Dietary Supplements for Weight Loss and Drug Interactions

Ci a ion: Ri as Ga cía, F.; Ga cía Sie a, A.; Val e de-Me ino, M.I.; Za zuelo Rome o, M.J. Die a y Supplemen s o Weigh Loss and D ug In e ac ions. Pha maceu icals 2024,17, 1658. h ps://doi.o g/ 10.3390/ph17121658 Academic Edi o : Elena Y. Eniou ina Recei ed: 12 No embe 2024 Re ised: 2 Decembe 2024 Accep ed: 4 Decembe 2024 Published: 9 Decembe 2024 Copy igh : © 2024 by he au ho s. Licensee MDPI, Basel, Swi ze land. This a icle is an open access a icle dis ibu ed unde he e ms and condi ions o he C ea i e Commons A ibu ion (CC BY) license (h ps:// c ea i ecommons.o g/licenses/by/ 4.0/). Re iew Die a y Supplemen s o Weigh Loss and D ug In e ac ions F ancisco Ri as Ga cía 1 , JoséAn onio Ga cía Sie a 2 , Ma ia-Isabel Val e de-Me ino 3, * and Ma ia Jose Za zuelo Rome o 4 1 Municipal Heal h and Consume Uni , Guadix Ci y Council, 18500 Guadix, Spain; [email p o ec ed] 2Vi cell S.L., Heal h Sciences Technology Pa k, 18016 G anada, Spain; [email p o ec ed] 3Pha maceu ical Ca e Resea ch G oup, Uni e si y o G anada, 18071 G anada, Spain 4Depa men o Pha macy and Pha maceu ical Technology, Facul y o Pha macy, Uni e si y o G anada, 18071 G anada, Spain; mjza zuelo@ug .es *Co espondence: misabel al e [email p o ec ed] Abs ac : Food supplemen s a e used o a a ie y o pu poses, one o which is weigh educ ion. As excess weigh is a long- e m condi ion, some supplemen s a e expec ed o be used o long pe iods o ime. The long- e m use o hese die a y supplemen s makes i highly likely ha hey will be combined wi h medica ions, inc easing he isk o ood supplemen –d ug in e ac ions, which a e no always known o disclosed, and can lead o se ious heal h p oblems, as has been obse ed. This a icle discusses some o he compounds used as ood supplemen s o weigh educ ion (g een ea ex ac , Ga cinia cambogia, chi osan, que ce in and es e a ol) and he in e ac ions hey may cause wi h some d ugs such as: dex ome ho phan, buspi one, diclo enac, i ino ecan, 5- luo ou acil, cy och ome P450 induce s and inhibi o s, s a ins, o lis a , wa a ina, acenocouma ol, luoxe ine, alp oa e, que iapine, ca bamazepine. This in o ma ion is expec ed o be use ul o heal hca e p o essionals o de ec and in e ene on ood supplemen –d ug in e ac ions o ensu e he op imiza ion o he apy and pa ien sa e y. Keywo ds: ood supplemen s; d ug in e ac ions; obesi y 1. In oduc ion Obesi y is de ined as an abno mal o excessi e accumula ion o a in he body ha may be de imen al o heal h, p ima ily due o an ene gy imbalance be ween calo ies consumed and calo ies expended [ 1 ]. The body mass index (BMI) is o en used o as- sess his. Fo example, he Wo ld Heal h O ganiza ion (WHO) de ines o e weigh as a BMI ≥25 kg/m2and obesi y as a BMI ≥30 kg/m2[1]. Being o e weigh o obese is a majo isk ac o o many diseases, including ca dio as- cula disease ( he leading cause o dea h wo ldwide in 2019 [ 2 ], diabe es, musculoskele al diso de s (especially os eoa h i is), and some cance s (such as endome ial, p os a e, kidney, and colo ec al cance s) [1]. O e weigh and obesi y ha e inc eased s eadily in ecen yea s, o he ex en ha by 2035, acco ding o he Wo ld Obesi y A las 2023 epo , he e will be an es ima ed 4005 million people wi h a BMI g ea e han 25 kg/m 2 , ep esen ing 51% o he wo ld’s popula ion, o whom 24% will be obese [ 3 ]. Epidemic p opo ions ha e undoub edly been eached, wi h mo e han 4 million people dying in 2017 as a esul o being o e weigh o obese [ 4 , 5 ]. The size o he die a y supplemen s ma ke is es ima ed a USD 139.38 billion in 2024 and is expec ed o each USD 173.69 billion by 2029, g owing a a CAGR o 4.5% du ing he o ecas pe iod (2024–2029) [3–5]. The desi e o an es he ically pleasing body and inc easing awa eness o he isk o de eloping ch onic degene a i e diseases means ha mo e and mo e people a e y- ing o comba his end [ 6 ]. O e weigh and obesi y a e la gely a oidable. A bal- anced die , limi ing ene gy in ake om a s and suga s, and egula physical ac i i y Pha maceu icals 2024,17, 1658. h ps://doi.o g/10.3390/ph17121658 h ps://www.mdpi.com/jou nal/pha maceu icals Pha maceu icals 2024,17, 1658 2 o 14 a e he mos e ec i e ways o educe he isk o becoming o e weigh o obese [ 1 ]. How- e e , hese me hods do no p oduce immedia e