Herb-drug Herb-drug interactionsinteractionsCharlotte Gyllenhaal, Ph.D.Charlotte Gyllenhaal, Ph.D.1,31,3

Gail Mahady, Ph.D.Gail Mahady, Ph.D.22

Departments of Medicinal Chemistry and Departments of Medicinal Chemistry and Pharmacognosy,Pharmacognosy,11 Pharmacy Practice Pharmacy Practice22

Block Center for Integrative Cancer TreatmentBlock Center for Integrative Cancer Treatment33

6-1870, gyllenha@uic.edu6-1870, gyllenha@uic.edu

OutlineOutline

► Evidence for herb-drug interactionsEvidence for herb-drug interactions► Pharmacokinetic (PK) versus pharmacodynamic Pharmacokinetic (PK) versus pharmacodynamic

(PD) interactions(PD) interactions► St. John’s wortSt. John’s wort► WarfarinWarfarin► MiscellaneousMiscellaneous► Herb-drug interactions and surgical/dental Herb-drug interactions and surgical/dental

proceduresprocedures► Use of computer databases for clinical Use of computer databases for clinical

questionsquestions

Evidence for herb-drug Evidence for herb-drug interactionsinteractions

► Case reportsCase reports Underreported? 70% “don’t ask-don’t tell”Underreported? 70% “don’t ask-don’t tell”

► Lab studiesLab studies Define mechanismsDefine mechanisms

► Recent interest in CYP450 inductionRecent interest in CYP450 induction► Not necessarily borne out in trials Not necessarily borne out in trials

► Human studiesHuman studies Trials using probe drugsTrials using probe drugs May be too short or expensiveMay be too short or expensive May be done on healthy population (not always)May be done on healthy population (not always) Genetic polymorphismsGenetic polymorphisms Multiple drug/herb users, elderly patientsMultiple drug/herb users, elderly patients

De Smet, Br J Clin Pharm 2006; 63:258-67

Drug Interaction ResolutionDrug Interaction Resolution

►Require dosage adjustmentsRequire dosage adjustments►Temporary or complete elimination of Temporary or complete elimination of

one or the other agent to avoid serious one or the other agent to avoid serious consequencesconsequences

►Close monitoring of the subjectClose monitoring of the subject►Total change of drug therapyTotal change of drug therapy

PK vs PDPK vs PD

► PK: absorption, distribution, metabolism, PK: absorption, distribution, metabolism, eliminationelimination CYP450, PgPCYP450, PgP Absorption from GI tract (laxatives)Absorption from GI tract (laxatives)

► PD: pharmacological functionPD: pharmacological function Anticoagulant drugs plus anticoagulant herbsAnticoagulant drugs plus anticoagulant herbs Sedative herbs plus anesthesiaSedative herbs plus anesthesia

► NegativeNegative MostMost

► Positive or synergisticPositive or synergistic Possible PD or PKPossible PD or PK Decrease side effectsDecrease side effects

Prevalence: unknown but under Prevalence: unknown but under investigationinvestigation

► Canadian seniors with osteoarthritisCanadian seniors with osteoarthritis Survey, n = 191. Average 2.8 prescriptions, 1.9 Survey, n = 191. Average 2.8 prescriptions, 1.9

self-care productsself-care products► Potential interactions detected using standard Potential interactions detected using standard

databasesdatabases 214 instances, 14% possible clinical significance214 instances, 14% possible clinical significance 7 herbs/supplements, associated with 5 clinically 7 herbs/supplements, associated with 5 clinically

insignificant interactionsinsignificant interactions 1 recommendation to stop medications (dilatiazem 1 recommendation to stop medications (dilatiazem

+ atrorvastatin -> statin side effects intensified)+ atrorvastatin -> statin side effects intensified) Clinically significant interactions may be rare – but Clinically significant interactions may be rare – but

thus easier to forget about and harder to monitor!thus easier to forget about and harder to monitor!

