herb drug interactions a literature review

Herb-drug interactions: A literature review

• Children's Medical Center Research Institute At Ut Southwestern

Research output : Contribution to journal › Review article › peer-review

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations. Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients. Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine). In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

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• Pharmacology (medical)

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• 10.2165/00003495-200565090-00005

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• Herb-Drug Interactions Medicine & Life Sciences 100%
• Warfarin Medicine & Life Sciences 58%
• Kava Medicine & Life Sciences 53%
• Hypericum Medicine & Life Sciences 47%
• Garlic Medicine & Life Sciences 43%
• Panax Medicine & Life Sciences 41%
• Milk Thistle Medicine & Life Sciences 34%
• Scutellaria baicalensis Medicine & Life Sciences 32%

T1 - Herb-drug interactions

T2 - A literature review

AU - Hu, Zeping

AU - Yang, Xiaoxia

AU - Ho, Paul Chi Lui

AU - Sui, Yung Chan

AU - Heng, Paul Wan Sia

AU - Chan, Eli

AU - Duan, Wei

AU - Hwee, Ling Koh

AU - Zhou, Shufeng

N2 - Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations. Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients. Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine). In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

AB - Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations. Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients. Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine). In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

UR - http://www.scopus.com/inward/record.url?scp=22844441147&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=22844441147&partnerID=8YFLogxK

U2 - 10.2165/00003495-200565090-00005

DO - 10.2165/00003495-200565090-00005

M3 - Review article

C2 - 15916450

AN - SCOPUS:22844441147

SN - 0012-6667

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Herb-Drug Interactions

A Literature Review

• Review Article
• Published: 17 September 2012
• Volume 65 , pages 1239–1282, ( 2005 )

Cite this article

• Zeping Hu 1 ,
• Xiaoxia Yang 1 ,
• Paul Chi Lui Ho 1 ,
• Sui Yung Chan 1 ,
• Paul Wan Sia Heng 1 ,
• Eli Chan 1 ,
• Wei Duan 2 ,
• Hwee Ling Koh 1 &
• Shufeng Zhou 1  

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Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.

Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.

Piper methysticum (kava) increased the ‘off’ periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black ( Piper nigrum Linn ) and long ( P. longum Linn ) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John’s wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).

In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

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Zeping Hu, Xiaoxia Yang, Paul Chi Lui Ho, Sui Yung Chan, Paul Wan Sia Heng, Eli Chan, Hwee Ling Koh &  Shufeng Zhou

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Hu, Z., Yang, X., Ho, P.C.L. et al. Herb-Drug Interactions. Drugs 65 , 1239–1282 (2005). https://doi.org/10.2165/00003495-200565090-00005

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Cardiovascular effects of herbal products and their interaction with antihypertensive drugs—comprehensive review.

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Nyulas, K.-I.; Simon-Szabó, Z.; Pál, S.; Fodor, M.-A.; Dénes, L.; Cseh, M.J.; Barabás-Hajdu, E.; Csipor, B.; Szakács, J.; Preg, Z.; et al. Cardiovascular Effects of Herbal Products and Their Interaction with Antihypertensive Drugs—Comprehensive Review. Int. J. Mol. Sci. 2024 , 25 , 6388. https://doi.org/10.3390/ijms25126388

Nyulas K-I, Simon-Szabó Z, Pál S, Fodor M-A, Dénes L, Cseh MJ, Barabás-Hajdu E, Csipor B, Szakács J, Preg Z, et al. Cardiovascular Effects of Herbal Products and Their Interaction with Antihypertensive Drugs—Comprehensive Review. International Journal of Molecular Sciences . 2024; 25(12):6388. https://doi.org/10.3390/ijms25126388

Nyulas, Kinga-Ilona, Zsuzsánna Simon-Szabó, Sándor Pál, Márta-Andrea Fodor, Lóránd Dénes, Margit Judit Cseh, Enikő Barabás-Hajdu, Bernadett Csipor, Juliánna Szakács, Zoltán Preg, and et al. 2024. "Cardiovascular Effects of Herbal Products and Their Interaction with Antihypertensive Drugs—Comprehensive Review" International Journal of Molecular Sciences 25, no. 12: 6388. https://doi.org/10.3390/ijms25126388

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Current perspectives in herbal and conventional drug interactions based on clinical manifestations

• Ajaykumar Rikhabchand Surana   ORCID: orcid.org/0000-0002-3855-4602 1 ,
• Shivam Puranmal Agrawal 1 ,
• Manoj Ramesh Kumbhare 1 &
• Snehal Balu Gaikwad 1  

Future Journal of Pharmaceutical Sciences volume  7 , Article number:  103 ( 2021 ) Cite this article

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Herbs are an important source of pharmaceuticals. Herbs are traditionally used by millions of peoples for medicine, food and drink in developed and developing nations considering that they are safe. But, interaction of herbs with other medicines may cause serious adverse effects or reduces their efficacy. The demand for “alternative” medicines has been increased significantly, which include medicine derived from plant or herbal origin. The objective of this review article mainly focuses on drug interactions of commonly used herbs along with possible mechanisms. The method adopted for this review is searching of herb-drug interactions in online database.

Herb-drug interaction leads to pharmacological modification. The drug use along with herbs may show pharmacodynamic and pharmacokinetic interactions. Pharmacokinetic interaction causes alteration in absorption, distribution, metabolism and elimination. Similarly, pharmacodynamic interaction causes additive or synergistic or antagonist effect on the drugs or vice versa. Researchers had demonstrated that herbs show the toxicities and drug interactions like other pharmacologically active compounds. There is lack of knowledge amongst physician, pharmacist and consumers related to pharmacological action and mechanism of herb-drug interaction. This review article focuses on the herb-drug interaction of danshen ( Salvia miltiorrhiza ), Echinacea ( Echinacea purpurea ), garlic ( Allium sativum ), ginkgo ( Ginkgo biloba ), goldenseal ( Hydrastis canadensis ), green tea ( Camellia sinensis ), kava ( Piper methysticum ), liquorice ( Glycyrrhiza glabra ), milk thistle ( Silybum marianum ) and St. John’s wort ( Hypericum perforatum ) along with probable mechanisms and clinical manifestation based on case studies reported in literature.

Herb-drug interactions may lead to serious side effects. Physician, pharmacist and patients must be more cautious while prescribing and or consuming these herbs.

Interaction is referred to as when the effect of one drug is changed due to the presence of another compound (food, herbal or drug) [ 1 ]. The demand for “alternative” medicines has been raised significantly, which include medicine derived from plant, animal and mineral source, i.e. herbal origin [ 2 ]. Herbal medications comprise of many phytochemicals, thus, may increase the chances of herb-drug interactions (HDIs) [ 3 ]. The global dietary supplement market size in 2019 was expected to reach about USD 123.28 billion. The same was projected to increase at a CAGR of 8.2% during the span of 2020–2027 [ 4 ]. Fifty-two million Americans (40% adults) accounted for use of complementary and alternative medicines reported in the survey of Centers for Disease Control and Prevention USA [ 5 ]. A 2011 survey by the Harvard Opinion Research Program revealed that most Americans regularly consume dietary supplements for boosting the immune system [ 6 ]. Herbals are considered to be the best option as alternative medicine all around the world due to less cost, easy availability and less side effects as compared to synthetic medicines. People should be sure of herbal drugs, owing synthetic drug has adverse effects not only in developed nations but also in developing nations. The consumption of herbal products and food supplements is not reported by people to their physicians or pharmacist. Almost all herbal products are easily available (OTC) in the market. The herbs contain various pharmacological properties due to the presence of multiple chemical constituents. Many times, the label of herbal products contain half-truth or misleading information. Given above are the major factors for HDIs, thereby increasing the likelihood of the HDIs not being identified and resolved in time. Furthermore, clinical trials addressing the safety and risk of coadministered drugs with certain herbal products showed that the outcomes are greatly affected by pharmacogenetics and/or individual.

There is lack of information about use of herbals by patients to physician and pharmacist. Many physicians are unaware about of the possible risks of HDIs. There appears to be dearth of knowledge amongst physician, pharmacist and consumers related to pharmacological action and mechanism of HDIs [ 7 ]. As HDIs occur between conventional drugs and herbal products, identification and awareness of exact HDIs become necessary. This review article focuses on the HDIs along with probable mechanisms and clinical manifestation based on case studies reported in the literature.

To collect all cases of HDIs and adverse effects, a selective literature search using publicly available electronic databases (especially the PubMed database, Scopus, and Korean databases) was performed. We used the search items including “Herbal Drug Interactions”, “drug safety pharmacology”, “Danshen Interaction”, “Echinacea Interactions”, “Garlic Interactions”, “ Ginkgo Biloba Interactions”, “Goldenseal Interactions”, “Green Tea Interactions”, “Kava Interactions”, “Liqcorice Interactions”, “Milk Thistle Interactions”, “St. Jhon’s Wort Interactions” alone and combined with the terms “herbal hepatotoxicity”, or “herb induced liver injury”. The search was primarily focused on English-language case reports, case series and clinical reviews, published till Nov. 2020. The literature with language other than English was used by converting them into English.

Mechanism involved in herb-drug interactions

Mechanism of HDIs is often clinically significant since it influences both the time course and methods of circumventing the interaction. Different mechanisms of HDIs were reported. It mainly includes the change in the gastrointestinal functions which leads to overall changes in transportation of the drug in the body. The HDI mechanism is broadly classified into pharmacokinetic and pharmacodynamic interactions.

Pharmacokinetic interactions

Inhibition and induction of transport and efflux proteins.

The absorption, distribution and elimination of drugs is widely affected by the ATP-binding cassette family which are required for drug transportation.