esul s and equi e a s ong commi men om he pa ien [6]. O he app oaches o ea ing obesi y include su ge y, pha macological ea men , o he use o die a y supplemen s [ 7 ]. The la e a e some imes p e e ed by consume s who belie e ha p oduc s o na u al o igin, unlike syn he ic d ugs, will no ha m hei heal h wi h nega i e side e ec s [ 6 ]. Al hough he e icacy o mos die a y supplemen s o weigh con ol is highly con o e sial, wi h con lic ing scien i ic e idence and unclea mechanisms o ac ion, hei use is inc easing s eadily. The quali y o hese p oduc s can some imes be ques ionable. Legisla ion, which is o en lax and a ies om coun y o coun y, and he lack o common de ini ions may mean ha he quali y and composi ion es s o which hese p oduc s mus be subjec ed a e no su icien ly igo ous. Cases ha e been obse ed o i egula i ies in he manu ac u e o p oduc s, inco ec quan i ies o ing edien s con ained o in en ional o unin en ional adul e a ion wi h o he subs ances, known o unknown [7–11]. The ac ha hey a e o e ed as sel -ca e p oduc s, a e easily accessible ( eadily a ailable on he In e ne ) and a e p omo ed as ‘na u al’ emedies c ea es a alse pe - cep ion o ha mlessness among he popula ion; his, oge he wi h he g owing ejec- ion o adi ional medicine and he in ense ad e ising ha accompanies i , means ha sales o ood supplemen s con inue o inc ease. Recen da a show ha he Eu opean ma ke o die a y supplemen s is es ima ed a $14.95 billion and is expec ed o each $33.80 billion by 2027 [12,13]. Al hough he sale o hese p oduc s is no exclusi ely ese ed o pha macies, he pha macy is he place whe e mos ood supplemen s (45% o he o al) and special weigh - loss p oduc s (27%) a e pu chased [ 8 ]. The communi y pha macis is in a p i ileged posi ion o p o ide in o ma ion on he use and indica ions o hese p oduc s, o wa n pa ien s o ad e se e ec s, and o a oid possible in e ac ions wi h he pa ien ’s medica ion. P o iding co ec ad ice o pa ien s abou die a y supplemen s is a eal challenge o ou p o ession, as an inc easing numbe o die a y supplemen s a e being ma ke ed, some imes be o e solid scien i ic e idence o hei e icacy and sa e y is a ailable, and he li e a u e on po en ial d ug in e ac ions is cons an ly being upda ed. [14]. The coexis ence o he wo condi ions, obesi y and die a y supplemen s, oge he wi h he use o medicines o o he heal h p oblems, jus i ies he need o be awa e o he po en ial in e ac ions ha exis be ween die a y supplemen s and medicines and o de ine he ole o he pha macis in o de o a oid, as a as possible, isk si ua ions o he pa ien . In iew o he abo e, he main objec i e o his s udy is o desc ibe he main in e ac ions be ween medicines and die a y supplemen s ma ke ed o weigh loss. 2. Me hodology The wo k in ol ed a sea ch o he Medline, Coch ane Lib a y, and Scopus da abases, s uc u ed in h ee s ages: Fi s —Die a y supplemen s indica ed o weigh loss we e iden i ied, using he ol- lowing MeSH e ms and Boolean ope a o s: ‘Die a y Supplemen s’ AND ‘Weigh Loss’ OR ‘An i-obesi y Agen s’. Second—Speci ic ing edien s and hei mechanisms o an i-obesi y ac ion we e s ud- ied using he ollowing MeSH e ms: ‘Camellia sinensis’; ‘Ca echin’; ‘Ga cinia cambogia’; ‘Que ce in’; ‘Chi osan’; and ‘Res e a ol’. Thi d—Rele an in e ac ions we e examined, including in he sea ch equa ion he Boolean AND ope a o ‘D ug In e ac ions’ (Mesh). The subheadings ‘ad e se e ec ’, ‘pha macokine ics’, and ‘ oxici y’ we e also included when he sea ch allowed i . The inclusion c i e ia, acco ding o which a icles we e selec ed, we e as ollows: (a) a icles accessible in ull ex , w i en in English o Spanish; (b) a icles published wi hin he las i e yea s; (c) a icles e alua ing in e ac ions be ween nu i ional supplemen s Pha maceu icals 2024,17, 1658 3 o 14 o obesi y and d ugs; (d) ull ex access om any da abase used; and (e) e iew a icles, clinical ials and andomized con olled ials Th ee au ho s (J-GS, MI-VM, and F-RG) independen ly iden i ied s udies and pe - o med da a ex ac ion. To ensu e in e - a e ag eemen , we used pe cen age ag eemen , whe eby we added he numbe o imes he wo e iewe s who pe o med he assessmen ag eed on he same ques ion, and hen di ided his sum by he o al numbe o da a i ems conside ed. To ensu e ep oducibili y and minimize bias, disag