Putnam, Can Fam Physician 2006; 52:340-45

St. John’s wort (St. John’s wort (Hypericum Hypericum perforatumperforatum))

► Mild-moderate depression -> long-term Mild-moderate depression -> long-term treatment; multiple clinical trials, fewer AEs treatment; multiple clinical trials, fewer AEs than conventional drugsthan conventional drugs

► Case reports suggesting PK interactions Case reports suggesting PK interactions (most important of SWJ interactions)(most important of SWJ interactions)

► Lab studies indicate PK interactions:Lab studies indicate PK interactions:► CYP450 3A4 mechanism CYP450 3A4 mechanism

► short-term inhibitionshort-term inhibition► Long-term induction; of most importance clinicallyLong-term induction; of most importance clinically► Reduces various drugs to subtherapeutic levelsReduces various drugs to subtherapeutic levels► Hyperforin, an active constituent, is a ligand for the Hyperforin, an active constituent, is a ligand for the

xenobiotic pregnane X receptor -> CYP450 3A4 xenobiotic pregnane X receptor -> CYP450 3A4

St John’s wortSt John’s wort

►Other PK interactionsOther PK interactions►P-glycoprotein (PgP): involved in P-glycoprotein (PgP): involved in

multidrug resistance, acts as a pump multidrug resistance, acts as a pump to remove drugs from cellsto remove drugs from cells SJW induces this orphan nuclear receptorSJW induces this orphan nuclear receptor Also regulates MDR-1 (multidrug Also regulates MDR-1 (multidrug

resistance gene) and other drug resistance gene) and other drug transporterstransporters

Chavez, Life Sci 2006; 78:2146-57

St. John’s wort: PK St. John’s wort: PK interactionsinteractions

► Human trial with irinotecan (cancer)Human trial with irinotecan (cancer) Blood levels of active metabolite were reducedBlood levels of active metabolite were reduced

► Other drugs affectedOther drugs affected Cyclosporin, tacrolimus, indinavir, nevirapine, imatinib, Cyclosporin, tacrolimus, indinavir, nevirapine, imatinib,

alprazolam, midazolam, amitriptyline, digoxin, alprazolam, midazolam, amitriptyline, digoxin, fexofenadine, methadone, omeprazole, theophylline, fexofenadine, methadone, omeprazole, theophylline, verapamil, etoposide. verapamil, etoposide.

Human study with oral contraceptives indicating reduce Human study with oral contraceptives indicating reduce OC exposure and breakthrough bleeding. OC exposure and breakthrough bleeding.

Case of delayed emergence from general anesthesia Case of delayed emergence from general anesthesia observed. observed.

Multiple potential interactions with oncology drugs (but Multiple potential interactions with oncology drugs (but rare use by oncology patients?).rare use by oncology patients?).

► Other CYP450sOther CYP450s May inhibit CYP1A2, does not inhibit CYP2D6May inhibit CYP1A2, does not inhibit CYP2D6

Murphy Contraception 2005; 71:402-8

St. John’s wortSt. John’s wort► PD interactionsPD interactions

With other antidepressantsWith other antidepressants► Serotonin syndromeSerotonin syndrome

SJW has both SSRI and MAO inhibitor activitySJW has both SSRI and MAO inhibitor activity Restlessness, nausea, vomiting, tachycardia, Restlessness, nausea, vomiting, tachycardia,

hallucinations etc.hallucinations etc. Case reports with buspirone, loperamil, Case reports with buspirone, loperamil,

nefazodone, paroxetine, sertraline, venlafaxinenefazodone, paroxetine, sertraline, venlafaxine► Possible adrenergic crisisPossible adrenergic crisis

MAO inhibitor activityMAO inhibitor activity► PhotosensitivityPhotosensitivity

Active constituent hypericin is photosensitizing Active constituent hypericin is photosensitizing but generally not a problem with healthy but generally not a problem with healthy persons. Potential interaction with other persons. Potential interaction with other photosensitizing drugsphotosensitizing drugs

Clinical strategyClinical strategy

►Avoid use with other medications Avoid use with other medications unless checked out in an interaction unless checked out in an interaction database. Will have similar interaction database. Will have similar interaction profile to other CYP450 3A4 inducers.profile to other CYP450 3A4 inducers. Major drug-drug interaction pathwayMajor drug-drug interaction pathway

Warfarin-herb interactionsWarfarin-herb interactions► Numerous drug-drug interactions: macrolides, Numerous drug-drug interactions: macrolides,

NSAIDs, COX2s, SSRIs, omeprazole, 5FU etc NSAIDs, COX2s, SSRIs, omeprazole, 5FU etc (variable quality of evidence).(variable quality of evidence).