P-Glycoprotein (P-gp)

The absorption, distribution and elimination/reabsorption of many clinically important therapeutic substances are regulated by P-gp family proteins. Direct interaction with binding sites on the P-gp molecule takes place through competitive or non-competitive inhibition or induction of the efflux of drugs, due to modulation of P-gp by herbal constituents. The pharmacokinetic interaction based on P-gp occurs mainly by depletion of energy required for driving the translocation of P-gp-bound drug substrate, which takes place due to inhibition of ATP binding, hydrolysis or coupling of ATP-hydrolysed molecules by the phytochemicals present in herbs [ 8 ].

Multidrug resistance-associated protein-2 (MRP2)

MRP2 family is ATP-dependent, which is responsible for the transport of hydrophobic anionic conjugates and extrudes hydrophobic neutral molecules. MRP2 from liver cells exports bulky hydrophilic compounds like glutathione, glucuronide, sulfate conjugates, camptothecin and paracetamol into the bile [ 9 ].

Alteration of gastrointestinal functions

Alteration of absorption of concomitantly administered medicines along with herbal medicines takes place through several mechanisms: alteration in gastric pH, formation of insoluble complexes due to complexation and chelation, alteration in gastrointestinal motility and alteration in gastrointestinal transit time [ 10 ].

Herb-drug interactions at metabolism level

The enzymes responsible for the metabolism of synthetic drugs or their transporters are either inhibited or induced by herbal products, which cause HDIs. The enzyme degrades, deactivates or conjugates to drugs before excretion. The inhibition or induction of this enzyme by herbs causes HDIs.

I.Enzyme inhibition

The half-lives of drugs can be prolonged by inhibition of drug-metabolizing enzymes. Due to increase in half-lives of drug, plasma concentration of drug may hike unexpectedly after more doses which results into prolonged action or toxicity. Efficacy of drug may be lowered by inhibiting drug transporters, which decreases absorption of therapeutic agents. Inhibition can be of two types, viz. reversible inhibition and irreversible inhibition. The systemic exposure of the victim drug due to a decrease in metabolic clearance and/or increase in bioavailability is manifested by reversible inhibition. Competitive inhibition occurs when herb binds to the active sites of the enzyme and prevents the binding of synthetic drug and enzyme [ 8 , 11 ]. Irreversible inhibition or quasi-irreversible inhibition is characterised by time-dependent inhibition or mechanism-based inhibition. Irreversible noncovalent binding of an herb to the enzyme takes place in irreversible inhibition. Unlike reversible inhibition, the interaction can continue after removal of the perpetrator since recovery of enzyme activity depends on de novo protein synthesis [ 12 ].

II.Enzyme induction

Due to enzyme induction, plasma concentration of drug reaches subtherapeutic levels. Toxicity may be due to enhanced blood levels caused by induction of drug transporter. The enzyme induction by herbs may result in a reduction of serum drug concentrations. If metabolite is active, it may result in toxicity [ 13 ].

Metabolism occurs in two phases. Phase I reactions involve conversion to a newly formed derivative or cleavage of original drug via oxidation, reduction and hydrolysis reactions. In phase I, P450 enzymes and their subfamilies CYP1A, CYP1B, CYP2C, CYP2D, CYP2E and CYP3A play an important role. These enzymes naturally are present in the liver endoplasmic reticulum and also in the intestine [ 14 ]. Phase II reactions involve conjugation with an endogenous substance like glucuronic acid and sulfate. UDP-glucuronosyltransferase and sulfotransferase enzymes catalyse phase II conjugation reaction. Donation of a cofactor through a reaction which is catalysed by transferase causes conjugation of a substrate with a nucleophilic group (amino, hydroxyl, thiol, etc.) [ 15 ].

Alteration in renal elimination

Herbal products interact with renal functioning, leading to alteration in elimination of drug via inhibition of tubular secretion, tubular reabsorption or interference with glomerular filtration [ 16 ]. Certain herbal diuretics increase the glomerular filtration rate, and few act as direct tubular irritants [ 17 ].

Pharmacodynamic interactions

Pharmacodynamic interactions are either additive (or synergetic) or antagonistic. Additive or synergistic interaction potentiates the action of synthetic drug. Antagonistic interaction reduces the efficacy of synthetic drugs [ 18 ].

Herbal-drug interactions

The herbs which were frequently used by physicians and also as home remedies for various ailments in alternative system of medicines are selected for this review.

Danshen ( Salvia miltiorrhiza )

Danshen is used as an antibacterial, antioxidative, antineoplastic, anticoagulation and anti-inflammatory. Danshen contains diterpenoids (tanshinones and royleanones) and phenolic acids including danshensu, caffeic acid, protocatechuic aldehyde, protocatechuic acid, salvianolic acid A−E, lithospermic acid and rosmarinic acid. Danshen also contains essential oils, triterpenoids, flavone, amino acids, metallic elements and many others [ 19 ].

Danshen shows haemostasis effects like platelet aggregation inhibition, interference with the extrinsic blood coagulation, antithrombin III-like activity and promotion of fibrinolytic activity. Danshen has reported to increase area under the plasma drug concentration-time curve (AUC), elimination half-lives (t 1/2 ) and maximum plasma concentrations (C max ) and decrease total body clearance (CL) and apparent volume of distribution (V d ) of R- and S- isoform of warfarin in rats. In humans, there was increase in international normalized ratio (INR) after taking danshen and warfarin together [ 20 ]. Case report reported interaction between warfarin and danshen, leading to increase in INR, which potentiated anticoagulant effect of warfarin and increased risk of bleeding [ 21 ]. Another case was reported which lead to abnormalities of clotting in patient having rheumatic heart disease, caused by danshen and warfarin concomitant use [ 22 ].

A sequential pharmacokinetic interaction study reported induction of CYP3A4 enzyme in the gut by danshen. The confidence intervals of C max , t 1/2 , oral clearance (CL/F) and AUC zero to infinity (AUC ∞ ) of midazolam before and after oral administration of danshen tablets were (0.559, 0.849), (0.908, 1.142), (1.086, 1.688) and (0.592, 0.921), respectively, was to be 90%. There was a decline in bioavailability of midazolam due to danshen use [ 23 ].

Echinacea ( Echinacea purpurea )

Echinacea contains alkamides, caffeic acid derivative, cichoric acid, flavonoids and phenolic acids. Echinacea is worldwide used for its immunomodulatory and anti-inflammatory properties. The plant is also reported to show larvicidal activity and antibacterial and antiviral activities, especially against influenza viruses [ 24 ].

In in vivo clinical studies, 12 healthy subjects were dosed 1600 mg/day with E. purpurea extracts (for 8 days) along with caffeine, tolbutamide and midazolam to evaluate CYP1A2, CYP2C9 and CYP3A enzyme activities, respectively. The results obtained showed Echinacea extract inhibited hepatic CYP1A2 and CYP2C9, and induced CYP3A4 enzyme activity, which lead to 27% decrease in caffeine CL/F, 12% decrease in tolbutamide CL/F and 42% increase in the systematic clearance and reduced AUC by 23% of midazolam respectively [ 25 ]. Similarly, another in vivo assessment showed that E. purpurea extract inhibited CYP1A2 and induced CYP3A4 [ 26 ]. Thus, it is recommended not to use drugs that are substrate of CYP1A2, CYP2C9 and CYP3A4 enzyme along with concomitant use of Echinacea extract.

Garlic ( Allium sativum )

Garlic mainly contains organosulfur compounds such as allicin, diallyl disulfide, diallyl trisulfide and S-allyl cysteine. Garlic is used as antihyperlipidemic, antimicrobial, anti-inflammatory, antiprotozoal, anticancer and immunomodulatory activity. Garlic has been reported to show toxicity at higher doses. In contrast, some studies also showed intoxication after consumption of garlic [ 27 ].

The two in vivo pharmacokinetic trials were conducted to study the effect of garlic on the antiviral drug saquinavir. The study found that ingestion of garlic increased expression of duodenal P-gp to 131% in subjects. The average AUC and C max of saquinavir was decreased by garlic up to 51% and 54% respectively, in subjects with concomitant use along with garlic. The AUC values and C max values returned up to 60–70% of their values after the 10-day washout period. Saquinavir is metabolised by the enzyme cytochrome P450 (CYP3A4) and is also a substrate of P-gp. Thus, increased clearance and decreased bioavailability of saquinavir are possible due to induction of P-gp along with concomitant use of garlic [ 28 , 29 ].

Clinical study shows that the intake of S-allyl cysteine (active constituent of garlic) inhibits platelet aggregation [ 30 ]. A human survey found that a significant number of patients who used herbs in conjunction with warfarin had higher INR levels, indicating that this combination had potential or additive effects. Thus, inhibition of platelet aggregation shows an additive anticoagulant effect, which is a possible mechanism for warfarin and garlic interaction, which ultimately increases the anticoagulant effect. Increased anticoagulant may increase the risk of bleeding [ 31 ].

The randomized clinical trial of garlic-chlorzoxazone cocktails was given for 28 days on healthy subjects. The pre-supplementation and post-supplementation effect of garlic on CYP2E1 enzyme was evaluated by measuring 6-hydroxychlorzoxazone/chlorzoxazone serum ratio. A controlled trial showed a decrease in 6-hydroxychlorazoxazone/chlorzoxazone serum ratio by about 22%, which suggests inhibition of CYP2E1 activity by garlic [ 32 ]. Similarly, another study showed a 40% decrease in 6-hydroxychlorzoxazone/chlorzoxazone serum ratio [ 33 ].