eemen s we e esol ed by discussion wi h a hi d esea che (M-ZR). The selec ion was made by eading he i le and abs ac o he publica ions, excluding hose ha clea ly did no add ess he opic o his e iew and e aining hose whe e he e was ce ain y o doub . This p ocess included e iewing he i le and abs ac o sc eening, hen eading o he publica ions, and inally eading he ull ex o he selec ed s udies. A e exhaus i e eading o each publica ion in i s en i e y, hose ha de ini ely did no add ess he opic o his e iew we e excluded. Fo da a ex ac ion, a o m was used con aining he a iables o in e es : da abase, jou nal, au ho s, a icle i les, yea s o publica ion, languages, coun ies o o igin o he publica ion, objec i es, me hods, esul s, conclusions, and le el o e idence. Ini ially, acco ding o he de ined selec ion c i e ia, 390 a icles we e ound, which, a e applying he il e o language and age o less han 10 yea s (excep in he case o chi osan, due o he insu icien li e a u e), esul ed in 273 eco ds. O hese, 250 we e disca ded a e eading he i le, abs ac , and/o ull ex , as hey we e no ela ed o he speci ic opic. Finally, 27 a icles we e conside ed ha included in e ac ions o die a y supplemen s wi h medicines, 7 ha desc ibed se e al weigh loss compounds independen ly (‘Die a y supplemen s’ [Mesh] AND ‘An i-Obesi y Agen s’ [Mesh]), 17 ha deal wi h mechanisms o ac ion o speci ic die a y supplemen s, and 14 included in he sec ions o in oduc ion and ole o he pha macis . In o al 65 a icles we e included o he e iew, om which he mos ele an in o ma ion was ex ac ed (Figu e 1). Figu e 1. Flow diag am o a icle selec ion. Pha maceu icals 2024,17, 1658 4 o 14 3. Resul s and Discussion Die a y supplemen s o weigh con ol ac by a ious mechanisms, such as educing appe i e, modula ing ene gy expendi u e and lipid me abolism, o dec easing a and/o ca bohyd a e abso p ion [15]. Mos d ug–d ug in e ac ions occu h ough a pha macokine ic mechanism, i.e., sup- plemen s in e e e wi h he abso p ion, dis ibu ion, me abolism, o exc e ion o d ugs and may al e hei concen a ion in he blood, which may esul in a educ ion o exace ba ion o hei pha macological e ec o an inc eased isk o ad e se e ec s. Fo una ely, mos o hese in e ac ions, i known, a e p edic able and he d ug dose can be adjus ed o he supplemen discon inued i necessa y [16]. Some o he mos commonly used compounds as ing edien s in weigh loss sup- plemen s (g een ea ex ac , Ga cinia cambogia, chi osan, que ce in, and es e a ol) a e discussed below, wi h an eye o hei mechanism o ac ion in obesi y and weigh loss, as well as possible d ug–d ug in e ac ions obse ed in human, animal, and in i o s udies, in o de o pu wha is cu en ly known in o con ex . 3.1. G een Tea Ex ac /Epigalloca echin-3-Galla e (EGCG) (A) E ec on obesi y and weigh loss G een ea is he in usion o he un e men ed (unoxidized) lea es o he Camellia sinensis plan , which has been used o medicinal pu poses h oughou his o y and has been ex ensi ely s udied in ecen decades o i s po en ial heal h bene i s [ 17 ]. The p ope ies o g een ea a e linked o i s composi ion o ca echins, a class o la onoids wi h po en an ioxidan ac i i y, o which epigalloca echin-3-galla e (EGCG) is he mos abundan (50–80% concen a ion) and he mos po en an ioxidan [ 18 ]. Some o ms o g een ea ex ac con ain low concen a ions o ca eine, which is hough o con ibu e o he an i- obesi y e ec by supp essing appe i e and he mogenesis (inc eased ene gy expendi u e o p oduce hea ) [19]. G een ea may help o educe body weigh , bu he he e ogenei y o he s udies con- duc ed (in e ms o du a ion, supplemen dose, sample size, di e en e hnici ies, ca eine consump ion, and pa icipan s’ mic obio a) means ha i s e icacy has no ye been con- i med in a quan i iable way [ 18 , 19 ]. Se e al mechanisms ha e been p oposed o explain his e ec ; EGCG is hough o al e ene gy expendi u e by inhibi ing he enzyme ca echol- O-me hyl ans e ase (COMT), he eby delaying he b eakdown o no epineph ine (and o he ca echolamines), which would esul in con inued s imula ion o ad ene gic ecep o s, leading o inc eased ene gy expendi u e and a oxida ion [ 17 ]. In addi ion, g een ea is able o inhibi o he enzymes in he gas oin es inal ac , such as panc ea ic lipase, amylase, and glucosidase, esul ing in educed abso p