et al., 2020). Synthetic agonists at cannabinoid receptors encompass dronabinol (Δ9-THC) and nabilone (both are used as antiemetic agents during cancer treatment and in the treatment of anorexia of patients with HIV) (Beal et al., 1995; DAC, 2001; Ng & Gupta, 2022). Cannabidiol (CBD) is used as an orphan drug in the therapy of specific forms of epilepsy: the Dravet syndrome (European Medicines Agency, 2014; Chen, Borgelt & Blackmer, 2019b) and the Lennox-Gastaut syndrome (European Medicines Agency, 2017c; Chen, Borgelt & Blackmer, 2019b). EMA granted an orphan designation for cannabidiol for the treatment of tuberous sclerosis (European Medicines Agency, 2018) and glioma (European Medicines Agency, 2016b). An inverse agonist at cannabinoid receptors, rimonabant, was tested in the treatment of addiction and obesity, but was withdrawn from the market due to side effects (2% incidence of depression) and suicidal risk (Bielawiec, Harasim-Symbor & Chabowski, 2020; Leite et al., 2009; European Pharmacopoeia, 2023h). Cannabis sativae oleum, the fatty oil obtained from Cannabis semen is important for the treatment of eczema and intertrigo (Sklenář, 2021).

Pharmacokinetic interactions occur mainly at the level of metabolism (Table 6). Phytocannabinoids are extensively metabolized by the cytochrome P450 (Czigle & Tóth, 2011, 2016). Cannabinoids inhibit CYP2C9 and CYP3A4 (Czigle & Tóth, 2011; Williamson, Driver & Baxter, 2009, 2013, 2018), while marijuana smoking induces CYP1A2 (Czigle & Tóth, 2011, 2016; Williamson, Driver & Baxter, 2009, 2013, 2018). THC and CBD inhibit CYP2D6, CYP2C19, CYP2B6 and CYP2J2 (Qian, Gurley & Markowitz, 2019). CYP3A4/5/7 is potentially inhibited by CBD (Qian, Gurley & Markowitz, 2019). Δ9-THC induces CYP1A1 also activates CYP2C9 (Czigle & Tóth, 2011, 2016; Qian, Gurley & Markowitz, 2019; Williamson, Driver & Baxter, 2009, 2013, 2018), the cannabinoids mixture also induces the expression of CYP2E1 (Czigle & Tóth, 2011, 2016; Williamson, Driver & Baxter, 2013) and CYP2D6 (Czigle & Tóth, 2011, 2016; Williamson, Driver & Baxter, 2009, 2013, 2018). UGT1A9 is inhibited by CBN and CBD, UGT2B7 is activated by CBN but inhibited by CBD (Qian, Gurley & Markowitz, 2019). Carboxylesterase 1 (CES1) is potentially inhibited by CBD and THC (Qian, Gurley & Markowitz, 2019). Pharmacodynamic interactions are related to the mechanism of action of cannabinoids (Table 6).

Table 6. Drug interactions of cannabinoids-containing herbal drugs (Cannabis flos, Cannabis herba, Cannabis resina).