A case report showed abnormal INR level in patients using a cocktail of fluindione-garlic. Garlic has been previously reported to inhibit some cytochrome P450 isoforms. Thus, garlic can putatively increase fluindione metabolism, thereby garlic acting as an enzymatic inducer. INR level decreased from 2.4 to 1.8 (post-supplementation of garlic for 12 days), and INR level increased to 2.8 (7 days after stopping garlic). A low INR level reduces the anticoagulant effect, increasing the risk of blood clotting (the cause of stroke). Another mechanism could be inhibition of fluindione binding to plasma proteins, but no such studies have been reported [ 34 ]. It is thus suggested that concomitant use of saquinavir, warfarin, chlorzoxazone and fluindione with garlic should be prevented.

Gingko ( Ginkgo biloba )

Ginkgo biloba leaf contains flavonol glycosides (kaempferol, quercetin, myricetin, apigenin, isorhamnetin, luteolin and tamarixetin) and terpene trilactones (ginkgolide A, B, C, J, K, L, M, P, and Q and bilobalide), proanthocyanidins and organic acids. G. biloba leaf extract is used in the treatment of Alzheimer’s disease, neurodegenerative disease, cerebral insufficiency, neurosensory problems, eye ailments, vascular insufficiencies, age-related memory deficit and oxidative stress. In addition, G. biloba is leaf used as anti-angiogenesis, anti-inflammatory, and anti-asthmatic [ 35 ].

In in vivo clinical trials, 10 healthy volunteers were given G. biloba extract (GBE) to test its effect on CYP2C9 using tolbutamide as a probe. The AUC for tolbutamide after taking GBE was reduced by 16% as compared to AUC before use of garlic along with tolbutamide. Although the interaction is considered minor, caution must be taken during concomitant use [ 36 ].

An open-label study in healthy volunteers showed a decrease in the AUC and C max of midazolam by 34% and 31% respectively when used along with GBE. This research found that GBE induces CYP3A metabolism, which leads to a decrease in midazolam concentrations [ 37 ].

In a comparative clinical study, the C max of nifedipine was nearly doubled in two subjects when GBE was taken at the same time. The probable mechanism of action is inhibition of CYP3A by GBE. Increased nifedipine causes severe and longer-lasting headaches, with dizziness or hot flushes [ 38 ].

The human trial reported significantly reduced C max of omeprazole (from 0.69 ± 0.27 to 0.48 ± 0.27 mg/ml) and omeprazole sulfone (from 0.20 ± 0.07 to 0.13 ± 0.06 mg/ml) and an increase in C max of 5-hydroxyomeprazole (from 0.28 ± 0.14 to 0.45 ± 0.21mg/ml) post-administration of G. biloba with omeprazole. Omeprazole is metabolized to 5-hydroxyomeprazole in the body. Also, after post-administration of G. biloba , renal clearance of 5-hydroxyomeprazole was significantly decreased (from 2.70 ± 1.17 to 1.53 ± 0.79 mL/min/kg). The mechanism for this interaction is increased hydroxylation of omeprazole by induction of CYP2C19 [ 39 ].

A single oral dose of GBE did not show any change in the pharmacokinetics of talinolol in 10 healthy, non-smoking male volunteers. C max of talinolol was raised by 36%, AUC (0–24) by 26% and AUC ∞ by 22% respectively. A study suggests that long-term use of GBE prejudiced talinolol disposition in humans, by affecting the activity of drug transporters like P-gp [ 40 ].

Randomized controlled trials showed elevation in AUC and C max of fexofenadine by 55% and 68% respectively. Probable mechanism for this is inhibition of P-gp-mediated efflux in humans by GBE. The AUC and C max of fexofenadine were expressively increased after coadministration quercetin (constituent of gingko) as compared to that of the placebo treatment.

A case report suggested that fatal cerebral haemorrhage was associated with concomitant use of G. biloba and ibuprofen intake in healthy men. Potential inhibition of platelet-activating factor takes place due to ginkgolide B that is a component of G. biloba . G. biloba has been reported with bleeding complications. The interaction takes place possibly due to the additive effect of GBE on ibuprofen by the inhibition of the TXA2-dependent platelet aggregation [ 41 ].

A case study showed that there was an increase in BP in a man, with coadministration of thiazide diuretics and GBE. The blood pressure increased further for a few weeks. BP returned to normal level when both diuretics and GBE were stopped. Due to the severity of complication of the interaction, the responses were not rechallenged. Diuretics are known to lower the BP, but use of GBE leads to the opposite pharmacodynamic effect (increased blood pressure). The possible mechanism for this interaction could be agonism. There are no clinical trials recorded for increase in blood pressure by GBE, but the combination should be prevented [ 42 ].

In a case study, fatal seizures were reported with anticonvulsant medications like valproic acid. GBE has been reported to induce CYP2C19 enzyme activity. The CYP450 enzyme is reported to metabolise valproate, chiefly by CYP2C9 and CYP2C19. Thus, this coadministration of valproic acid and Ginkgo biloba extract should be prevented [ 43 ].

A case study reported that a man with a persistent and painful erection of the penis that had lasted for 4 h was admitted to a hospital. Metabolism of risperidone by CYP2D6 and CYP3A4 has been recorded in literature. Both the enzymes CYP2D6 and CYP3A4 are inhibited by GBE, which is a mechanism or interaction between risperidone and GBE. Simultaneous use of GBE and risperidone increases the serum concentration of risperidone and increases the hazard of adverse effects, such as priapism [ 44 ].

Negative pharmacokinetic interaction of efavirenz was reported, in a case study (47-year-old HIV infected patient), with terpenoids (component of G. biloba ). The probable mechanism of interaction was either by induction of CYP3A4 and P-gp. Induction of CYP3A4 and P-gp by terpenoids lowers the efavirenz plasma level in patients (from 1.26 to 0.48 mg/l). The lowering of human plasma efavirenz level results in virological failure. So, it is recommended that the combination should be avoided [ 45 ].

Flavonoids are a component of G. biloba bound to benzodiazepine binding site, which possess GABAergic activity. Trazadone is used to treat behavioural disturbances as it possesses hypnotic and sedative activity. The CYP3A4 enzyme is responsible for metabolism of trazodone into active compound 1-(m-chlorophenyl) piperazine (mCPP). Flavonoids increase the activity of CYP3A4 in humans. A case study reported that flavonoids act on benzodiazepine receptors and increase the GABAergic activity by increasing mCPP production (mCPP enhances the release of GABA), which leads to increased GABAergic activity and leads to coma in patients [ 46 ].

Goldenseal ( Hydrastis canadensis )

Goldenseal mainly contains berberine, 3,4-dimethoxy-2-(methoxycarbonyl) benzoic acid, 3,5,30 -trihydroxy-7,40 -dimethoxy-6,8-C-dimethyl-flavone, chilenine, (2R)-5,40 -dihydroxy-6-C-methyl -7-methoxy-flavanone, 5,40 -dihydroxy-6,8-di-C-methyl-7-methoxy-flavanone, noroxyhydrastinine, oxyhydrastinine and 40,50-dimethoxy-4-methyl-30-oxo-(1,2,5,6-tetrahydro-4H-1,3-dioxolo-[40 ,50 :4,5] -benzo [1,2-e]-1,2-oxazocin)-2-spiro-10-phtalan [ 47 ]. Goldenseal is reported in folk medicine for the treatment of urinary disorders, gastrointestinal disturbances and skin ailments [ 48 ].

In vivo clinical study was performed for the action of goldenseal on CYP isoform enzyme, which reported inhibition of CYP2D6 and CYP3A4/5 by 40% [ 49 ].

A study on humans was performed to determine CYP2D6 activity using debrisoquine. By evaluating debrisoquine urinary recovery ratios, 50% inhibition of CYP2D6 activity was observed by post-supplementation of goldenseal along with debrisoquine, which lead to a decrease in debrisoquine urinary recovery ratios [ 50 ].

Randomized clinical trials in healthy humans showed that AUC ∞ and C max increased from 107.9 ± 43.3 to 175.3 ± 74.8 ng.h/ml and from 50.6 ± 26.9 to 71.2 ± 50.5 ng/ml respectively for midazolam, with concomitant use of goldenseal. AUC and C max of midazolam were increased by inhibition of CYP3A4/5 [ 51 ].

Berberine is a chemical found in goldenseal extract. A clinical trial was performed on humans to check the effect of berberine on pharmacokinetics of cyclosporin A. The results obtained from this trial showed an increase in AUC of cyclosporin A from 104 to 123 mg/l. This study proves berberine mediated increase in cyclosporin A bioavailability by inhibition of CYP3A4 [ 52 ].

Green tea ( Camellia sinensis )

Green tea mainly contains catechins, polyphenols and epigallocatechin-3-gallate. Green tea possesses antioxidant, antimutagenic, antidiabetic, anti-inflammatory, antibacterial and antiviral properties. Green tea is used for weight loss and preventing ageing and prostate and other cancers [ 53 ].

An in vivo study reported that catechins (present in green tea extract) inhibit folic acid uptake. Catechins are competitive inhibitors of DHFR, which adversely affect folate uptake. DHFR is responsible for folate intestinal absorption. Folate is reduced to tetrahydrofolate and methylated to 5-methyltetrahydrofolate during intestinal absorption of folate before it is absorbed in the blood [ 54 ]. In vivo studies in humans reported reduction in C max and AUC of folic acid by 58.4% and 43.9%, during concomitant use of folic acid and green tea, leading to a decrease in bioavailability of folic acid. The probable mechanism of interaction is inhibition of carrier-mediated absorption of folates [ 55 ].

A clinical trial in humans reported that green tea weakly inhibits CYP450 3A4, which is the main metabolizing enzyme of simvastatin [ 56 ]. A study showed that consumption of green tea with simvastatin leads to increase in C max of simvastatin lactone (metabolite of simvastatin lactone prodrug) from 3.70 to 7.21ng/mL, before and after supplementation of green tea. Similarly, the AUC of simvastatin lactone increased from 6.3 to 12.5 ng.h/mL. The subject improved tolerance to simvastatin after the patient stopped drinking green tea and simvastatin [ 57 ].