ion o a and ca bohyd a es, he eby educing ene gy in ake [15]. G een ea may also a ec he gu mic obio a, which may be a seconda y mechanism o weigh loss h ough inhibi ion o amylase and glucosidase, inc easing he p esence o undiges ed ca bohyd a es in he gas oin es inal ac , which bac e ia use o p oduce sho -chain a y acids capable o ac i a ing AMP-ac i a ed p o ein kinase (AMPK), he eby educing lipogenesis and inducing lipolysis. In addi ion, mos ea polyphenols a e no abso bed in he small in es ine (due o hei low bioa ailabili y) and ac as a subs a e o he gu mic obio a [15,17,19,20]. On he o he hand, g een ea ex ac and i s ca echins ha e been ex ensi ely s udied o pha macokine ic in e ac ions. Clinical s udies ha e shown ha he maximum concen a ion (Cmax) and a ea unde he cu e (AUC)—pa ame e s ha measu e he bioa ailabili y o a d ug o nadolol, a non-speci ic be a-blocke —a e educed by 85% in heal hy olun ee s who we e p e- ea ed wi h g een ea o 14 days be o e ecei ing a dose o he d ug. Nadolol is a s ong subs a e o OATP (o ganic anion anspo ing polypep ide) anspo e s ound in en e ocy es and hepa ocy es, speci ically OATP1A2. This con i ms, wi h e idence in humans, he dec ease in abso p ion e iciency o EGCG a OATPs ha has al eady been demons a ed in i o and in animals [ 18 , 21 ]. Reduced bioa ailabili y is also obse ed Pha maceu icals 2024,17, 1658 5 o 14 wi h a o as a in, a lipid-lowe ing d ug ha is also a subs a e o OATPs [ 22 , 23 ], and wi h lisinop il, an an ihype ensi e d ug whose anspo e is unknown bu which, like nadolol, is e y hyd ophilic. To in es iga e he e ec o ca echin on cy och ome P-450 (CYP) isoenzymes, which a e esponsible o he me abolism o mo e han 80% o p esc ip ion d ugs [ 16 ], a s udy was conduc ed in which pa ien s p e- ea ed o 4 weeks wi h EGCG we e gi en a cock ail o di e en d ugs, each a subs a e o he majo CYP enzymes (ca eine o CYP1A2, dex ome ho phan o CYP2D6, losa an o CYP2C9, and buspi one o CYP3A4). No signi ican changes in enzyme ac i i y we e obse ed. I should be no ed, howe e , ha he e was a one-day delay be ween aking he d ugs and s opping he g een ea ex ac . This delay may ha e esul ed in he clea ance o much o he ca echins [ 18 ]. Ano he s udy, wi h a smalle numbe o subjec s, du a ion, and EGCG concen a ion, concluded ha g een ea ex ac consump ion did no al e he concen a ions o alp azolam and dex ome ho phan, which a e subs a es o he CYP3A4 and CYP2D6 enzymes, espec i ely [18]. Howe e , in i o and oden s udies showed he inhibi ion o a numbe o CYP enzymes in con ac wi h EGCG. The Cmax and AUC o CYP3A subs a es such as dil iazem, e apamil, amoxi en, sim as a in, and nica dipine we e inc eased in oden s. These d ugs a e, in u n, anspo ed by he e lux pump P-glycop o ein (P-gp), which has been shown o be inhibi ed by EGCG in i o ; he e ec may be due o inhibi ion o P-gp a he han CYP3A4. In con as , concen a ions o he CYP1A2 subs a e clozapine we e educed due o induc ion o CYP1A2 by EGCG [18]. Disc epancies be ween in i o and in i o esul s a e no uncommon in d ug–d ug in e ac ion s udies. I has been obse ed ha in i o CYP2C9 is inhibi ed by EGCG using diclo enac as a CYP2C9 subs a e. Howe e , an in i o s udy ound ha he e was no signi ican di e ence in Cmax and AUC when lu as a in (CYP2C9 subs a e) was adminis e ed in combina ion wi h g een ea ex ac compa ed wi h lu as a in alone [ 24 ]. One possible explana ion o hese esul s is he low memb ane pe meabili y o ca echins. Ca echins mus c oss memb anes o inhibi CYPs (cy osolic enzymes), so he concen a ion o ca echins a ound CYP2C9 and o he s a e a single dose o g een ea ex ac may no be su icien o inhibi hem. Fu he s udies a e needed o cla i y whe he highe doses o ca echins may al e he pha macokine ics o CYP subs a es [ 24 ]. On he o he hand, a educ ion in se um ola e was conside ed when 0.4 mg olic acid was adminis e ed wi h g een o black ea (wi h lowe EGCG con en ). The mechanism o in e ac ion is no de ined, bu i is hough ha ea would in e e e wi h ola e abso p ion in he small in es ine [18]. G een ea is used by cance pa ien s unde going chemo he apy. One s udy showed ha he AUC o 5- luo ou acil (5-FU) inc eased by 524% and he Cmax by 151% in he g een ea- ea ed a g oup. So, he au ho s sugges ed ha pa ien s who egula ly consume g een ea du ing 5-FU ea men may be candida es o u he d ug moni o ing [ 25 ]. The co- adminis a ion o EGCG wi h i ino ecan may lead o accumula ion o he ac i e me aboli e, inc easing he isk o ad e se eac ions [18]. 