ATC therapeutic subgroup ATC pharmacological/chemical subgroup Drugs Pharmacokinetic basis of interaction Pharmacodynamic basis of interaction Manifestation of interaction
Stomatological preparation, in dentistry (A01) Salicylic acid and derivatives Acetylsalicylic acid CYP1A2
CYP2C9
CYP3A4
analgetic effect Petersen, Bergien & Staerk (2021)
Antithrombotic agents (B01)
Analgetics (N02)
Antihypertensives (C02) Imidazoline receptor agonists Clonidine CYP1A2 Cannabis has β-agonistic effect. adverse reaction (tachycardia)
! exclude marijuana
Cone, Welch & Lange (1988)
Analgesics (N02) Other antimigraine preparations
Ophtalmologicals (S01) Sympathomimetics in glaucoma therapy
Antivirals for systemic use (J05) Protease inhibitors Indinavir
Nelfinavir
CYP3A4
P-gp
plasma level
AUC (10%, and 14%)
Kosel et al. (2002)
Antineoplastic agents (L01) Cytotoxic antibiotics and related substances Bleomycin CYP2B1 Cannabis and Δ9-THC are used as analgesics and antiemetics in oncology. adverse reactions (cephalea, paresis, aphasia, stroke, exitus)
! exclude marijuana
Merkle & Tavernier (2018)
Platinum compounds Cisplatin CYP3A4 Cannabis and Δ9-THC are used as analgesics and antiemetics in oncology. adverse reactions (cephalea, paresis, aphasia, stroke, exitus)
! exclude marijuana
! medicinal Cannabis herbal tea does not affect the level of cytostatics but inhalation (joint smoking) is risky
Marzęda et al. (2022)
Topoisomerase 1 inhibitors Irinotecan CYP3A4 Cannabis and Δ9-THC are used as analgesics and antiemetics in oncology. adverse reactions (cephalea, paresis, aphasia, stroke, exitus)
! exclude marijuana
! medicinal Cannabis herbal tea does not affect the level of cytostatics but inhalation (joint smoking) is risky
Engels et al. (2007)
Immunosuppressants drugs (L04) Calcineurin inhibitors Cyclosporine
Tacrolimus
CYP3A4
P-gp
cyclosporine plasma level (73%–83%)
metabolism
Czigle & Tóth (2011), Leino et al. (2019)
Anti-inflammatory and antirheumatic drugs (M01) Anti-inflammatory and antirheumatic products, non-steroids Celecoxib
Diclofenac
Ibuprofen
Indometacin
Naproxen
Piroxicam
CYP2C9
CYP3A4
Cannabis affects prostaglandins levels. antagonistic effect
NSAIDs effect
Czigle & Tóth (2011), Emiga et al. (2020)
Analgesics (N02) Opioids, natural opium alkaloids Morphine
Codeine
Hydromorphone
Oxymorphone
CYP2D6 Phytocannabinoids are CB1, CB2 receptor agonists. Improvement in analgesic effects (without adverse reactions increase).
! dosage adjustment (reduce the dose of anodyne by 60–100%)
Czigle & Tóth (2011), Fattore et al. (2004)
Opioids, benzomorphan derivatives Methadone CYP3A4
CYP2C19
Phytocannabinoids are CB1, CB2 receptor agonists. Improvement in analgesic effects (without adverse reactions increase).
! dosage adjustment (reduce the dose of anodyne by 60–100%)
Madden, Tanco & Bruera (2020)
Other analgesics and antipyretics, anilides Paracetamol CYP1A2
CYP3A4
CYP2E1
Cannabis affects prostaglandins levels. analgetic effect van Amerongen et al. (2018)
Antiepileptics (N03) Antiepileptics, barbiturates and derivatives Phenobarbital
Pentobarbital
Secobarbital
CYP2C9 Cannabinol is a CB1, CB2 receptor agonist, used as antiepileptic (Dravet-, and Lennox-Gastaut syndrome). metabolism
anticonvulsive effect
Czigle & Tóth (2011), Hollister (1986)
Antiepileptics, hydantoin derivatives Phenytoin CYP2C9
CYP2C19
Cannabinol is a CB1, CB2 receptor agonist, used as antiepileptic (Dravet-, and Lennox-Gastaut syndrome). metabolism
anticonvulsive effect
! exclude marijuana
Jessen (2004)
Psycholeptics (N05) Antipsychotics Chlorpromazine
Clozapine
Lithium
CYP1A2
CYP2D6
Phytocannabinoids are CB1, CB2 receptor agonists. chlorpromazine plasma level
chlorpromazine clearance (tobacco smoking: by 38%, joint smoking: by 50%, smoking both: by 107%)
! exclude marijuana
Babatope et al. (2016), Brunette et al. (2011), Singh et al. (2020)
Anxiolytics, benzodiazepine derivatives Alprazolam
Diazepam
CYP2C19
CYP3A4
Phytocannabinoids are CB1, CB2 receptor agonists. anxiolytic effect Lile, Kelly & Hays (2014)
Hypnotics and sedatives, benzodiazepine derivatives Midazolam CYP2C19
CYP3A4
Phytocannabinoids are CB1, CB2 receptor agonists. hypnotic effect Twardowski, Link & Twardowski (2019)
Psychoanaleptics (N06) Antidepressants, non-selective monoamine reuptake inhibitors Amitriptyline
Nortriptyline
Desipramine
Imipramine
CYP3A4
CYP2C9
CYP2D6
Pgp
Cannabis has β-agonistic effect. additive β-agonistic effect
adverse reactions (tachycardia, delirium)
! exclude marijuana
Vázquez et al. (2020)
Antidepressants, selective serotonin reuptake inhibitors Fluoxetine
Sertraline
CYP2D6
CYP3A4
Phytocannabinoids are CB1, CB2 receptor agonists. synergistic (serotonergic) effect
adverse reactions (serotonin syndrome, hypomanic periode risk)
! exclude marijuana
Vaughn et al. (2021)
Other nervous system drugs (N07) Drugs used in nicotine dependence Nicotine
(transdermally)
CYP2C9 Phytocannabinoids are CB1, CB2 receptor agonists. additive effect
adverse reactions
(tachycardia, vigilantia)
! exclude marijuana
Mohamed et al. (2011), Tucker et al. (2019)
Drugs used in alcohol dependence Disulfiram CYP1A2
CYP3A4
Phytocannabinoids are CB1, CB2 receptor agonists. adverse reactions (hypomanic syndrome)
! exclude marijuana
Lacoursiere & Swatek (1983)
Drugs for obstructive airway diseases (R03) Other systemic drugs for obstructive airway diseases, xanthines Aminophylline
Theophylline
CYP1A2 Cannabinoids have bronchodilatory effects. metabolism
plasma level
! exclude marijuana
Antoniou, Bodkin & Ho (2020), Jusko et al. (1978)
All other therapeutic products (V03) Nerve depressants Ethanol CYP2D6 Phytocannabinoids are CB1, CB2 receptor agonists. additive effect
adverse reaction (delirium)
psychomotoric test results
! exclude marijuana ( fatal accident risk)
Mohamed et al. (2011)