Green tea is a source of vitamin K [ 58 ]. Green tea products accentuate the anticoagulant effect of warfarin, leading to bleeding complications. Exogenous intake of vitamin K antagonises the effect of warfarin. A study on humans showed a decrease in INR level from 3.79 to 1.14 (after 1 month) on concomitant consumption of green tea and warfarin. The INR level increased to 2.55 on the discontinuation of green tea [ 59 ].

Kava ( Piper methysticum )

Kava contains kavain, dihydrokavain, methysticin, dihydromethysticin, demethoxyyangonin, and yangonin. Kava has a beneficial effect in euphoria, analgesia, neuroprotection, and anticonvulsant properties. Kava is also used in the treatment of anxiety [ 60 ].

The active components of kava (pyrones) are reported to have neuropharmacologic interactions with the central nervous system receptors. Kava also has weak effects on GABA or benzodiazepine receptors [ 61 ]. A study showed additive pharmacodynamic effects between a-pyrones and other GABA-active sedatives [ 62 ]. A case study showed a lethargic and disoriented state in patients during concomitant use of kava and alprazolam (benzodiazepine) [ 63 ]. Previous studies showed that this interaction is possible due to the additive effect of kava on benzodiazepine receptors, leading to life-threatening conditions.

Kava inhibits CYP2E1, and chlorzoxazone is a CYP2E1 probe. Clinical trials reported that kava showed a significant reduction in 6-hydroxychlorzoxazone/chlorzoxazone serum ratios by 40%. It is, thus, suggested that kava should not be taken simultaneously with chlorzoxazone [ 49 ].

Kava is reported to have dopamine antagonism property. A case report in a 76-year-old Parkinson’s disease patient showed reduced activity of levodopa (a precursor of dopamine). On further investigation, it was reported that the patient simultaneously consumed kava and dopamine, which lead to decrease in dopamine efficacy (decreased dopamine level) due to an antagonising property of kava [ 64 ].

Liquorice ( Glycyrrhiza glabra )

Biologically active compounds present in liquorice are glycosides (glycyrrhizic acid), flavonoids (chalcones, liquiritin, isoliquiritin, liquiritin apioside and isoprenoid-substituted flavonoids), chromenes (coumarins and dihydrostilbenes) and saponins (triterpenoid saponins). Liquorice is reported for wide-ranging biological activities like antiviral, antimicrobial, antioxidant, antiallergic, hepatoprotective, neuroprotective, anti-inflammatory and dermatological activities [ 65 ].

Glycyrrhizin is a potent inducer of the CYP3A4-metabolizing enzyme. CYP3A4 catalyses sulfoxidation of omeprazole. A study reported that glycyrrhizin induces CYP3A4-catalysed sulfoxidation of omeprazole leading to a decrease in C max of omeprazole, during simultaneous use of liquorice and omeprazole [ 66 ].

Glycyrrhizin induces CYP3A4 enzyme (which catalyses midazolam 11-hydroxylation), leading to a reduction in plasma concentrations of midazolam. This inhibition was confirmed by an in vivo study, where mRNA expression of CYP3A4 and other CYP450 family members in mice was decreased significantly by liquorice. Human study confirmed an interaction between midazolam and liquorice [ 67 ].

Milk thistle ( Silybum marianum )

Silybin A and B, isosilybin A and B, silychristin A, silyhermin, neosilyhermine A, neosilyhermine B, mariamides A and B, quercetin, morin, chlorogenic acid and caffeic acid are some of the major chemical constituents present in milk thistle. Milk thistle is widely used in jaundice and calculi of the liver and gallbladder and is useful in controlling haemorrhages [ 68 ].

Metronidazole is a substrate of CYP3A4-metabolizing enzyme. A clinical trial on 12 human subjects confirmed increased CL of metronidazole (by 29.51%) with concomitant use of milk thistle. It also decreased t½, C max and AUC, as a cause of induction of both intestinal P-gp and CYP3A4 [ 69 ].

Milk thistle decreased the AUC of E-3174 (active metabolite of losartan) and increased the AUC of losartan, reported in a clinical trial on 12 healthy men. The study reported that the decrease in losartan AUC is dependent on inhibition of CYP2C9 [ 70 ].

Talinolol C max increased potentially from 172.68 ± 61.53 to 219.20 ± 52.77 ng/ml (after 14 days) after simultaneous administration of milk thistle as compared to placebo treatment, in human studies. AUC of talinolol increased by 36.2%, and oral clearance of talinolol decreased by 23.1% during milk thistle-talinolol coadministration, by inhibition of P-gp [ 71 ].

St. John’s wort ( Hypericum perforatum )

The major active constituents present in St. John’s wort are hyperforin and hypericin (pseudohypericin, isohypericin, protohypericin, protopseudohypericin, Cyclopseudohypericin) and also flavonoids (kaempferol, quercetin, luteolin, biapigenin), tannins and volatile oils. St. John’s wort is used as an antidepressant, antiviral and antibacterial. It also shows sedative and astringent properties. It is used traditionally for the treatment of excitability, neuralgia, sciatica, fibrositis, anxiety, menopausal neurosis and depression and as a nerve tonic and topical application for wound treatment [ 72 ].

The study confirmed that long-term use of SJW may cause reduced clinical effectiveness of CPY3A4 substrate drugs by CPY3A4 induction, which may lead to an increase in dosage of the drug [ 73 ]. The study showed direct induction of intestinal P-gp/MDR1 by SJW in humans [ 74 ].

CYP2C19 carries out demethylation of amitriptyline to nortriptyline, at low amitriptyline concentration. When the concentration of amitriptyline is higher, the CYP3A4 enzyme carries out its demethylation [ 75 , 76 ]. P-gp is a drug transporter which is responsible for efflux of amitriptyline from gut epithelial cells to the gut lumen, which causes co-regulation of systemic availability. Increase activity of P-gp causes reduced systemic availability [ 77 ]. A clinical trial showed that concomitant use of amitriptyline and SJW extract LI160 decreases the AUC of amitriptyline (by 22%) and nortriptyline (by 41%), which is a metabolite of amitriptyline in humans. The pharmacokinetics of St. John’s wort is affected by induction of CYP3A4 and/or induction of P-gp [ 78 ].

Atorvastatin is a substrate of CYP3A4 and P-gp; thus, its use with SJW should be prevented. In a human trial, concomitant treatment with a SJW product reduced the efficacy and effect of atorvastatin, resulting in an increase in LDL cholesterol levels of 0.32 mmol/l, or about 30% of the expected treatment. The possible mechanism of action is increased in CYP3A4 and P-gp activity [ 79 ].

Cyclosporine is widely used to prevent rejection of organs after organ transplantation. Various case reports have reported of serious organ rejection after transplantation due to simultaneous use of cyclosporine with SJW [ 80 , 81 , 82 , 83 ]. The efficacy of cyclosporine is decreased, which causes rejection of organs [ 73 , 74 ]. Thus, serious and potentially fatal interactions between cyclosporine and SJW are likely to occur via induction of CYP3A4 and/or P-gp by St. John’s wort.

MDR1/P-gp mediates the intestinal absorption and distribution and renal excretion of digoxin. SJW is reported to induce P-gp drug transporter. Clinical trials showed that concomitant use of SJW and digoxin lead to an increase in efflux function of P-gp into the intestinal lumen, which lead to a decrease of digoxin AUC by 25% [ 84 , 85 ].

A case report on four patients showed a median decrease of 47% of the original methadone concentration, during concomitant use of methadone and SJW [ 86 ].

A study on humans showed a two-fold increase in CL of alprazolam after administration of alprazolam with SJW for 14 days. The increase in CL of alprazolam was observed due to CYP3A4 enzyme induction. The increased CL leads to a decrease in alprazolam blood concentration [ 73 ].

Imatinib is predominantly metabolized by cytochrome CYP3A4. Concomitant use of SJW and imatinib lead to increased imatinib CL by 43% (12.5 to 17.9 l/h), imatinib AUC was decreased by 30% (from 34.5 to 24.2 mg. h/ml) and C max was also significantly decreased [ 87 , 88 ].

HIV-1 protease inhibitors are substrates of the CYP3A4 enzyme. A clinical trial was performed to evaluate the effect of SJW on plasma concentrations of the HIV-1 protease inhibitor (indinavir), which was found to decrease plasma levels of indinavir in 8 volunteers by an average of 57% [ 89 ].

A trial performed in 5 cancer patients showed decreased plasma levels of SN-38 (active metabolite of irinotecan) by 42% on post-supplementation of SJW and irinotecan as compared to the placebo treatment [ 90 ].

NNRTI and nevirapine are substrates of multidrug transporter P-gp and are extensively metabolized via the cytochrome CYP3A4 enzyme system. A human study showed a decrease in blood concentration of nevirapine by increasing its oral clearance by 35%, due to induction of CYP3A4 enzyme [ 91 ].

In a human subject, it was found that SJW significantly induced the activity of CYP2E1 (approximately 140%) on comparing pre-supplementation and post-supplementation ratios. The two clinical trials found that SJW extract lead to increase in the hydroxychlorzoxazone/chlorzoxazone serum ratios. This increase in ratio is due to induction of CYP2E1 enzyme [ 32 , 33 ].

