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Nutrient- and non-nutrient-based natural health product (NHP) use in adults with mood disorders: prevalence,… Davison, Karen M; Kaplan, Bonnie J Apr 9, 2013

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RESEARCH ARTICLE Open AccessNutrient- and non-nutrient-based natural healthproduct (NHP) use in adults with mood disorders:prevalence, characteristics and potential forexposure to adverse eventsKaren M Davison1,2* and Bonnie J Kaplan1,3AbstractBackground: To address knowledge gaps regarding natural health product (NHP) usage in mental healthpopulations, we examined their use in adults with mood disorders, and explored the potential for adverse events.Methods: Food and NHP intake was obtained from 97 adults with mood disorders. NHP data was used to compareprevalence with population norms (British Columbia Nutrition Survey; BCNS). Bivariate and regression analysesexamined factors associated with NHP use. Assessment of potential adverse effects of NHP use was based oncomparing nutrient intakes from food plus supplements with the Dietary Reference Intakes and by reviewingdatabases for reported adverse health effects.Results: Two-thirds (66%; 95% CI 56 to 75) were taking at least one NHP; 58% (95% CI 47 to 68) were taking NHPsin combination with psychiatric medications. The proportion of each type of NHP used was generally higher thanthe BCNS (range of p’s < 0.05 to 0.0001). When intakes from food and NHP sources were combined, a smallproportion exceeded any Lowest-Observed-Adverse-Effect-Levels: only for niacin (n = 17) and magnesium (n = 6),two nutrients for which the potential for adverse effects is minimal. Conversely, about 38% (95% CI 28 to 49) of thesample were taking a non-nutrient based NHP for which previous adverse events had been documented.Conclusions: The prevalent use of NHPs in this population suggests that health care providers need to beknowledgeable about their characteristics. The efficacy and safety of NHPs in relation to mental health warrantsfurther investigation.Keywords: Natural health products, Adverse events, Mood disordersBackgroundPeople with mental health conditions often use a varietyof therapeutic alternatives which are not necessarilydisclosed to their primary health care provider. Remediesused may include natural health products (NHPs), definedas agents that include constituents such as vitamins andminerals, herbs, homeopathic medicines, traditional medi-cines, probiotics, and other products like amino acids andessential fatty acids [1].National surveys of general populations have found thatNHP use is increasing around the world [2-5], but fewstudies have examined individuals with mental healthconditions. Available data suggest that NHP use tendsto be higher in those with anxiety and depressive disor-ders [6-11]. From a public health perspective, there issome concern that NHPs may interact with conventionaltherapies. For example, studies have reported that St. John’swort combined with trazodone, sertraline, or nefazodonemay cause serotonin syndrome [12]. Reporting the po-tential for adverse health-related events such as thesehas gained increased attention globally as the informa-tion serves as a means to prevent harm to individualsand help formulate recommendations for health systems* Correspondence: karen.davison@ubc.ca1Department of Community Health Sciences, University of Calgary, Calgary,AB, Canada2University of British Columbia, School of Population and Public Health, 2206East Mall, Vancouver BC V6T 1Z3, CanadaFull list of author information is available at the end of the article© 2013 Davison and Kaplan; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.Davison and Kaplan BMC Complementary and Alternative Medicine 2013, 13:80http://www.biomedcentral.com/1472-6882/13/80change [13]. Conversely, other investigations report bene-ficial effects of NHPs including lowered requirement dosesof medications [14-17]. In either case, it would be usefulto know more about NHP use in people with mentalhealth conditions. This