3.2. Malaba Tama ind o Ga cinia cambogia (A) E ec on obesi y and weigh loss Malaba ama ind, be e known by i s scien i ic name Ga cinia cambogia (GC), is an e e g een ee na i e o Sou heas Asia, India, and Cen al A ica [ 26 ]. The ui s o G. cambogia ha e adi ionally been used in cooking and in adi ional medicine o ea condi ions such as cons ipa ion, edema, and i egula mens ua ion [ 15 , 27 ]. La ge amoun s o hyd oxyci ic acid (HCA) a e ex ac ed om he exoca p o ind, which is hough o ha e po en ial an i-obesi y e ec s [15]. Mos GC supplemen s con ain 20–60% HCA [ 26 ], which has been shown o be a compe i i e inhibi o o adenosine iphospha e (ATP)-ci a e lyase, he eby educing he a ailabili y o ATP ace yl-Coenzyme A o he o ma ion o a y acids and choles e ol, a enua ing a accumula ion [ 15 ]. The an i-obesi y e ec s a e also associa ed wi h he s imula ion o hepa ic bglycogenesis, in u n p omo ing ene gy expendi u e [ 28 ] and Pha maceu icals 2024,17, 1658 6 o 14 an inc ease in sa ie y h ough he egula ion o se o onin le els [ 28 , 29 ]. Howe e , hu- man s udies o es i s e icacy in weigh educ ion ha e yielded con lic ing esul s. In 20 human s udies, 12 epo ed signi ican educ ions in body weigh , and he es we e conside ed ine ec i e. I should be men ioned ha he e a e impo an di e ences in he design and me hodology be ween he di e en s udies as well as in he ype and dose o supplemen a ion adminis e ed [ 28 ]. Al hough no ad e se e ec s we e ound in mos o hese s udies, and he ew ha did occu we e mino (bu ning, dia hea, c amps, among o he s), se e al cases p esen ing se ious ad e se e ec s ha e been epo ed a e aking GC (o HCA) supplemen s in 90 subjec s wi hin he dose ange ecommended by he manu ac u e s, mos o hem ela ed o hepa o oxici y (including cases o dea h), and o a lesse ex en cases o oxici y due o se o onin synd ome and psychosis, and cases o habdomyolysis [ 28 , 30 ]. In any case, GC consump ion should be discou aged in cases such as p egnan women and in an s. HCA can a ec he p oduc ion o a y acids and choles e ol, which can a ec he p oduc ion o s e ols and s e oid ho mones. P egnancy is an ex emely sensi i e pe iod o s e oid ho mones, so hese p oduc s a e no ecommended. On he o he hand, pa ien s wi h dep ession o manic episodes who ake GC should be moni o ed, because he clinical mani es a ions o hei pa hology may wo sen [28]. (B) D ug in e ac ion s udies In ela ion o possible pha macokine ic in e ac ions o GC, a s udy was conduc ed o look a he e ec o inhibi ion on he ac i i y o cy och ome P450 enzymes, which showed ha GC ex ac mode a ely inhibi ed CYP2B6 (al hough his was no so much dependen on HCA, bu on o he componen s). I was concluded ha an in e ac ion wi h his enzyme was likely in clinical p ac ice, bu he e a e no in i o s udies o con i m his. In he mean ime, cau ion is ad ised when consuming GC ex ac wi h d ugs ha a e subs a es o he CYP2B6 enzyme (such as bup opion, which was used as a subs a e in he s udy) [27]. Ve y ew s udies ha e been conduc ed on GC o i s componen s, HCA, o d ug– d ug in e ac ions. Howe e , cases ha e been epo ed in which he in ake o his ood supplemen seems o ha e had an in luence on o he d ugs ha pa ien s we e al eady aking. Thus, wi h ega d o hepa o oxici y, one s udy desc ibed he case o a 45-yea -old emale pa ien who had been on mon elukas o 5 yea s and who de eloped li e ailu e a e 7 days o aking 2 ood supplemen s, 1 wi h GC and he o he wi h C. au an ium. The au ho s pos ula ed ha HCA inc eased mon elukas ’s own li e oxici y [30]. Ano he po en ially se ious ad e se e ec associa ed wi h GC use is se o onin syn- d ome and psychosis. HCA has been shown o ac as a selec i e se o onin eup ake inhibi o (SSRI), inc easing se o onin le els and se o onin oxici y [ 28 ]. This is he case o a 35-yea - old woman on s able ea men wi h esci alop am (an SSRI) o one yea , who de eloped emo s, lushing, and diapho esis a e using a GC ex ac (60% HCA) supplemen o weigh loss du ing he las 2–3 mon hs. She was diagnosed wi h se o one gic synd ome and ea men wi h esci alop am was s