Serotonin reuptake in the central nervous system is inhibited by bupropion [ 92 ]. Serotonin reuptake is weakly inhibited by SJW. Various reports of SJW interacting with SSRIs have been reported, leading to various side effects, including serotonin syndrome. The side effect is due to an additive effect of two similarly acting drugs [ 93 ]. Dystonia is a syndrome which causes sustained muscle contractions, producing twisting and repetitive movements and postures. Dystonia syndrome is a very well-recognised side-effect of many medicines (antipsychotics and serotonin reuptake inhibitor drugs) affecting dopamine concentrations. A 58-year-old female reported prolonged orofacial dystonia. On evaluation, it was found that the woman was consuming bupropion and St. John’s wort together. Both bupropion and St. John’s wort are reported to inhibit the reuptake of dopamine, potentially resulting in additive effects on dopaminergic transmission and hence causing dopaminergic side effects such as dystonia [ 94 ].

Buspirone is a partial agonist at 5-HT1A receptors. St. John’s wort is testified to be a non-selective 5-HT reuptake inhibitor, which upregulated the postsynaptic 5-HT1A and 5-HT2A receptors. A case study reported that the concomitant administration of buspirone and St. John’s wort medications leads to overstimulation of the 5-HT1A receptors, therefore leading to the development of serotonin syndrome and hypomanic episode [ 95 ].

A systematic representation of herb-drug interactions of herbs with possible mechanism, outcome and level of HDIs is given in Table 1 .

Herb-drug interactions may lead to serious side effects. The reviewed studies clearly indicate that herbal medicines can interact with allopathic or modern medicines and show unwanted effects. Most of the interaction may have negligible clinical significance, but some may lead to life-threatening effect on public health. Our review suggests to physician, pharmacist and common people to avoid such combination in practice. Patients should be aware of the herb-drug interactions for their safety. In this review, we have discussed in details herb-drug interaction of most commonly used herbs in a regular practice by physicians all over the world. It is, therefore, important that health care professionals should take into account of herb-drug interactions when prescribing drugs to patients.

Availability of data and materials

Not applicable

Abbreviations

5-hydroxy tryptamine

Adenosine triphosphate

Area under plasma drug concentration-time curve

AUC zero to infinity

Compound annual growth rate

Oral clearance

Body clearance

Maximum plasma concentrations

Cytochrome-P

Dihydrofolate reductase

Gamma-aminobutyric acid

G. biloba extract

• Herb-drug interactions

International normalized ratio

1-(m-chlorophenyl) piperazine

Multidrug resistance

Multidrug resistance-associated protein-2

Non-nucleoside reverse transcriptase inhibitors

Over the counter

P-Glycoprotein

St. John’s wort

Elimination half-lives

Thromboxane A2

Uridine diphosphate

United States dollar

Apparent volume of distribution

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Authors are also thankful to the Principal, S.M.B.T. College of Pharmacy, Dhamangaon, India, for providing necessary facilities.

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Surana, A.R., Agrawal, S.P., Kumbhare, M.R. et al. Current perspectives in herbal and conventional drug interactions based on clinical manifestations. Futur J Pharm Sci 7 , 103 (2021). https://doi.org/10.1186/s43094-021-00256-w

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Herb-Drug Interactions: A Literature Review

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Neuroleptic malignant syndrome and serotonin syndrome: a comparative bibliometric analysis

• Waleed M. Sweileh 1  

Orphanet Journal of Rare Diseases volume  19 , Article number:  221 ( 2024 ) Cite this article

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This study aimed to analyze and map scientific literature on Neuroleptic Malignant Syndrome (NMS) and Serotonin Syndrome (SS) from prestigious, internationally indexed journals. The objective was to identify key topics, impactful articles, prominent journals, research output, growth patterns, hotspots, and leading countries in the field, providing valuable insights for scholars, medical students, and international funding agencies.

A systematic search strategy was implemented in the PubMed MeSH database using specific keywords for NMS and SS. The search was conducted in the Scopus database, renowned for its extensive coverage of scholarly publications. Inclusion criteria comprised articles published from 1950 to December 31st, 2022, restricted to journal research and review articles written in English. Data were analyzed using Microsoft Excel for descriptive analysis, and VOSviewer was employed for bibliometric mapping.

The search yielded 1150 articles on NMS and 587 on SS, with the majority being case reports. Growth patterns revealed a surge in NMS research between 1981 and 1991, while SS research increased notably between 1993 and 1997. Active countries and journals differed between NMS and SS, with psychiatry journals predominating for NMS and pharmacology/toxicology journals for SS. Authorship analysis indicated higher multi-authored articles for NMS. Top impactful articles focused on review articles and pathogenic mechanisms. Research hotspots included antipsychotics and catatonia for NMS, while SS highlighted drug interactions and specific medications like linezolid and tramadol.

Conclusions

NMS and SS represent rare but life-threatening conditions, requiring detailed clinical and scientific understanding. Differential diagnosis and management necessitate caution in prescribing medications affecting central serotonin or dopamine systems, with awareness of potential drug interactions. International diagnostic tools and genetic screening tests may aid in safe diagnosis and prevention. Reporting rare cases and utilizing bibliometric analysis enhance knowledge dissemination and research exploration in the field of rare drug-induced medical conditions.

Introduction

Neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) are drug-induced, potentially life-threatening conditions that are infrequently encountered in medical practice, necessitating prompt intervention [ 1 , 2 , 3 , 4 ]. Neuroleptic Malignant Syndrome is characterized by a decrease in dopamine activity in the brain, often associated with the use of dopamine antagonists, primarily neuroleptic or antipsychotic medications [ 5 , 6 ]. While the exact pathophysiology of NMS remains incompletely understood, it is believed to involve dopamine dysregulation in the basal ganglia and hypothalamus. This dysregulation, particularly the blockade of dopamine receptors, especially D2 receptors, leads to a state of dopamine deficiency, manifesting in symptoms such as muscle rigidity, hyperthermia, and autonomic instability. Furthermore, withdrawal from dopamine agonists, such as L-Dopa, can also precipitate NMS in susceptible individuals. Serotonin Syndrome is characterized by an excess of serotonin (5-HT) in the central nervous system, typically stemming from the use of serotonergic medications or substances that elevate serotonin levels [ 7 , 8 ]. These drugs encompass antidepressants, notably selective serotonin reuptake inhibitors (SSRIs), opioids, specific psychedelics, serotonin agonists, and herbal supplements. The pathophysiology of SS revolves around the excessive stimulation of serotonin receptors, particularly the 5-HT2A receptors. This heightened stimulation precipitates a spectrum of symptoms, ranging from agitation, confusion, hyperthermia, muscle rigidity, to autonomic dysfunction. The severity of SS can vary widely, from mild manifestations to life-threatening conditions, contingent upon the extent of serotonin excess and individual susceptibility factors.

Both NMS and SS exhibit shared clinical manifestations, including hyperthermia, hypertension, hypersalivation, diaphoresis, and altered mental status [ 4 ], with instances of coexistence reported in some patients [ 9 ]. However, they diverge in their etiologies and clinical presentations. For instance, individuals with NMS typically display hyporeflexia, normal pupil size, and normal bowel sounds, contrasting with SS patients who often present with hyperreflexia, dilated pupils, and hyperactive bowel activity [ 10 ]. NMS is typified by lead-pipe muscle rigidity, whereas SS manifests with increased muscle tone, particularly in the lower extremities [ 11 , 12 ]. Given these distinctions, treatment strategies for NMS and SS diverge based on their underlying causes [ 2 ]. The mechanisms driving these syndromes differ significantly; while NMS involves diminished dopamine activity in the brain, SS is characterized by elevated serotonin levels [ 13 ]. Dopamine antagonists, such as neuroleptics or antipsychotics, are commonly implicated in NMS [ 14 , 15 , 16 ], although other triggers like withdrawal from dopamine agonists, like L-Dopa, can also induce NMS [ 17 , 18 ]. Conversely, SS can result from various drug classes, including antidepressants, opioids, psychedelics, serotonin agonists, and certain herbs [ 7 , 19 , 20 , 21 , 22 , 23 ]. Consequently, distinct medications are employed for their management; benzodiazepines and serotonin antagonists are standard therapy for SS, whereas dopaminergic agents and dantrolene are preferred for NMS [ 10 ]. While the incidence of NMS remains low, particularly among patients receiving newer generation antipsychotics [ 24 , 25 ], recent studies on SS incidence are lacking. However, a 1999 study reported an incidence of 0.4 cases per 1000 patient-months with nefazodone [ 26 ], while SS incidence reaches 14–16% in cases of selective serotonin reuptake inhibitor (SSRI) overdose [ 27 ].

Research context and objectives

The landscape of psychiatric pharmacotherapy has evolved over time, witnessing a surge in the number of approved drugs and the introduction of novel classes into clinical practice [ 28 , 29 , 30 , 31 ]. This trend is particularly notable in the treatment of depression and schizophrenia, where the absence of universally safe and effective drugs persists [ 32 , 33 , 34 , 35 , 36 ]. Additionally, off-label utilization of antidepressants and antipsychotics has been observed among patients with dementia and other neuro-cognitive disorders [ 37 , 38 , 39 , 40 , 41 ], contributing to an upward trajectory in psychiatric drug consumption [ 42 , 43 ]. The risk of SS is linked to any medication or herb augmenting the central serotonergic pathway, necessitating vigilant monitoring by healthcare professionals due to the potential for adverse effects, whether as a primary mechanism or side effect [ 20 ]. A concerning trend of unsupported polypharmacy in psychiatric medications has also emerged [ 44 ], along with significant prescribing of antidepressants and antipsychotics to dementia patients without documented indications of depression or psychosis [ 45 , 46 ], mirroring similar trends among individuals with intellectual disabilities [ 47 ]. The escalating demand for psychiatric therapy raises apprehensions regarding the likelihood of adverse medication effects [ 48 ], exacerbated by increased prescribing rates, polypharmacy, and off-label usage, which heighten the incidence of drug-induced toxicities, including NMS and SS. Analyzing published literature on drug-induced NMS and SS provides valuable insights into these rare yet severe toxicities, aligning with the pressing global public health burden of depression, schizophrenia, and related conditions, accentuated by the fatal toxicities associated with specific psychiatric medications. This scientific literature on NMS and SS is ripe for analysis and mapping to delineate current research hotspots [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ], addressing the gap in the literature. Accordingly, the present study aims to analyze and map scientific research on NMS and SS published in prestigious, internationally indexed journals. Through this analysis, the study seeks to identify key topics, impactful articles, prominent journals, research output, growth patterns, hotspots, and leading countries in the field, providing valuable insights for scholars, medical students, and international funding agencies to discern research trajectories, bibliographic trends, and knowledge structures pertaining to NMS and SS. Ultimately, this endeavor aims to invigorate scholarly discourse and inform clinical practice in the field.