analysis examined characteristicsof NHP use including potential for adverse events inadults with mood disorders.MethodsSubjects, settings and proceduresData from a cross-sectional nutrition survey of adults(> 18 years; n = 97) that were randomly selected fromthe Mood Disorders Association of British Columbia(MDABC) membership list and resided in the lowermainland of British Columbia (n = 1400) was used; thelist was provided to researchers by the MDABC. Samplesize verification was obtained using one-sample inferencefor a binomial proportion [18] with estimates of NHP useat 60% in the study population and general populationuse being 46% [19], alpha of 0.05, and statistical powerof 80%.Individuals (n = 146) randomly selected from the MDABCmembership list were first sent a letter inviting their par-ticipation in the study. Subsequent to the invitation letter,a research staff member phoned the potential participantto ask if the research coordinator could contact them todiscuss the project. Ten attempts were made to contactthe potential participant if there continued to be no answer.Then the file was closed. For those who agreed to partici-pate, the research coordinator reviewed procedures of thestudy over the phone including instructions of how tocomplete their food records that were mailed out to them.Overall, 97% of the 146 names drawn for the study wereresolved; that is, they were located and contacted toparticipate. Of those, a range of 124 to 129 individualswere considered in-scope or eligible based on informa-tion available. Individuals were considered out-of-scopeor not eligible if they were dead, had moved out of thearea, or exhibited at least one of the exclusion criteria(e.g., pregnant, lactating, living in an institution). Ofthose contacted and eligible, 3% refused to participatein the study and 2% did not show up for their appoint-ment (based on the upper bound of 129 eligible).The study protocol including details about verificationof mood disorder diagnosis (i.e., bipolar I, bipolar II, anddepressive disorder) using the Structured Clinical Interviewfor DSM-IV Axis I Disorders [20] and Global Assessmentof Functioning (GAF) [21], exclusion criteria (i.e., presenceof another condition impacting mental health), currentsymptoms of depression and mania based on the HamiltonDepression Scale (Ham-D) [22], and Young Mania RatingScale (YMRS) [23], and collection of nutrient intake dataare detailed elsewhere [24]. Of those that participated inthe screening to assess eligibility, two were found to beineligible. The study’s protocol including consent pro-cedures were approved by the University of Calgary’sConjoint Health Research Ethics Board. The consentprocedures involved first mailing the study’s consentforms to those who agreed to participate, so that theycould review it at their leisure. Then when the participantsattended their appointment, they first reviewed the con-sent forms with the research coordinator or clinical inter-viewer and signed the form once they fully understoodall aspects of the study (i.e., all information would beheld in strict confidence) and were agreeable to partici-pating. Honourariums were provided to cover expenses(e.g., taxis, buses, gas, parking) and time associated withcompleting a 3-day food record and attending the officeinterview (about 180 minutes total).As part of the face-to-face survey interviews conductedat the MDABC office, respondents brought all medicationsand natural health products (e.g., vitamin, mineral, herbal,botanical, and homeopathic preparations) they were tak-ing. Details of NHP use based on type, composition (e.g.,ingredients and amounts recorded from the labels), andfrequency (e.g., taken daily, monthly) were taken by atrained interviewer.Statistical analysisNutrient and NHP intake data were collected using thestandardized procedures of the British Columbia NutritionSurvey (BCNS) that included nutrient analysis of 3-dayfood records using ESHA software and the CanadianNutrient File. Full information about the BCNS, nutrientanalyses methods, and quality