Note:

ATC, Anatomical Therapeutic Chemical Classification System (WHO, 2023); ↑, increase (of); ↓, decrease (of); !, warning; CB1, cannabinoid receptor type 1; CB2, cannabinoid receptor type 2; ∆9-THC, ∆9-tetrahydrocannabinol; P-gp, P-glycoprotein.

Preventing drug interactions/practical recommendations

General:

- Patient compliance is essential (Czigle & Tóth, 2016).

- The medical doctor/pharmacist should be informed about self-medication (Czigle & Tóth, 2016).

- The duration of use of traditional herbal medicinal products (self-medication) should not exceed 3 months. If symptoms persist for more than 1 (or 2–3) weeks during the use of the traditional herbal medicinal product, a qualified physician or a qualified health care practitioner should be consulted (Czigle & Tóth, 2016; European Medicines Agency, 2023).

- For many (traditional) herbal medicinal products, use in children and adolescents has not been established due to the lack of adequate data (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009, 2013, 2018).

- The elderly population is at risk due to reduced liver and kidney functions, on which drug clearance depends (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009, 2013, 2018).

- In the absence of sufficient data, the use of herbal drugs during pregnancy and lactation is not recommended (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009, 2013, 2018).

- Patients need to be monitored: for psychiatric, neurological (e.g., epilepsy), and/or cardiological diseases, for metabolic syndrome and diabetes mellitus (Czigle & Tóth, 2016).

- Patients using some medicines with high protein binding (e.g., warfarin) need to be monitored (Czigle & Tóth, 2016).

- Patients with any drugs that have a narrow therapeutic window or where it is necessary to keep serum levels at or above a suitable level (e.g., digoxin) should be more tightly observed (Czigle & Tóth, 2016).

- Hypersensitivity to the active substance(s) often occurs (Czigle & Tóth, 2016).

- If knowledge is available, the combination of substances that are inducers or inhibitors of cytochrome P450 isoenzymes (Czigle & Tóth, 2016; Zhao et al., 2021) and of the P-gp should be avoided (Czigle & Tóth, 2016).

- Many drugs and herbal medicines affect more than on type of target (receptor, enzyme etc.) (Czigle & Tóth, 2016; Williamson, Driver & Baxter, 2009, 2013, 2018).

- In the case of severe symptoms of interaction, it is usually the herbal medicine therapy that should be discontinued as first (Czigle & Tóth, 2016).