Database and keywords

In this study, we employed a systematic search strategy to extract relevant scientific literature on NMS and SS from the PubMed MeSH database. Specifically, we utilized the following keywords:

Malignant neuroleptic syndrome: “malignant neuroleptic syndrome”.

Serotonin syndrome: “serotonin syndrome” or “serotonin toxicity”.

To ensure comprehensive coverage, we conducted our search in Scopus, a prestigious scientific database owned by Elsevier, which has previously been utilized for analyzing research in psychiatry [ 56 , 57 ]. Scopus is renowned for its extensive coverage, encompassing a vast array of scholarly publications in the field. Notably, Scopus encompasses over 95% of the content included in other databases such as PubMed and Web of Science, rendering it an ideal platform for our study [ 58 ].

Inclusion and exclusion criteria

We restricted our search to articles published from 1950 to December 31st, 2022, and focused exclusively on journal research and review articles written in English. Excluded from our analysis were editorials, notes, letters, and conference abstracts. Additionally, articles pertaining to non-human subjects were excluded, ensuring the relevance of our findings. We meticulously reviewed the titles and abstracts of over 100 articles to eliminate irrelevant publications, such as those mentioning NMS or SS only marginally, thereby refining the scope of our analysis.

Our search strategy yielded results indicative of its validity, as evidenced by the prominent presence of leading scientists and journals in the fields of psychiatry and pharmacology. This reaffirmed the robustness of our search criteria and the relevance of the retrieved literature to our study objectives.

Data management, analysis, and mapping

The dataset comprising the retrieved articles was subjected to descriptive analysis using Microsoft Excel. Subsequently, we employed VOSviewer, a freely available online tool, for bibliometric mapping purposes [ 59 ]. VOSviewer maps offer researchers a visual tool for exploring bibliometric data, revealing patterns, relationships, and trends within a dataset. Interpretation of these maps involves understanding several key elements. Firstly, node size indicates the prominence or frequency of an item, with larger nodes representing more significant themes or influential publications. Secondly, node color categorizes items into clusters, with similar colors indicating thematic groupings. Thirdly, the thickness of connecting lines between nodes signifies the strength of associations, with thicker lines indicating stronger connections. Lastly, the distance between nodes reflects the similarity or dissimilarity between items, with closer nodes indicating stronger relationships. Overall, VOSviewer maps provide a comprehensive visual overview of bibliometric data, enabling researchers to identify clusters, influential publications, and emerging trends within their field of study by considering the interplay between node size, color, line thickness, and spatial relationships. Within the descriptive analysis, we presented lists of active countries and journals, alongside a linear graph illustrating the growth of publications over time. In the keyword visualization map generated using VOSviewer, node size corresponded to the frequency of occurrence of each keyword, enabling visual identification of prominent themes. Similarly, in the journal visualization map, node size reflected the normalized citation count received by each journal, providing insights into publication impact within the field.

Number of publications

The search strategy yielded a total of 1150 articles on NMS and 587 on SS. Among the articles on NMS, 791 (68.8%) were case reports, while 384 (65.4%) of the articles on SS took the form of case reports.

Growth of publications

The earliest scientific publication on NMS dates back to 1973 [ 60 ], while publications on SS emerged in 1979 [ 61 ]. Research on NMS experienced a notable surge between 1981 and 1991, followed by a fluctuating decline. Conversely, research on SS saw a steep increase between 1993 and 1997, followed by a fluctuating rise. Figure  1 illustrates the growth trends of research on NMS and SS.

Annual growth of publications of NMS (blue line) and SS (green line). The Figure was created by SPSS program

Active countries and journals

Table  1 outlines the top five countries contributing articles on NMS and SS. Japan ranked second in NMS publications but fifth in SS publications. Table  2 presents the top five active journals for both NMS and SS, with NMS publications primarily within psychiatry journals and SS publications within pharmacology/toxicology journals.

Authorship analysis

Articles on NMS involved 3820 authors (mean = 3.1 authors per article), with 89 (7.3%) single-authored and 171 (14.1%) multi-authored articles. Similarly, articles on SS included 2105 authors (mean = 3.0 authors per article), with 102 (16.0%) single-authored and 41 (7.1%) multi-authored articles.

Most impactful articles

The top five impactful articles on NMS comprised mainly review articles and a research article focusing on the pathogenic role of dopamine antagonists [ 62 ]. For SS, the top five impactful articles included review articles and research articles discussing the Hunter diagnostic criteria [ 63 ] and the role of monoamine oxidase inhibitors (MAO-I) and opioid analgesics in serotonin toxicity [ 64 ].

Research hotspots

Research hotspots were identified by mapping author keywords with a minimum occurrence of five times (Figs.  2 and 3 ). Notable hotspots for SS included antidepressants, SSRIs, tramadol, linezolid, cyproheptadine, and drug interactions. For NMS, hotspots included antipsychotics (various drug names), catatonia, and rhabdomyolysis.

Network visualization map of author keywords with minimum occurrences of five times. Large nodes represent research hotspots on NMS. The term NMS was not shown to make other keywords more visible

Network visualization map of author keywords with minimum occurrences of five times. Large nodes represent research hotspots on SS. The term SS was not shown to make other keywords more visible

Journal citation analysis

The top 15 active journals in publishing articles on NMS and SS were mapped (Figs.  4 and 5 ). Notably, articles on NMS published in the American Journal of Psychiatry and the Journal of Clinical Psychiatry received the highest number of citations per article. Similarly, articles on SS published in Clinical Toxicology and the Annals of Pharmacotherapy garnered the most citations per article.

Network visualization map of the top 15 journals in the field of NMS. Large node sized indicates higher normalized citation count

Network visualization map of the top 15 journals in the field of SS. Large node sized indicates higher normalized citation count

Geographic mapping

The geographic distribution of research publications on NMS and SS was illustrated on a worldwide map (Fig.  6 ), with the majority of contributions originating from the US. Several countries in specific regions showed minimal to no research output on either NMS or SS.

Worldwide distribution of research publications on NMS and SS. Figure was created by Microsoft Excel

Molecular genetics

The retrieved literature on NMS has 20 articles that discussed the potential link between NMS and certain genetics. Ten articles discussed the potential linkage between Cytochrome 2D6 and potential risk for NMS [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Five articles discussed the potential linkage between dopamine receptor 2 gene polymorphism and NMS [ 75 , 76 , 77 , 78 , 79 ]. Four articles discussed the linkage between ryanodine receptor gene mutations and susceptibility to NMS [ 80 , 81 , 82 , 83 ]. No association was found between NMS and serotonin receptor gene variation [ 84 ]. The literature on SS has few articles that discussed the genetic predisposition of patients to SS such as the 5-HT receptor gene or the CYP 2D6 gene polymorphism [ 85 , 86 ].

Drug interactions

Serious drug-drug interactions leading to NMS were mentioned in a limited number of articles and involved the administration of two dopamine antagonists [ 87 ] or two atypical antipsychotic drugs [ 88 ]. However, there were many articles discussing potential SS caused by drug-drug interactions, which included SSRI–methylene blue [ 89 ], SSRI–metoclopramide [ 89 ], sertraline–phenelzine [ 90 ], anti-depressants–opioids [ 91 ], citalopram-fentanyl [ 92 ], a combination of two anti-depressants [ 93 ], SSRI-linezolid [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ], sertraline–phenelzine [ 90 ], citalopram-buspirone [ 103 ], venlafaxine-tranylcypromine [ 104 ], and many others [ 92 , 105 , 106 , 107 , 108 , 109 ].

Non-psychiatric causative agents

The retrieved literature on SS, showed that several drugs and drug classes not related to antidepressants can induce SS. Examples of such drugs included Linezolid, CNS stimulants (amphetamine), hallucinogens (LSD), opioids (fentanyl), ondansetron, sumatriptan, and certain herbs (St. John’s wort), metoclopramide, ritonavir, and others [ 5 , 20 , 110 , 111 ]. The retrieved literature on NMS showed that drug-induced NMS is limited to antipsychotics and withdrawal of dopamine agonists [ 112 , 113 , 114 ].

Diagnostic criteria

For NMS, there were 30 articles that discussed issues related to diagnosis. In 2011, an international panel tried to develop NMS diagnostic criteria [ 115 , 116 ]. The neutrophil-lymphocyte ratio was suggested by certain researchers as a diagnostic test for NMS [ 117 , 118 ]. The differential diagnosis for NMS compared to SS and catatonia was also published [ 13 , 118 , 119 ]. For SS, there were 17 articles that discussed issues related to diagnosis of SS. The Hunter diagnostic criteria was one of these articles [ 63 ]. Other articles discussed controversies and the importance of differential diagnosis in SS [ 120 ].

The current study analyzed and compared the scientific literature on two rare drug-induced conditions with certain overlapping clinical features. Both syndromes are mainly caused by medications used in psychiatry, such as those for schizophrenia and depression. The name “NMS” implies that the syndrome is correlated with the use of neuroleptic medications, while the name “SS” implies that it is correlated with any medication or herb that raises serotonin centrally.