control procedures [25] aredetailed elsewhere.Comparisons of NHP use (e.g., prevalence) were madewith the BCNS (population norm) and associated factorssuch as socio-demographic (i.e., sex, age, relationshipstatus, education, income) and clinical (i.e., medicationuse, depressive versus bipolar disorder, GAF, years sincediagnosis, BMI, psychiatric symptom scores) characteris-tics were analysed using binomial tests of two proportions,Fisher Exact statistics, Student t-tests, Mann–Whitneytests and correlations where appropriate. Variables thatwere found to be significant based on the bivariate analysiswere then analyzed in the logistic (i.e., NHP use as dichot-omous dependent variable) and multiple regression (i.e.,number of NHPs used as continuous dependent variable)models to examine factors associated with NHP use. Nomore than four variables were placed into a model atone time and all models were evaluated to ensure theymet statistical test assumptions (e.g., normality, homo-scedasticity) and goodness of fit (e.g., graphical depictionsof the residuals, Hosmer and Lemeshow’s goodness-of-fittest). All statistical analyses were conducted using Stata7.0 software.Davison and Kaplan BMC Complementary and Alternative Medicine 2013, 13:80 Page 2 of 10http://www.biomedcentral.com/1472-6882/13/80Safety of NHP Use: Nutrient content in NHPs wasrecorded for each participant, expressed as a daily amountand added to the usual intake obtained from food sourcesalone. For example, vitamin C from food sources averagedover 3 days was added to vitamin C from supplementsexpressed as a daily amount based on previous month’suse. Nutrient intakes (from food and NHPs combined)were compared to the Tolerable Upper Intake Levels (UL)of the Dietary Reference Intakes (DRIs), where applicable,to estimate prevalence of excess intakes. The ULs repre-sent a daily nutrient amount for almost all healthy individ-uals where risk of adverse effects increases as intake levelsexceed the standard [26]. For those intakes exceedingthe ULs, the amounts were then compared to the LowestObserved Adverse Effect Levels (LOAELs) of the DRIs,when available. The LOAEL is the lowest amount forwhich an adverse effect has been reported [26].For NHPs without DRI comparison data, safety ofuse was examined by conducting detailed electronicsearches of all products taken by participants for anyreported adverse events. The databases searched in-cluded MEDLINE, EMBASE, PsychINFO, the CochraneLibrary, CINAHL, NAPRALERT, MedEffect™ Canada,International Pharmaceutical Abstracts, CISCOM, andHerbMed. Search terms included common and scien-tific names, as well as synonyms for the NHPs andtheir primary active constituents. Adverse events in-cluded those reported from individual NHPs as well asany potential interactions that may have occurred fromconcurrent NHP use and with medications that partici-pants were taking. We refer to this as the potential foradverse events previously defined as an unsafe state,not currently an event, but likely to lead to an event ifit persists without intervention [27].ResultsSampleThe response rate was about 75% (97/129), calculatedwith the assumption that all the unresolved cases werein-scope (eligible). Those who did not want to partici-pate in the study were asked a set of demographic healthbehaviour questions including their marital status, edu-cation level, use of vitamin and mineral supplements,type of bread and milk they consumed, and whether theysmoked; no significant group differences were found be-tween study participants and the non-responders basedon these variables. The first author verified with theMDABC that the sample reflected the demographics (e.g.,gender, age range) of their membership.Most of the sample was female (n = 69; 71%; 95% CI62% to 80%), had government-defined low income levels(n = 47; 49%; 95% CI 39% to 58%), had educational attain-ment levels less than a university degree (n = 76; 78.4%;95% CI 70% to 87%), tended to carry excess weight (BMI >25; n = 65; 67%; 95% CI 58% to 76%), had bipolar I or IIdisorder (60%; 