opped. The pa ien did no men ion he GC in ake o he doc o , so a e 2 weeks wi hou aking any an idep essan , he doc o p esc ibed ano he an idep essan . The pa ien was admi ed o hospi al wi h symp oms o se o onin synd ome, and ea men wi h SSRIs and GC supplemen s was discon inued [26]. Also, due o cases o habdomyolysis [ 30 ], i is no ecommended o ake GC wi h lipid-lowe ing d ugs such as HMG-CoA educ ase inhibi o s (s a ins), as he e may be an inc eased isk o his ad e se e ec [ 31 ]. Gi en ha he e icacy o GC ex ac has no been ully demons a ed and ha he occu ence o se ious ad e se e ec s appea s o be a ibu able o HCA, he isk–bene i balance is no in a o o aking his supplemen . Pha maceu icals 2024,17, 1658 7 o 14 3.3. Chi osan (A) E ec on obesi y and weigh loss Chi osan is a na u al polysaccha ide o β -1,4-linked glucosamine esidues om he deace yla ion o chi in [ 15 ]. I is ound mainly in he exoskele on o c us aceans and insec s. Al hough no ound na u ally in human issues, chi osan is biodeg adable, non- oxic, non- immunogenic and biocompa ible, so i is also used in d essings o educe bleeding [ 19 ]. I is impo an o no e ha , being de i ed om c us aceans, chi osan should be a oided in indi iduals wi h a shell ish alle gy [31]. O al chi osan appea s in many ood supplemen o mula ions o he managemen o obesi y, hype choles e olaemia, and hype ension [ 7 ]. This is because i educes lipid abso p ion in he gu [ 19 ]. This p ocess can be explained by wo possible mechanisms: (a) he posi i e cha ges o chi osan [ 32 ] bind o a y acids and bile acids (bo h nega i ely cha ged) c ea ing a non-diges ible ( he e o e non-abso bable) complex ha is exc e ed in e- ces; and (b) he c ea ion o a ne wo k e ec , by which chi osan could also bind o neu ally cha ged lipids, such as iglyce ides and choles e ol, by hyd ophobic in e ac ions [ 33 ]. In i o s udies ha e also sugges ed ha chi osan can modula e adipokine sec e ion, educing adipogenesis [31]. Se e al me a-analyses ha e a emp ed o es he e icacy o chi osan in weigh loss wi h con lic ing esul s. Ea ly s udies showed signi ican weigh loss, bu mo e ecen s udies do no show he same esul s; when only he highes quali y clinical ials a e analyzed, he a e age amoun o weigh los is only 0.6 kg. Ano he compa a i e s udy be ween chi osan and o lis a (a panc ea ic lipase inhibi o ) concluded ha chi osan did no inhibi he abso p ion o die a y a [7]. (B) D ug in e ac ion s udies Chi osan may sca enge a -soluble subs ances, he eby in e e ing wi h he abso p ion o i amins A, D, E, and K ( a -soluble) [ 31 ], which in combina ion wi h i amin K an ago- nis s such as wa a in and acenocouma ol may inc ease he an icoagulan e ec , he eby inc easing he isk o bleeding. In addi ion, i has been obse ed ha chi osan may in e e e wi h he coagula ion cascade p ocess [20]. I was concluded ha chi osan was able o seques e luoxe ine and i amin B12. Al- hough hey poin ou ha a ecommended doses he in e ac ion is unlikely o be clinically ele an , hey do wa n ha i may be a p oblem when he e is excessi e consump ion o chi osan. This jus i ies he need o u he s udies wi h o he subs ances ha may in e ac wi h chi osan in a simila way [ 31 – 34 ]. No in i o s udies ha e been ound o con i m his in e ac ion. Howe e , wo cases we e epo ed o a p obable in e ac ion be ween chi osan and sodium alp oa e, a commonly used an icon ulsan , p esumably by his o a simila in e ac ion mechanism. Bo h cases [ 35 ] in ol ed young women on s able ea men wi h alp oa e and ee o seizu es who, a e a ew days o aking chi osan as a ood supplemen , expe ienced seizu e symp oms. The plasma concen a ion o alp oa e was unde ec able and he seizu es s opped when he chi osan was emo ed. I is hough ha he nega i e side o he ca boxylic g oup o alp oa e may ha e bound o he posi i e side o chi osan and p e en ed i s abso p ion, esul ing in he d op in blood concen a ion. Al hough chi osan may ha e shown p omising esul s, he eali y is ha s udies o da e ha e no been able o demons a e i s e icacy in he managemen o obesi y, and he ad e se e ec s, howe e ew and howe e mild (bloa ing, cons ipa ion, nausea, e c.), mean ha , o he ime being, chi osan canno be ecommended o weigh educ ion [7,15,31]. 