The analysis showed that the volume of research publications on NMS was larger and started earlier than research publications on SS. The NMS is associated with the use of dopamine antagonists (neuroleptics). The history of using old-generation antipsychotics for the treatment of schizophrenia dates back to the 1950s [ 121 , 122 , 123 , 124 , 125 ]. On the other hand, the introduction of the SSRI drug class, the main causative agent of SS, dates back to the late 1980s [ 126 ]. The difference in the history of introduction into clinical practice explains the differences between SS and NMS in growth patterns. The difference in the volume of literature between the two syndromes could be due to diagnostic uncertainty [ 127 ] for NMS versus SS, the seriousness of medical complications, or debate regarding whether an atypical antipsychotic drug class causes NMS in a similar way to conventional antipsychotics [ 13 , 30 , 128 , 129 , 130 ]. The current study showed that the number of research publications on NMS started to decline after 1991 but the number of publications on SS started to increase after 1997. The introduction of atypical antipsychotics with lesser dopaminergic side effects than conventional antipsychotics decreased the incidence of NMS and therefore decreased the number of publications with time. On the other hand, the increased number of SS publications after 1997 could be explained by the many reported drug interactions at serotonin level leading to more cases of SS with time.

The current study showed that journals in the field of psychiatry ranked highest in publishing articles on NMS, while those in the field of pharmacology/toxicology ranked highest in publishing articles on SS. The reason for this difference is difficult to explain. However, NMS is primarily limited to schizophrenia patients taking antipsychotic drugs, while SS might occur in normal people taking SSRIs for depression or any other condition. Furthermore, the potentially large numbers of drug- or drug-herb interactions make the SS interesting to pharmacology/toxicology journals [ 22 ]. Actually, SS has been termed “serotonin toxicity” implying relatedness to toxicology [ 131 ].

The findings of the current study regarding active countries were not surprising. The English-speaking countries, the US, the UK, Australia, and Canada showed leading roles in many scientific disciplines and ranked first in several studies that analyzed research activity [ 132 , 133 , 134 , 135 ]. This is due to advancements in technology, medicine, clinical practice, and research funding in high-income countries relative to other countries. However, there are also reasons related to the nature of journals indexed in Scopus. The vast majority of Scopus-indexed journals publish articles in English, and the vast majority of the journals are issued by publishers and institutions based in the US, Europe, or Australia. Therefore, Scopus might be biased toward scholars in English-speaking countries. The finding that research articles on NMS tend to be multi-authored while those on SS are not is not easy to explain. However, it is possible that cases of NMS tend to involve a larger medical team due to the nature of complications that might involve renal and blood complications. Furthermore, the treatment of NMS requires medications and follow-up. All this makes the number of authors in a case study of NMS higher than those involved in SS cases [ 13 , 136 , 137 ].

Of the retrieved articles on SS and NMS, the research article “The hunter serotonin toxicity criteria: Simple and accurate diagnostic decision rules for serotonin toxicity” [ 63 ] received the highest number of citations excluding the review articles. The diagnosis of SS is based on the clinical symptoms and the medical history of the patient. Harvey Sternbach introduced the first diagnostic criteria for SS in 1991 and the Hunter Diagnostic Criteria tool was introduced in 2003 [ 63 , 138 ].

Mapping the retrieved literature on NMS showed that rhabdomyolysis and catatonia constituted distinct research hotspots in addition to those related to antipsychotic medications and schizophrenia. However, mapping the author keywords of SS research publications showed that linezolid, drug interactions, and tramadol constituted research hotspots in addition to antidepressants and SSRIs. Rhabdomyolysis has been reported as a consequence of NMS even among children and adolescents [ 139 , 140 ]. However, reports of rhabdomyolysis among patients taking antipsychotics were published, suggesting that rhabdomyolysis could be a side effect of antipsychotics even in the absence of NMS [ 139 , 140 ]. Catatonia is, as NMS, a consequence of neuroleptic drugs, and there is an overlap in clinical features between the symptoms of catatonia and those of NMS, which makes the distinction between them difficult [ 141 ]. Linezolid is an antibiotic that was originally designed to be used as an anti-depressant by virtue of its MAO enzyme inhibition property [ 142 ]. This explains the many cases of SS induced by drug interactions with Linezolid [ 141 ]. The relatively higher number of research articles on drug/herb interactions leading to SS is attributed to the presence of many and different drug classes that affect and increase serotonergic pathways in the brain [ 90 , 105 , 109 , 143 ]. The scientific controversy about the potential ability of tramadol to cause SS received a high number of citations. Current scientific evidence supports the ability of tramadol to cause SS due to its molecular pharmacological effects on both the opioid and serotonergic systems [ 105 , 107 , 144 , 145 , 146 , 147 ]. Cyproheptadine was also a research hotspot in the field of SS. Cyproheptadine has anti-histaminic, anticholinergic, and anti-serotonergic properties and that is why it has been used to counter the symptoms of SS [ 148 , 149 , 150 ].

The current study showed that SS has a wide range of possible drug/herb interactions due to the many drugs that affect the serotonin system. Of particular interest is the one with opioid analgesics, since they are commonly used in hospital settings. Opioids, including fentanyl and even dextromethorphan in cough syrups, were reported to increase serotonin levels, and therefore caution should be practiced when given to patients with SSRIs in their medical records [ 19 , 22 , 109 , 151 ].

Limitations

Limitations arise in this study from various factors. Firstly, the reliance on the Scopus database for literature retrieval could potentially limit the inclusivity of articles from low- and middle-income countries. Although Scopus offers extensive coverage, the possibility exists that some relevant journals from these regions may not be indexed, thereby leading to a potential underestimation of publications from certain geographic areas. Secondly, despite efforts to employ a comprehensive search strategy, the use of a title-abstract search method might have resulted in the retrieval of some false-positive results. While validation tests were conducted to mitigate this issue, the possibility of false positives cannot be entirely ruled out. Thirdly, the analysis focused solely on articles published in English-language journals, which could introduce a language bias and limit the generalizability of findings. This exclusion of literature published in other languages may have led to the omission of relevant data from non-English sources. Lastly, diagnostic uncertainty poses a challenge in distinguishing between neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) due to overlapping clinical features and the absence of definitive diagnostic tests. Misdiagnosis or underreporting of cases may have occurred, potentially impacting the accuracy of the literature analysis and conclusions drawn from it.

In conclusion, NMS and SS represent rare but potentially life-threatening conditions associated with drug-induced dysregulation of dopamine and serotonin systems, respectively. The study analyzed and compared the scientific literature on these syndromes, revealing distinct growth patterns, research hotspots, and publication trends. The findings underscored the evolving landscape of psychiatric pharmacotherapy and the complexities involved in diagnosing and managing NMS and SS. While NMS research exhibited a longer history and a decline in publications over time, SS research witnessed a notable increase in publications, reflecting advancements in pharmacological understanding and the recognition of SS as a significant clinical entity. Identified research hotspots provided valuable insights into emerging areas of interest, including drug interactions, molecular genetics, and diagnostic criteria. Understanding these trends is essential for informing clinical practice, guiding future research endeavors, and promoting collaboration among scholars and healthcare professionals. Despite the study’s contributions, several limitations warrant consideration, including database restrictions, potential publication bias, and diagnostic uncertainties. Addressing these limitations through expanded literature search strategies, international collaboration, and improved diagnostic tools is crucial for advancing knowledge and enhancing patient care in the field of rare drug-induced syndromes. Moving forward, efforts to develop standardized diagnostic criteria, genetic screening tools, and international reporting mechanisms for NMS and SS are warranted. Additionally, continued bibliometric analysis and mapping of literature on rare medical conditions can facilitate ongoing research and contribute to the dissemination of knowledge across global healthcare communities.

Data availability

All data present in this article can be retrieved from Scopus using keywords listed in the methodology.

Abbreviations

• Neuroleptic malignant syndrome

Serotonin Syndrome/ Serotonin toxicity

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Sweileh, W.M. Neuroleptic malignant syndrome and serotonin syndrome: a comparative bibliometric analysis. Orphanet J Rare Dis 19 , 221 (2024). https://doi.org/10.1186/s13023-024-03227-5

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Dietary supplements can help improve health but can also have risks. Get the facts on supplements and how the FDA regulates them to help keep you safe.

Multivitamins, vitamin D, echinacea, and fish oil are among the many dietary supplements lining store shelves or available online. Perhaps you already take a supplement or are thinking about using one. Dietary supplements can be beneficial to your health, but they can also involve health risks. So, it’s important that you talk with a health care professional to help you decide if a supplement is right for you.

Read on to learn what dietary supplements are (and are not), what role the U.S. Food and Drug Administration has in regulating them, and how to make sure you and your family use supplements safely.

What Are Dietary Supplements?

Dietary supplements are intended to add to or supplement the diet and are different from conventional food. Generally, to the extent a product is intended to treat, diagnose, cure, or prevent diseases, it is a drug, even if it is labeled as a dietary supplement. Supplements are ingested and come in many forms, including tablets, capsules, soft gels, gel caps, powders, bars, gummies, and liquids.

Common supplements include:

• Vitamins (such as multivitamins or individual vitamins like vitamin D and biotin).
• Minerals (such as calcium, magnesium, and iron).
• Botanicals or herbs (such as echinacea and ginger).
• Botanical compounds (such as caffeine and curcumin).
• Amino acids (such as tryptophan and glutamine).
• Live microbials (commonly referred to as “probiotics”).

What Are the Benefits of Dietary Supplements?

Dietary supplements can help you improve or maintain your overall health, and supplements can also help you meet your daily requirements of essential nutrients.