In addition to adhering to the general rules for preventing drug interactions, some more specific practical recommendations are summarized below for the herbal drugs listed in the previous chapters based on their pharmacodynamic properties and known adverse effects (Czigle & Tóth, 2016).

Specific:

Caffeine and herbal drugs containing caffeine

- Drinking tea and/or coffee is not recommended before bedtime, as it can cause sleep disturbances due to the stimulating effect of caffeine (Czigle & Tóth, 2010b).

- Gastric and duodenal ulcers, cardiovascular disorders (e.g., hypertension and arrhythmia) and hyperthyroidism should be considered a contraindication during the use of herbal substances containing caffeine (green/black tea—Camelliae folium (non) fermentatum, coffee—Coffeae semen, guarana—Guaranae semen/Paulliniae semen/Guarana, maté leaf—Mate folium, cola—Colae semen); this applies both to the use of medicines and food/beverages (Czigle & Tóth, 2010b, 2016).

- When taking Mate folium to achieve flushing of the urinary tract, the fluid intake has to be observed (at least 2 L of water should be consumed daily). Conditions in which reduced fluid intake is recommended, for example, obstruction of the urinary tract, represent a contraindication. If complaints or symptoms such as fever, dysuria, spasms or blood in the urine occur during the use of the medicinal product, a qualified physician or qualified health care practitioner should be consulted (European Pharmacopoeia, 2023j).

Ginkgo biloba

- Preparations containing Ginkgo leaf or standardized extracts (Ginkgonis folium, Ginkgonis extractum siccum raffinatum et quantificatum) might increase susceptibility to bleeding; the medicinal product should be discontinued as a precaution at least 3 to 4 days before surgery (Czigle & Tóth, 2016).

- In patients with a pathologically increased bleeding tendency (hemorrhagic diathesis) and concomitant anticoagulant and antiplatelet treatment, the Ginkgo biloba medicinal product should only be used after consultation with a medical doctor (Czigle & Tóth, 2016).

- When patients with epilepsy take Ginkgo preparations (medicines or dietary supplements), an onset of further seizures promoted by the herbal drug cannot be excluded (Czigle & Tóth, 2016).

- Dietary supplements (foods) do not have pharmaceutical quality; they are not suitable for therapy. Herbal medicinal products must maintain quality, efficacy, and safety (Czigle et al., 2018).

Hypericum perforatum

- Intense UV exposure should be avoided in the course of treatment with St. John’s wort—Hyperici herba and its standardized extracts, due to phototoxicity (hypericism) (Czigle & Tóth, 2016).

Valeriana officinalis and Humulus lupulus

- In the course of treatment with valerian root—Valerianae radix and/or hop strobile—Lupuli flos affected patients should not drive or operate machinery, as the herbal drugs and extracts may impair such abilities (Czigle & Tóth, 2016; European Medicines Agency, 2005, 2013, 2015a, 2015c, 2017b).

Cannabis sativa

- In many countries, the use, cultivation, and distribution of marijuana (Cannabis herba) and hashish (Cannabis resina) are restricted and/or regulated by laws on narcotic and psychotropic substances (Czigle & Tóth, 2011, 2016).

- The potential risk of Cannabis-drug interactions is not negligible in clinical practice (Czigle & Tóth, 2011, 2016).

- Healthcare professionals should actively inquire about the use of Cannabis-based drugs and provide warning advice about it (Czigle & Tóth, 2011, 2016).

- Hemp extracts are not recommended for patients under 18 years of age, even in countries where they are marketed as registered medicines (Czigle & Tóth, 2011).

- Latent mental illnesses can manifest through the use of cannabis-based drugs (Czigle & Tóth, 2011, 2016).

- The use during pregnancy and lactation is contraindicated, as cannabinoids have a teratogenic effect (Czigle & Tóth, 2011, 2016).