► Possible pathways: Vitamin K activity lowers Possible pathways: Vitamin K activity lowers INRINR Foods: leafy greens (healthy diet)Foods: leafy greens (healthy diet) ““Green drinks” – clinical interactions with oncology Green drinks” – clinical interactions with oncology

patients. Case reports with cranberry juice also.patients. Case reports with cranberry juice also. MultivitaminsMultivitamins CoQ10: similar structure to vitamin K, but RCT found CoQ10: similar structure to vitamin K, but RCT found

no effect on INR. Case reports suggest monitoring.no effect on INR. Case reports suggest monitoring.

Rhode, Curr Opin Clin Nutr Metab 2007; 10:1-5Engelsen, Throm Hemost 2002; 87:1075-6

Warfarin-herb interactionsWarfarin-herb interactions

► PK PK decreased absorption from GI tract due to decreased absorption from GI tract due to

mucilage (comfrey, Iceland moss) or laxative mucilage (comfrey, Iceland moss) or laxative herbs (senna, rhubarb etc)herbs (senna, rhubarb etc)

CYP450 2C9 inhibition/induction, which CYP450 2C9 inhibition/induction, which metabolizes the active S-enantiomer of warfarinmetabolizes the active S-enantiomer of warfarin

► PD PD herbs that decrease platelet aggregationherbs that decrease platelet aggregation Decreased thromboxane synthesisDecreased thromboxane synthesis Herbs with coumarin content (though this is a Herbs with coumarin content (though this is a

relatively weak anticoagulant)relatively weak anticoagulant)

Warfarin and Chinese herbsWarfarin and Chinese herbs

► Dan-shen (Dan-shen (Salvia miltiorrhizaSalvia miltiorrhiza) – animal studies, case ) – animal studies, case reportsreports

► Dong quai (Dong quai (Angelica sinensisAngelica sinensis) – animal studies, case ) – animal studies, case reportsreports

► Asian ginseng (Asian ginseng (Panax ginsengPanax ginseng) – ginsenosides may ) – ginsenosides may inhibit platelet aggregation (anticoagulant). 2 case inhibit platelet aggregation (anticoagulant). 2 case reports of lowered or unsteady INR (procoagulant)reports of lowered or unsteady INR (procoagulant) RCT in healthy volunteers showed no effect of Asian RCT in healthy volunteers showed no effect of Asian

ginseng on INR, platelet aggregation. Vitamin K in ginseng on INR, platelet aggregation. Vitamin K in extracts? Monitor closely.extracts? Monitor closely.

► American ginseng (American ginseng (Panax quinquefoliusPanax quinquefolius) – RCT in ) – RCT in healthy volunteers indicated moderately reduced healthy volunteers indicated moderately reduced INR, warfarin levels, AUC. Avoid with warfarin.INR, warfarin levels, AUC. Avoid with warfarin.Chavez, Life Sci 2006; 78:2146-57

Jiang, Br J Clin Pharm 2004; 57:592-9Yuan, Ann Intern Med 2004; 141:23-7

Warfarin and “G” herbsWarfarin and “G” herbs

► Garlic (Garlic (Allium sativumAllium sativum) – 2 case reports. Continuing ) – 2 case reports. Continuing ingestion of high levels of garlic or garlic oil can ingestion of high levels of garlic or garlic oil can decrease platelet aggregationdecrease platelet aggregation

► Ginger (Ginger (Zingiber officinalisZingiber officinalis) – Inconclusive results in ) – Inconclusive results in studies in healthy volunteers but case reports exist. studies in healthy volunteers but case reports exist.

► Ginkgo (Ginkgo (Ginkgo bilobaGinkgo biloba) – Ginkgolide B decreases PAF, ) – Ginkgolide B decreases PAF, extract inhibits thromboxane and prostacyclin in extract inhibits thromboxane and prostacyclin in diabetics. Preliminary human study indicates no effect diabetics. Preliminary human study indicates no effect on INR, but a case report suggests interaction on INR, but a case report suggests interaction

► Green tea (Green tea (Camellia sinensisCamellia sinensis) – Inhibits platelet ) – Inhibits platelet synthesis of thromboxane. Case report of decreased synthesis of thromboxane. Case report of decreased INR in patient drinking 1 gal/day green tea.INR in patient drinking 1 gal/day green tea.