3.4. Que ce in (A) E ec on obesi y and weigh loss Que ce in is one o he mos abundan la onoids in ui s and ege ables and one o he mos widely consumed in he daily die ; i is mainly ound in onions, apples, g apes, and be e ages such as whi e ea [ 36 , 37 ]. Que ce in is hough o ha e an ioxidan , an i-diabe ic, an i-in lamma o y, and an i-obesi y p ope ies [38]. Pha maceu icals 2024,17, 1658 8 o 14 Que ce in is hough o help educe obesi y h ough se e al mechanisms. These e ec s ha e been s udied in cell cul u e and in i o , bu human s udies a e e y limi ed. One o he i s obse a ions in oden s was ha que ce in binds di ec ly o he glucose anspo e GLUT4 (o e exp ession o which is associa ed wi h obesi y), inhibi ing glucose up ake [ 39 ]. Que ce in may also be able o educe obesi y in oden s on a high- a die by modi ying he gu mic obio a; howe e , i appea s ha mos o he an i-obesi y e ec s o que ce in a e due o i s an ioxidan and an i-in lamma o y p ope ies [37–39]. Obesi y is he esul o an imbalance be ween calo ie in ake and lack o ene gy expen- di u e, which leads o a cons an expansion o adipose issue, causing hype ophy and hype plasia, esul ing in inc eased pe meabili y o adipose issue o mac ophages. The lack o oxygen causes mac ophages o become ac i a ed and p oduce p o-in lamma o y cy- okines. Ele a ed le els o hese, including TNF- α , IL-6, and IL-1 β (which ha e been shown o be o e -exp essed in obese people), cause a s a e o ch onic low-in ensi y in lamma ion in obese people. In addi ion, high le els o hese can a ec sys emic insulin sensi i i y and p omo e he de elopmen o cance [38]. Que ce in has been shown in in i o and animal s udies o educe he le els o o e -exp essed p o-in lamma o y molecules in obese people by al e ing he exp ession o hei genes [ 38 , 40 ] h ough he inhibi ion o se e al signaling pa hways [ 38 ]. In addi- ion, que ce in ea men has also been shown o educe he exp ession o pe oxisome p oli e a o -ac i a ed ecep o γ (PPAR γ ), he key egula o o adipocy e di e en ia ion, sugges ing ha que ce in may hus educe adipogenesis [ 41 ]. Se e al s udies in oden s ha e con i med weigh loss wi h que ce in in ea men s las ing a leas wo weeks [ 41 , 42 ], as well as imp o ed adipocy e hype ophy and educed lipid accumula ion [ 38 ]. A he same ime, a educ ion in blood glucose le els has been obse ed wi h sho ea men s, which may imp o e he managemen o diabe es [ 41 ]. This may be due o a educ ion in oxida i e s ess and a enua ion o β -panc ea ic cell damage [ 42 ]. The e a e insu icien hu- man ials o sugges ha que ce in may educe BMI, wais ci cum e ence, and iglyce ide concen a ions in o e weigh and obese people [ 42 ]; howe e , o he ials ha e shown no signi ican di e ences compa ed wi h placebo [39]. (B) D ug in e ac ion s udies Va ious s udies ha e demons a ed a signi ican inhibi ion by que ce in o se e al isoenzymes o cy och ome P-450. An inc ease in Cmax and AUC o chlo zoxazone, a sub- s a e o CYP2E1, was obse ed; his enzyme also ca alyzes he me abolism o e hanol [ 43 ] which could minimize he hepa o oxici y o alcohol. Diclo enac also showed an inc eased plasma concen a ion a e he in ake o que ce in. The enzyme CYP2C9 ca alyzes he ans o ma ion o diclo enac o i s pha macologically mo e ac i e me aboli e, 4 ′ -hyd oxy- diclo enac, whose bioa ailabili y was educed wi h he adminis a ion o que ce in [ 44 ]. The e o e, i is assumed ha he combina ion o que ce in and diclo enac is no ecom- mended o pain ea men [36]. In i o s udies in oden s ha e also obse ed a signi ican inc ease in he concen a ion o wa a in, me abolized by CYP2C9, and que iapine in a s p e ea ed wi h que ce in. The la e sugges s ha he inc eased plasma concen a ion o que iapine may be due, in addi ion o he inhibi ion o CYPs, o he inhibi ion o P-glycop o ein (P-gp), leading o a educ ion in he pe meabili y o he blood–b ain ba ie (BBB), p e en ing que iapine om ac ing in he cen al ne ous sys em and u he inc easing he amoun o d ug in plasma. The au ho s indica e a po en ially ele an in e ac ion [45,46]. In i o s udies ha e shown ha que ce in is a po en inhibi o o CYP1A2 [ 47 ] and CYP3A4, an e ec con i med in oden s [ 48 ]. Fo CYP1A2, he doses o d ugs me abolized by his enzyme (ca eine, mela onin, and clozapine) should be moni o ed [ 49 ]. Que ce in also inc eased in se e al s udies in a s he concen a ion o subs