95% CI 50% to 70%), and were consideredto be high functioning based on mean GAF scores (62.7 ±14.7) and median YMRS (Median = 3; 25th%ile = 1; 75th%ile = 5) and Ham-D scores (Median = 9.7, 25th%ile = 3.75;75th%ile = 14.75).Prevalence and characteristics of NHP useA total of 267 different NHPs were used in this sample.The proportion of the respondents taking at least oneNHP was 66% (95% CI 56% to 75%). Fifty-eight percentof the sample (95% CI 47% to 68%) were taking NHPsin combination with their psychiatric medications thatmainly included typical and atypical antipsychotics, anti-depressants, and mood stabilizers; 8% (95% CI 4% to 16%)were taking these products without prescription medica-tions. Of those who were taking NHPs, the average (mean)number of products used was 3 (range of 1 to 21; 95% CI4 to 10). More than half of the sample were taking singleor combination vitamin and mineral therapies, herbs andnatural products and other nutrients such as glucosamine,amino acids, essential fatty acids from oils, and lacticacid bacteria (Table 1). Males had higher intakes of mostsingle and combination preparations of vitamins, replace-ment preparations, and other nutrients (Table 1) (rangeof p’s < 0.05 to 0.0001). Comparisons of NHP use basedon bivariate and regression statistical analyses withsociodemographic (i.e., age, education, income, relation-ship status) and clinical factors (i.e., psychiatric medica-tion use, depressive vs. bipolar I and II disorder, GAF,years since diagnosis of mental health condition, BMI,depression scores, mania scores) showed no significantassociations.NHPs and potential for adverse eventsWhen vitamin and mineral intakes from food and sup-plements were combined and compared to the DRIs, 2%(95% CI 0.3 to 7) to 8% (95% CI 4 to 16) of the samplehad intakes that exceeded the ULs for 8 nutrients(Table 2); of these, 19% (95% CI 11 to 28) had niacin in-takes above the LOAEL of 50 mg, and 6% (95% CI 2 to13) had magnesium intakes above the LOAEL of360 mg. In addition to the NHPs that had DRI compari-son data, 16 other products used by 38% (95% CI 28 to49) of the total sample were identified that could poten-tially lead to adverse effects as described in Table 3.The evidence cited in Table 3 often represents anec-dotal reports of incidents that ranged from mildgastrointestinal discomfort to significant clinical eventsincluding worsening of mental symptoms.DiscussionThe results of this analysis indicate that there tends tobe a higher prevalence of NHP use among persons withDavison and Kaplan BMC Complementary and Alternative Medicine 2013, 13:80 Page 3 of 10http://www.biomedcentral.com/1472-6882/13/80mood disorders, particularly males, than in the generalpopulation (i.e., BCNS data). A small proportion of thesample exceeded levels deemed to be the upper marginof safety for the general healthy population for 8 nutrients,none of which represented significant harms. Finally,about 38% of survey respondents were potentially expos-ing themselves to adverse reactions associated with theiruse of NHPs that did not contain vitamins or minerals.The use of NHPs appears to be of a similar scale tothat found in other investigations of mental health popu-lations where reported prevalence ranges from 50 to80% [4]. The common use of NHPs may be attributableto many factors that include media interest in the topic,increased availability of various information sources (e.g.,the Internet), the perceived efficacy and “naturalness” ofthe therapies, desire to reduce side effects, and dissatis-faction with conventional therapies leading to experi-mentation with different products [102-104]. Unlike otherstudies, our results did not indicate differences in NHPuse according to socioeconomic status which is contraryto the inverse supplement hypothesis [105], which sug-gests that those in need of more nutrients due to factorssuch as disease risk or limited income are usually not theones who take supplements. People with mood disordersmay not consider income a barrier if they believe that theNHPs will alleviate symptoms.Table 