Chavez, Life Sci 2006; 78:2146-57

Warfarin and lipid-based Warfarin and lipid-based agentsagents

► Omega-3 fatty acids (fish oil, algal formulas) Omega-3 fatty acids (fish oil, algal formulas) – case report of increased INR with fish oil in – case report of increased INR with fish oil in a stabilized warfarin patient, 67-y/o female.a stabilized warfarin patient, 67-y/o female. Strong antiinflammatory effects, but did not Strong antiinflammatory effects, but did not

affect INR in an RCT.affect INR in an RCT.

► Saw palmetto – lipid extract. Case report of Saw palmetto – lipid extract. Case report of intraoperative hemorrhage (w/o warfarin) intraoperative hemorrhage (w/o warfarin) and increased INR in 2 warfarin patients.and increased INR in 2 warfarin patients.

Chavez, Life Sci 2006; 78:2146-57

Case ReportCase Report

Female, age 76, hx of hypertension, Female, age 76, hx of hypertension, osteoarthritis, gastropathy due to osteoarthritis, gastropathy due to NSAIDs, atrial fibrillation, stroke: NSAIDs, atrial fibrillation, stroke: presents at ER with hematuria and presents at ER with hematuria and bleeding gums.bleeding gums.

Meds: hydrochlorothiazide, warfarin, Meds: hydrochlorothiazide, warfarin, acetaminophen. No recent illnesses, acetaminophen. No recent illnesses, antibiotics, diet change reported.antibiotics, diet change reported.

CBC normal, previous INR was 2.1 but CBC normal, previous INR was 2.1 but now 7.0now 7.0

Case ReportCase Report

Appropriate INR for stroke patients is 2.0-3.0.Appropriate INR for stroke patients is 2.0-3.0.Elderly are at risk for bleeding d/t lower body Elderly are at risk for bleeding d/t lower body

weight, low vitamin K intake, drug weight, low vitamin K intake, drug interactions.interactions.

Drug interactions include acetaminophen Drug interactions include acetaminophen (not widely recognized): metabolized by (not widely recognized): metabolized by 2C9, as is warfarin.2C9, as is warfarin.

Patient recently increased acetaminophen Patient recently increased acetaminophen intake d/t osteoarthritis flare; cautioned to intake d/t osteoarthritis flare; cautioned to reduce dose, use daily (not intermittently) reduce dose, use daily (not intermittently) and monitor INR more frequently.and monitor INR more frequently.

Case ReportCase Report

INR at a therapeutic level for 6 m.INR at a therapeutic level for 6 m.

Patient then returned with nosebleed Patient then returned with nosebleed and INR of 10.and INR of 10.

Acetaminophen, aspirin, warfarin doses Acetaminophen, aspirin, warfarin doses had remained the same, no illnesses.had remained the same, no illnesses.

Closer questioning revealed use of Closer questioning revealed use of ginger for upset stomach – ginger tea ginger for upset stomach – ginger tea and ginger root.and ginger root.

Case ReportCase Report

Patient advised to stop ginger consumption & Patient advised to stop ginger consumption & monitor INR more frequently; excessive monitor INR more frequently; excessive anticoagulation stopped with iv vitamin K. anticoagulation stopped with iv vitamin K.

Problem: ginger did not cause CYPProblem: ginger did not cause CYP450450 interaction in interaction in pharmacodynamic/pharmacokinetic study pharmacodynamic/pharmacokinetic study and trials in healthy patients indicated only and trials in healthy patients indicated only questionable clinical effect on coagulationquestionable clinical effect on coagulation

Combined effect of ginger anticoagulant effect Combined effect of ginger anticoagulant effect and acetaminophen 2C9 effect? Patient and acetaminophen 2C9 effect? Patient age? age?

Very similar story for chamomile.Very similar story for chamomile.Lesho EP et al. Cleve Clinic J Med 2004; 71:651-655Segal R et al CMAJ 2006; 174:1281-2

Garlic (Garlic (Allium sativumAllium sativum))

►Drug Interactions:Drug Interactions: Alters pharmacokinetic Alters pharmacokinetic

variables of variables of acetaminophenacetaminophen

Decreases blood Decreases blood concentrations of concentrations of warfarinwarfarin

Produces hypoglycemia Produces hypoglycemia when taken with when taken with chlorpropamidechlorpropamide

Izzo AA, Ernst E. Drugs, 2001, 61:2163-2175Izzo AA, Ernst E. Drugs, 2001, 61:2163-2175