a es o CYP3A4 (doxo u- bicin, alsa an, cyclospo ine, amoxi en, and piogli azone) [50]. In addi ion o i s ole in o e weigh and obesi y, que ce in is widely used in cance pa- ien s. Tuca inib, a y osine kinase inhibi o used in he ea men o HER-2 posi i e cance s, is p ima ily me abolized by CYP2C8; in a s, i has been obse ed ha co-adminis a ion Pha maceu icals 2024,17, 1658 9 o 14 wi h que ce in signi ican ly inc eased i s bioa ailabili y. An in i o s udy conduc ed wi h palbociclib and ibociclib, selec i e inhibi o s o cyclin-dependen kinases 4 and 6 (CDK- 4/6), demons a ed ha in bo h cases, he hal -li e was signi ican ly p olonged, depending on he concen a ion o que ce in. I is no ed ha he pha macokine ic changes obse ed may also occu in humans [ 46 , 51 ]. The e o e, co-adminis a ion o que ce in wi h uca inib, palbociclib, o ibociclib should be a oided o p e en he occu ence o ad e se e ec s. Finally, que ce in has been shown o bind o human se um albumin wi h high a ini y in in i o s udies. Mo eo e , i is capable o displacing molecules al eady bound o albumin. This is he case wi h amlodipine, an an ihype ensi e d ug ha sha es an ac i e binding si e on albumin, al hough wi h less a ini y han que ce in, which displaces i . This causes he ee ac ion o amlodipine ( esponsible o he pha macological e ec ) o inc ease in blood, enhancing i s e ec and po en ially al e ing he pa ien ’s blood p essu e, he eby inc easing he isk o ad e se eac ions [52]. 3.5. Res e a ol (A) E ec on obesi y and weigh loss Res e a ol is a na u al polyphenol, speci ically a s ilbene, p ima ily ound in ed g apes, be ies, and medicinal plan s such as Polygonum cuspida um. Res e a ol was conside ed he sou ce o he “F ench pa adox,” a phenomenon in which he F ench popula- ion, despi e ha ing a die ich in a s, had a lowe p e alence o obesi y and ca dio ascula diseases; his was a ibu ed o ed wine, which has a high con en o his polyphenol [ 53 ]. Res e a ol is c edi ed wi h a se ies o an ioxidan , an i-in lamma o y, ca diop o ec i e, and an i-obesi y p ope ies. In i o and animal s udies ha e ound ha es e a ol imp o es he me abolic syn- d ome p o ile and p e en s weigh gain. Addi ionally, i educes adipogenesis and he iabili y o p e-adipocy es. Howe e , i s e ec in humans appea s o be much mo e mod- e a e; al hough weigh educ ions ha e been obse ed compa ed o con ol g oups, hese a e o en no clinically signi ican [ 15 ]. Res e a ol exe s i s an i-obesi y e ec s h ough a ious mechanisms ha a e no ye ully unde s ood. I should be no ed ha es e a ol is a po en ac i a o o NAD-dependen si uin-1 deace ylase (SIRT-1), an enzyme ha plays a key ole in aging and me abolic s ess p ocesses and is implica ed in glucose ole ance, obesi y de elopmen , and cance . This enzyme ac i a es signaling pa hways esul ing in he inhibi ion o adipogenesis and adipocy e di e en ia ion. Addi ionally, SIRT-1 ac i a es PGC1 α (Pe oxisome p oli e a o -ac i a ed ecep o γ co-ac i a o 1 α ), leading o inc eased mi ochond ial ac i i y, gluconeogenesis, and he inhibi ion o glycolysis in he li e . SIRT-1 le els a e highe in indi iduals subjec ed o calo ie- es ic ed die s and physical exe cise, sugges ing ha es e a ol may mimic simila ac i a ion pa hways o alida ed he apies agains obesi y [ 53 ]. I also p omo es he phospho yla ion o AMPK (which ypically occu s in s a es o ene gy de iciency). Dephos- pho yla ed AMPK is a key signal o he induc ion o adipogenesis, so i s phospho yla ion hinde s his p ocess. In i o, a educ ion in adipogenesis was also obse ed due o lowe exp ession o genes ha a o i , such as PPARγ[54]. Res e a ol also ac s on b own adipose issue (BAT). BAT, which dec eases wi h aging, unc ions o main ain body empe a u e by ans o ming ene gy in o hea ( he mogenesis). The capaci y o BAT o dissipa e ene gy is due o he inc eased numbe o mi ochond ia in b own adipocy es, which con ain high amoun s o uncoupling p o ein 1 (UCP1), exp essed exclusi ely in hem [ 54 ]. Addi ionally, s udies in oden s ha e shown ha es e a ol inc eases UCP1, SIRT-1, and AMPK le els in BAT, he eby inc easing ene gy expendi u e. Fu he mo e, in mice, an induc ion o speci ic BAT genes has been obse ed, sugges ing ha es e a ol could induce he con e sion o whi e adipose issue o b own (“b owning”) [54–56].