1 Proportion taking NHPs in the previous month: comparison by sex and to the British Columbia NutritionSurvey (BCNS) (total sample = 97)NHP Males (n = 28)% (95% CI)Females (n = 69)% (95% CI)Total (n = 97)% (95% CI)BCNS (n = 1823)% (95% CI)Water Soluble Vitamins (Single)Vitamin B6 or pyridoxine 68 (51 to 85)*** 14 (6 to 23) 31 (22 to 41) 0aVitamin B9 or folic acid 71 (55 to 88)*** 28 (17 to 38) 40 (30 to 51) 0aVitamin C 64 (47 to 82) 67 (56 to 78) 66 (56 to 75)+++ 24 (22 to 26)Fat Soluble Vitamins (Single)Vitamin A 25 (9 to 41)* 4 (0 to 9) 10 (5 to 18)+++ 2 (1 to 3)Vitamin D 61 (43 to 79) 51 (40 to 62) 64 (54 to 79)+++ 1 (0 to 2)Vitamin E 46 (28 to 65) 46 (35 to 58) 47 (37 to 58)+++ 17 (15 to 19)Vitamin CombinationsVitamin B complex (with or without vitamin C) 68 (51 to 85) 49 (37 to 61) 55 (44 to 65)+++ 9 (8 to 10)Vitamin A and D combination 21 (6 to 37)* 4 (0 to 11) 9 (4 to 17)++ 3 (2 to 4)Multivitamins 14 (1 to 27) 19 (10 to 28) 18 (11 to 27)+ 9 (8 to 10)Minerals (Single and Combinations)Iron preparations 21 (6 to 37) 20 (11 to 30) 34 (25 to 44)+++ 1 (0 to 2)Singleb and multiple mineralsc 79 (63 to 94) 78 (69 to 87) 78 (69 to 86)+++ 13 (11 to 15)Vitamin and Mineral CombinationsVitamins and minerals 61 (43 to 79) 59 (49 to 71) 60 (49 to 70)+++ 31 (29 to 33)Other NHPsEnzymes or gastrointestinal productse 46 (28 to 65) 30 (20 to 41) 35 (26 to 45)+++ 6 (5 to 7)dReplacementf or homeopathic preparationsg 46 (28 to 65) 29 (18 to 37) 34 (25 to 44)+++ 5 (4 to 6)Herbal and natural productsh 61 (43 to 79) 51 (39 to 63) 54 (43 to 64)+++ 19 (17 to 21)Other productsi 61 (43 to 79)* 88 (81 to 96) 75 (65 to 83)+++ 20 (18 to 22)aPyridoxine and folic acid could not be analyzed statistically due to 0% prevalence in the BCNS.bIncludes chromium, selenium, zinc, and magnesium.cIncludes calcium plus magnesium; calcium, magnesium plus zinc; mineral combinations including bromide, calcium, silicon, nitrogen, selenium, phosphorous,iodide, chromium, manganese, titanium, rubidium, cobalt, copper, antimony, molybdenum, strontium, zinc, nickel, tungsten, germanium, scandium, vanadium,tellurium, tin, lanthanum, yttrium, silver, gallium, bismuth, zirconium, cerium, cesium, gold, beryllium, hafnium, samarium, terbium, europium, gadolinium,dysprosium, thorium, holmium, lutetium, erbium, ytterbium, neodymium, praseodymium, niobium, tantalum, thallium, rhenium, indium, and palladium.dBCNS proportion < 1% but rounded to 1%.eIncludes antacids, adsorbents, laxatives, digestants.fElectrolyte-type supplements intended to prevent or treat electrolyte imbalances that include sports drinks, over-the-counter powders and tablets, over-the-counter electrolyte replenishers, oral rehydration formulae, and multiple electrolyte injections. Most preparations contained sodium, potassium magnesium,and calcium.gHomeopathic preparations contain medicinal ingredients and are prepared in accordance with the methods outlined in homeopathic pharmacopoeias.hIncludes herbs, herbal materials, herbal preparations and finished herbal products, that contain as active ingredients parts of plants, or other plant materials,or combinations.iIncludes glucosamine, amino acids, evening primrose oil, coenzyme Q10, flax seed oil, lactic acid bacteria.Significant differences between males and females at *p < 0.05, **p < 0.001, and ***p < 0.0001.Significant differences between study sample and BCNS at +p < 0.05, ++p < 0.001, and +++p < 0.0001.Davison and Kaplan BMC Complementary and Alternative Medicine 2013, 13:80 Page 4 of 10http://www.biomedcentral.com/1472-6882/13/80Table 2 Potential adverse events of vitamin and mineral supplement use based on comparison of nutrient levels to Dietary Reference Intakes and databasesearches for reported adverse events for individual vitamins and minerals usedVitamin/mineral ULa % > ULa(95% CI) LOAELb % > LOAELb(95% CI)Effect at the LOAELbVitamins and Minerals with ULsa and LOAELsbVitamin B3 or niacin - mg 35c 28 (19 to 38) 50 19 (11 to 28) Vasodilation causing flushing of the skinVitamin B6 or pyridoxine - mg 100 8 (4 to 16) – – –Vitamin