Garlic (Garlic (Allium sativumAllium sativum))

► Drug Interactions:Drug Interactions: Saquinavir (Fortovase) study-10 healthy Saquinavir (Fortovase) study-10 healthy

volunteersvolunteers Dose of 1200 mg 3 times daily for 4 daysDose of 1200 mg 3 times daily for 4 days AUC during the 8 hour dosing interval decreased AUC during the 8 hour dosing interval decreased

by 51% by 51% 10 day wash out needed before Cmax, AUC 10 day wash out needed before Cmax, AUC

levels returned to 60-70% of normallevels returned to 60-70% of normal Garlic and Protease Inhibitors Garlic and Protease Inhibitors

Clin Infect DisClin Infect Dis, 2002, 34:234-238., 2002, 34:234-238.

GinkgoGinkgo

Case reports of interactions:Case reports of interactions: Aspirin – hyphemaAspirin – hyphema Acetaminophen - bilateral subdural Acetaminophen - bilateral subdural

hematomas hematomas Warfarin - intracerebral hemorrhageWarfarin - intracerebral hemorrhage Ibuprofen added to ginkgo supplementation Ibuprofen added to ginkgo supplementation

was followed by cerebral hemorrhagewas followed by cerebral hemorrhage Valproate: 2 cases of siezuresValproate: 2 cases of siezures Possible induction of CYP2C19 and CYP450 Possible induction of CYP2C19 and CYP450

3A4, but studies have conflicting results3A4, but studies have conflicting results

Ginkgo and psychotropicsGinkgo and psychotropics

►Antagonist of GABA activity at Antagonist of GABA activity at benzodiazepine receptors. Female benzodiazepine receptors. Female with Alzheimer disease was switched with Alzheimer disease was switched from bromazepam and vitamin E to from bromazepam and vitamin E to trazodone and ginkgo. Lapsed into a trazodone and ginkgo. Lapsed into a coma, but was reversed by giving coma, but was reversed by giving flumazenil.flumazenil.

►Antioxidant effect may result in Antioxidant effect may result in enhanced activity of haloperidol.enhanced activity of haloperidol.

Galluzzi, J Neurol Neurosurg Psych 68:679-80Zhang, J Clin Psychopharm 21:85-88

Kava (Kava (Piper methysticumPiper methysticum))► One case report of coma induced by a One case report of coma induced by a

combination of kava and alprazolam-a combination of kava and alprazolam-a benzodiazepine benzodiazepine

► Extrapyramidal side effects-4 cases of Extrapyramidal side effects-4 cases of dopamine antagonism-oral, lingual and dopamine antagonism-oral, lingual and trunk dyskinesiatrunk dyskinesia

► Do not combine with alcohol, sedatives, Do not combine with alcohol, sedatives, tranquilizers tranquilizers

Licorice (Licorice (Glycyrrhiza Glycyrrhiza glabraglabra))

► Sore throat, Sore throat, dyspepsia, peptic dyspepsia, peptic ulcer diseaseulcer disease

► Triterpene saponins-Triterpene saponins-glycyrrhizinglycyrrhizin

► Prolonged use > Prolonged use > 6weeks of >50 g/day-6weeks of >50 g/day-pseudaldosteronismpseudaldosteronism Potassium depletion, Potassium depletion,

sodium retention, sodium retention, edema, hypertension edema, hypertension and weight gainand weight gain

► Drug InteractionsDrug Interactions Thiazide and loop Thiazide and loop

diuretics, cardiac diuretics, cardiac glycosidesglycosides

AntihypertensivesAntihypertensives Spironolactone or Spironolactone or

amilorideamiloride Only clinically significant Only clinically significant

in cases of excessive in cases of excessive use, however… use, however… commonly licorice candycommonly licorice candy

Possible with multiple Possible with multiple use of herbal formulas use of herbal formulas containing licorice (ie in containing licorice (ie in Chinese formulas)Chinese formulas)

Licorice: positive interactionLicorice: positive interaction

Small trial of women being treated for Small trial of women being treated for polycystic ovary syndrome with polycystic ovary syndrome with spironolactone, which has side effects spironolactone, which has side effects of diuresis, low blood pressure, of diuresis, low blood pressure, volume depletion. 20% of drug-alone, volume depletion. 20% of drug-alone, none of drug + licorice had symptoms, none of drug + licorice had symptoms, also metrorrhagia improved. Also also metrorrhagia improved. Also useful due to estrogenic effect of useful due to estrogenic effect of licorice.licorice.