Conclusions

The possibility of drug interactions between conventional drugs and herbal medicines (or herbal food supplements) is an emerging concern for therapeutic safety, as subsequent side effects and direct toxicities constitute a possible hidden threat to successful clinical therapy. Simultaneous use of herbal products and other synthetic drugs can modify, increase, or decrease the therapeutic effects of a drug; in addition, new side effects can arise. Plausible cases of herb-drug interactions include: herbal medicines or beverages containing caffeine reduce the activity of sedatives and increase the side effects caused by sympathomimetic drugs; the stimulant effect of caffeine can oppose the hypnotic effects of Valeriana officinalis; additive anxiolytic effects are possible when benzodiazepines are combined with Valeriana officinalis or Humulus lupulus; bleeding may occur when anticoagulants/antiplatelet drugs are combined with Ginkgo biloba; serotonin syndrome can threaten patients who combine Hypericum perforatum with serotonin-affecting medications such as serotonin reuptake inhibitors. For medicinal Cannabis, antagonistic effects were observed for combinations with some NSAIDs, as well as a potentiation of the antinociceptive effect of anodynes. Patient compliance is essential. The medical doctor and pharmacist should be informed about self-medication.

List of abbreviations

A1 and A2 receptors

adenosine 1 and 2 receptors

α2-agonistic effect

alpha 2 adrenergic agonist

ABCB1

cassette sub-family B member 1

ADME

absorption, distribution, metabolism, elimination/excretion

AEA

anandamide

2-AG

2-arachidonoylglycerol

ATC system

Anatomical Therapeutic Chemical Classification System

CB1, CB2

cannabinoid receptors

CBD

cannabidiol

CBN

cannabinol

CES1

carboxylesterase 1

Cmax

maximum drug concentration

CNS

central nervous system

CYP1A1, CYP1A2, CYP2C8, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP3A4, CYP3A4/5/7

cytochrome P450 isoenzymes

D3 receptor

dopamine receptor subtype 3

EGb 761

refined and quantified dry Ginkgo leaf extract

ECG

(-)-epicatechin-3-O-gallate

EGCG

(-)-epigallocatechin-3-O-gallate

EMA-HMPC

European Medicines Agency—Committee on Herbal Medicinal Products

EU

European Union

excl.

excluding

GABA

γ-aminobutyric acid

GABAAR

γ-aminobutyric acid receptor subtype A

H

histamine

5-HT

5-hydroxytryptamine (serotonin)

5-HT1A, 5-HT1BD, 5-HT5A

5-hydroxytryptamine (serotonin) receptors 5-HT1A, 5-HT1BD, 5-HT5A subtypes

HIV

human immunodeficiency virus

INR

international normalized ratio

MAO

monoamine oxidase

MAO-A and MAO-B

monoamine oxidase A and B

MDR1

multidrug resistance protein 1

MRP1

multidrug resistance-associated protein 1

mGlu I and II

metabotropic glutamate receptors I and II

MT1 and MT2

melatonin receptors 1 and 2

Na+/K+-ATPase

sodium- and potassium-activated adenosine 5′-triphosphatase

NE

norepinephrine

NSAIDs

non-steroidal anti-inflammatory drugs

OATPs

organic anion-transporting polypeptides

OCTs

organic cation transporters

PAF

platelet-activating factor

PDE1, PDE4, PDE5

phosphodiesterase inhibitor

P-gp

P-glycoprotein

PT

prothrombin time

RCVS

reversible cerebral vasoconstriction syndrome

RYR

ryanodine receptor

Δ8-THC

Δ8-tetrahydrocannabinol

Δ9-THC

Δ9-tetrahydrocannabinol, dronabinol, (-)-trans-THC

TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7

transient receptor potential cation channels

UGT

UDP-glucuronyltransferases

UGT1A9, UGT2B7

UDP-glucuronosyltransferase (UGT) 1A9 and 2B7

UV

ultraviolet

WHO

World Health Organization

increase (of)

decrease (of)

!

warning

Funding Statement

This open-access review article was supported by the Erasmus+ Programme of the European Union, Key Action 2: Strategic Partnerships, Project No. 2020-1-CZ01-KA203-078218 (the Open Access Educational Materials on Naturally Occurring Molecules). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Contributor Information

Szilvia Czigle, Email: szilvia.czigle@uniba.sk.

Jaroslav Tóth, Email: Jaroslav.Toth@uniba.sk.

Additional Information and Declarations

Competing Interests

The authors declare that they have no competing interests.

Author Contributions

Szilvia Czigle conceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Milan Nagy performed the experiments, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Přemysl Mladěnka performed the experiments, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Jaroslav Tóth conceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Data Availability

The following information was supplied regarding data availability:

This is a literature review and did not utilize raw data.

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