For example, calcium and vitamin D can help build strong bones, and fiber can help to maintain bowel regularity. While the benefits of some supplements are well established, other supplements need more study. Also, keep in mind that supplements should not take the place of the variety of foods that are important for a healthy diet.

What Are the Risks of Dietary Supplements?

Before buying or taking a dietary supplement, talk with a health care professional—such as your doctor, nurse, registered dietician, or pharmacist—about the benefits and risks.

Many supplements contain ingredients that can have strong effects in the body. Additionally, some supplements can interact with medications, interfere with lab tests, or have dangerous effects during surgery. Your health care professional can help you decide what supplement, if any, is right for you.

When taking dietary supplements, be alert to the possibility of a bad reaction or side effect (also known as an adverse event).

Problems can occur especially if you:

• Combine supplements.
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If you experience an adverse event while taking a dietary supplement, immediately stop using the supplement, seek medical care or advice, and report the adverse event to the FDA .

How Are Dietary Supplements Regulated?

The Federal Food, Drug, and Cosmetic Act (FD&C Act) was amended in 1994 by the Dietary Supplement Health and Education Act (often referred to as DSHEA), which defined “dietary supplement” and set out FDA’s authority regarding such products. Under existing law:

• The FDA does NOT have the authority to approve dietary supplements for safety and effectiveness, or to approve their labeling, before the supplements are sold to the public.
• Under the FD&C Act, it is the responsibility of dietary supplement companies to ensure their products meet the safety standards for dietary supplements and are not otherwise in violation of the law.
• Dietary supplement labels are required to have nutrition information in the form of a Supplement Facts label that includes the serving size, the number of servings per container, a listing of all dietary ingredients in the product, and the amount per serving of those ingredients. They also must have a statement on the front of the product identifying it as a “dietary supplement” or similar descriptive term (e.g., “herbal supplement” or “calcium supplement”). 

In general, even if a product is labeled as a dietary supplement, a product intended to treat, prevent, cure, or alleviate the symptoms of a disease is a drug, and subject to all requirements that apply to drugs.

The FDA’s Role and Actions to Help Keep You Safe

Even though the FDA does not approve dietary supplements, there are roles for the agency in regulating them.

• Since companies can often introduce a dietary supplement to the market without notifying the FDA, the agency's role in regulating supplements primarily begins after the product enters the marketplace.
• The FDA periodically inspects dietary supplement manufacturing facilities to verify companies are meeting applicable manufacturing and labeling requirements.
• The FDA also reviews product labels and other labeling information, including websites, to ensure products are appropriately labeled and that they do not include claims that may render the products drugs (e.g., claims to treat, diagnose, cure, or prevent diseases).
• The FDA monitors adverse event reports submitted by dietary supplement companies, health care professionals, and consumers as well as other product complaints for valuable information about the safety of products once they are on the market.
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• Ask the company to voluntarily recall the product.
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Tips to Be a Safe and Informed Consumer

Before taking a dietary supplement, talk with your health care professional. They can help you decide which supplements, if any, are right for you. You can also contact the manufacturer for information about the product.

• Take only as described on the label. Some ingredients and products can be harmful when consumed in high amounts, when taken for a long time, or when used in combination with certain drugs or foods.
• Do not substitute a dietary supplement for a prescription medicine or for the variety of foods important to a healthy diet.
• Do not assume that the term "natural" to describe a product ensures that it is safe.
• Be wary of hype. Sound health advice is generally based upon research over time, not a single study.
• Learn to spot false claims. If something sounds too good to be true, it probably is.

Why Is It Important to Report an Adverse Event?

If you experience adverse event, also known as a side effect or bad reaction, the FDA encourages both you and your health care professional to report the adverse event to the FDA.

You can help the FDA, yourself, and other consumers by reporting an adverse event. A single adverse event report can help us identify a potentially dangerous product and possibly remove it from the market.

For a list of potential serious reactions to watch for, and to learn how to report an adverse event, please see the FDA’s webpage,  How to Report a Problem with Dietary Supplements .

Adverse events can also be reported to the product's manufacturer or distributor through the address or phone number listed on the product's label. Dietary supplement firms are required to report serious adverse events they receive about their dietary supplements to FDA within 15 days.

For a general, nonserious complaint or concern about dietary supplements, contact your local FDA Consumer Complaint Coordinator .

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• Information for Consumers on Using Dietary Supplements , FDA
• Dietary Supplement Fact Sheets , National Institutes of Health

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What is a drug interaction.

• A drug interaction is a reaction between two (or more) drugs or between a drug and a food, beverage, or supplement. Taking a drug while having certain medical conditions can also cause a drug interaction. For example, taking a nasal decongestant if you have high blood pressure may cause an unwanted reaction.

A drug interaction can affect how a drug works or cause unwanted side effects.

• Treatment with HIV medicines (called antiretroviral therapy or ART ) helps people with HIV live longer, healthier lives and reduces the risk of HIV transmission . But drug interactions can complicate HIV treatment.
• Health care providers carefully consider potential drug interactions before recommending an HIV treatment regimen . Before taking HIV medicines, tell your health care provider about all prescription and nonprescription medicines, vitamins, nutritional supplements, and herbal products you are taking or plan to take.

What is a drug interaction?

Medicines help us feel better and stay healthy. But sometimes drug interactions can cause problems. There are three types of drug interactions:

• Drug-drug interaction : A reaction between two (or more) drugs.
• Drug-food interaction : A reaction between a drug and a food or beverage.
• Drug-condition interaction: A reaction that occurs when taking a drug while having a certain medical condition. For example, taking a nasal decongestant if you have high blood pressure may cause an unwanted reaction.

Do HIV medicines ever cause drug interactions?

Treatment with HIV medicines (called antiretroviral therapy or ART ) helps people with HIV live longer, healthier lives and reduces the risk of HIV transmission . But drug interactions, especially drug-drug interactions, can complicate HIV treatment.

Drug-drug interactions between different HIV medicines and between HIV medicines and other medicines are common. Before recommending an HIV treatment regimen , health care providers carefully consider potential drug-drug interactions between HIV medicines. They also ask about other medicines a person may be taking. For example, some HIV medicines may make hormonal birth control less effective, so women using hormonal contraceptives may need to use an additional or different method of birth control to prevent pregnancy. For more information about using birth control and HIV medicines at the same time, view the HIV and Birth Control infographic from HIVinfo.

Can drug-food interactions and drug-condition interactions affect people taking HIV medicines?

Yes, the use of HIV medicines can lead to both drug-food interactions and drug-condition interactions.

Food can affect the absorption of some HIV medicines and increase or reduce the concentration of the medicine in the blood. Depending on the HIV medicine, the change in concentration may be helpful or harmful. Directions on how to take HIV medicines specify whether to take the medicine with food or on an empty stomach. Some HIV medicines can be taken with or without food, because food does not affect their absorption.

Conditions, such as kidney disease, hepatitis, and pregnancy, can affect how the body processes HIV medicines. The dosing of some HIV medicines may need to be adjusted in people with certain medical conditions.

How can a person avoid drug interactions?

You can take the following steps to avoid drug interactions:

• Tell your health care provider about all prescription and nonprescription medicines you are taking or plan to take. Also tell your health care provider about any vitamins, nutritional supplements, and herbal products you take.
• Tell your health care provider about any other conditions you may have, such as high blood pressure or diabetes.
• What is the medicine used for?
• How should I take the medicine?
• While taking the medicine, should I avoid any other medicines or certain foods or beverages?
• Can I take this medicine safely with the other medicines that I am taking? Are there any possible drug interactions I should know about? What are the signs of those drug interactions?
• In the case of a drug interaction, what should I do?
• Take medicines according to your health care provider's instructions. Always read the information and directions that come with a medicine. Drug labels and package inserts include important information about possible drug interactions.

This fact sheet is based on information from the following sources:

From the Department of Health and Human Services:

• Drug-Drug Interactions
• Considerations for Antiretroviral Use in Special Patient Populations: HIV and the Older Person , Transgender People with HIV , and Women with HIV

From the U.S. Food and Drug Administration:

• Drug Interactions: What You Should Know

From the National Institute on Aging:

• Safe Use of Medicines for Older Adults

Also see the HIV Source collection of HIV links and resources.

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Herb-drug interactions: a mechanistic approach

Affiliation.

• 1 School of Pharmaceutical Sciences, Shoolini University, Solan, India.
• PMID: 32160796
• DOI: 10.1080/01480545.2020.1738454

In India, traditional herbal medicines have been an essential part of therapy for the last centuries. However, a large portion of the general populace is using these therapies in combination with allopathy lacking a proper understanding of possible interactions (synergistic or antagonistic) between the herbal product and the allopathic drug. This is based on the assumption that herbal drugs are relatively safe, i.e. without side effects. We have established a comprehensive understanding of the possible herb-drug interactions and identified interaction patterns between the most common herbs and drugs currently in use in the Indian market. For this purpose, we listed common interactors (herbs and allopathic drugs) using available scientific literature. Drugs were then categorized into therapeutic classes and aligned to produce a recognizable pattern present only if interactions were observed between a drug class and herb in the scientific literature. Interestingly, the top three categories (with highest interactors), antibiotics, oral hypoglycemics, and anticonvulsants, displayed synergistic interactions only. Another major interactor category was CYP450 enzymes, a natural component of our metabolism. Both activation and inhibition of CYP450 enzymes were observed. As many allopathic drugs are known CYP substrates, inhibitors or inducers, ingestion of an interacting herb could result in interaction with the co-administered drug. This information is largely unavailable for the Indian population and should be studied in greater detail to avoid such interactions. Although this information is not absolute, the systematic literature review proves the existence of herb-drug interactions in the literature and studies where no interaction was detected are equally important.

Keywords: CYP450; Herb–drug interaction; Indian traditional medicine; synergism.

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