Armanini Eur J Obst Gynecol Reprod Biol. 2007; 131:61-7

Surgery and Dental Surgery and Dental ProceduresProcedures

Drug interactions and physiological reactions:Drug interactions and physiological reactions:CNS herbs: potential PD interactions with CNS herbs: potential PD interactions with

anesthesia:anesthesia:Valerian, kava, St. John’s wort (PK Valerian, kava, St. John’s wort (PK interaction also), lavender, passionflower, interaction also), lavender, passionflower, lemon balm, ashwaganda, ginseng, ephedra lemon balm, ashwaganda, ginseng, ephedra (now illegal but may be available (now illegal but may be available elsewhere).elsewhere).

Blood sugar – ginseng, bitter melon, Blood sugar – ginseng, bitter melon, chromium, fenugreek, cinnamonchromium, fenugreek, cinnamon

Ang-Lee, JAMA 2001; 286:208-16

Surgery and Dental Surgery and Dental ProceduresProcedures

Anticoagulant herbs: post-op bleedingAnticoagulant herbs: post-op bleeding

Garlic, ginger, ginkgo, ginseng, feverfew.Garlic, ginger, ginkgo, ginseng, feverfew.Angelica, asafoetida, anise, astragalus, arnica, Angelica, asafoetida, anise, astragalus, arnica,

bogbean, bromelain, borage seed, capsicum, bogbean, bromelain, borage seed, capsicum, clove, curcumin, dong quai, fenugreek, fish clove, curcumin, dong quai, fenugreek, fish oil, green tea, horsechestnut, juniper, licorice, oil, green tea, horsechestnut, juniper, licorice, meadowsweet, onion, pau d’arco, parsley, meadowsweet, onion, pau d’arco, parsley, passionflower, quassia, red clover, reishi, passionflower, quassia, red clover, reishi, salvia, turmeric, willow.salvia, turmeric, willow.

Surgery and Dental Surgery and Dental ProceduresProcedures

Stop herb and supplement use 7-14 Stop herb and supplement use 7-14 days prior to surgery.days prior to surgery.

All pre-surgical patients should be All pre-surgical patients should be questioned about herb/supplement questioned about herb/supplement use to determine recent consumption use to determine recent consumption of anticoagulant or drug-interacting of anticoagulant or drug-interacting herbs.herbs.

Clinical copingClinical coping

►Counteract “don’t ask-don’t tell”Counteract “don’t ask-don’t tell” Open and nonjudgmental discussionOpen and nonjudgmental discussion Follow up herb use found in case historiesFollow up herb use found in case histories Explain importance of potential interactionsExplain importance of potential interactions

►Avoid SJW and warfarin interactionsAvoid SJW and warfarin interactions►Patients on complicated medical Patients on complicated medical

regimens should avoid herbs and regimens should avoid herbs and supplements unless carefully supplements unless carefully screened/supervisedscreened/supervised

►Package inserts Package inserts

Checking for herb-drug Checking for herb-drug interactionsinteractions

►Natural Standard (Natural Standard (www.naturalstandard.comwww.naturalstandard.com). ). Subscriptions for PDA/desktop Subscriptions for PDA/desktop available.available. Partial database at MedlinePlus.govPartial database at MedlinePlus.gov

►Natural Medicines Comprehensive Natural Medicines Comprehensive Database (Database (www.naturaldatabase.comwww.naturaldatabase.com). Subscription service.). Subscription service.

Dental procedures: herb side Dental procedures: herb side effectseffects

►Feverfew (Feverfew (Tanacetum partheniumTanacetum parthenium): mouth ): mouth sores and irritation if leaves are chewedsores and irritation if leaves are chewed

►Feverfew, ginkgo: gingival bleeding due to Feverfew, ginkgo: gingival bleeding due to anticoagulant effectanticoagulant effect

►Echinacea (Echinacea (Echinacea purpureaEchinacea purpurea) and kava ) and kava ((Piper methysticumPiper methysticum): tongue numbness): tongue numbness

►St John’s wort: xerostomiaSt John’s wort: xerostomia►Yohimbine (Yohimbine (Pausinystalia yohimbePausinystalia yohimbe): ):

salivationsalivation