B9 or folate - mcg 1000c 17 (10 to 25) 5000 0% Precipitate or exacerbate neuropathy in vitamin B12 deficient individualsVitamin Dd – mcg and Vitamin Ed - mg D: 100; E:1000e3 (1 to 9)D: 50; E: 39,545 and18,000f0%Vitamin D: Hypercalcemia. Vitamin E: Increased tendency to hemorrhageseen in ratsCalcium - mg 2500 6 (2 to 13) 5000 0% Hypercalcemia, renal insufficiencyIron - mg 45 7 (3 to 14) – – –Magnesium - mg 350c; g 6 (2 to 13) 360 6 (2 to 13) DiarrheaZinc - mg 40 mg 6 (2 to 13) – – –Manganesed - mg 11 mg 8 (4 to 16) – – –Vitamins and Minerals (without ULsa and LOAELsb)Product names % (95% CI) Adverse Events Reported in the LiteraturehPantothenic acid, vitamin B5, pantethine, pantothenol, orD-pantothenate and Potassiumi37 (28 to 49)Forms of pantothenic acid: Diarrhea seen with 10 to 20 grams/day of calcium D-pantothenate [28]. Case report of eosinophilicpleuropericardial effusion in an elderly woman taking 10 mg of biotin and 300 mg of pantothenic acid daily for two months [29].Nausea and heartburn, have been reported with pantethine [30]Potassium: Supplementation of potassium only is generally prescribed to treat hypokalemia while preventing hyperkalemia andmedication interactions. Mild effects include nausea, vomiting, abdominal discomfort, and diarrhea [28]aTolerable Upper Intake Level.bLowest Observed Adverse Effect Level: The lowest intake (or experimental oral dose) at which an adverse effect has been identified.cThe UL for niacin, folate, and magnesium apply to synthetic forms obtained from supplements, fortified foods, or a combination of the two.dNutrient analysis software for food intakes of vitamin E, vitamin D and manganese have less than 50% coverage for nutrient; thus prevalence estimates of nutrient intakes exceeding the UL are conservative.eThe UL for vitamin E applies to any form of supplemental α-tocopherol, fortified foods, or a combination of the two.fLOAEL for vitamin E is based on 500 mg/kg of α-tocopherol.gThe UL for magnesium is based on gastrointestinal effects from consumption of 350 mg or more of the synthetic form.hBased on database searches of MEDLINE, EMBASE, PsychINFO, the Cochrane Library, CINAHL, NAPRALERT, MedEffect™ Canada, International Pharmaceutical Abstracts, CISCOM, and HerbMed.iPotassium in multi-vitamin and mineral supplements are limited to 99 mg per day. Reported frequency here includes only supplementation of potassium as the single nutrient as adverse effects have only beenreported with this.DavisonandKaplanBMCComplementaryandAlternativeMedicine2013,13:80Page5of10http://www.biomedcentral.com/1472-6882/13/80Table 3 Descriptions of potential adverse events for non-nutrient based NHPs used by sample based on database search of reported adverse events foreach NHPNHP used in sample Adverse events reported for that NHP in the literatureaCranberry (Vaccinium macrocarpon) More than one litre daily may cause kidney stones [31]. (Note: In this sample, cranberry pills were used and did not exceed this level)Dehydroepiandrosterone (DHEA) or 5-Dehydro-epiandrosterone(5-DHEA)People with mood disorders may experience mania, irritability, and sexual inappropriateness [32-35]Devil’s Claw (Harpago-phytum procumbens) Mild gastrointestinal upset, hypotension, diarrhea, loss of taste, anorexia, headache, and tinnitus [32-34]. May interact with warfarin; onecase report of purpura [36]Dong Quai (Angelica sinensis), Chinese angelica In a cross-sectional survey (n = 1818), one case was identified as a potential significant interaction between dong quai andanticoagulant/antiplatelet agents [37]Echinacea (Echinacea angustifolia, Echinacea pallida, Echinaceapurpurea)Gastrointestinal upset and rashes; in rare cases, has been associated with allergic reactions that may be severe [38]. May interact withamoxicillin [39]Evening Primrose Oil (Oenothera biennis) Case reports of seizures in patients with/without known seizure disorders [40,41]. In cross-sectional survey (n = 1818), two cases ofpotential significant interactions with anticoagulant/antiplatelet agents identified [37]Feverfew (Tanacetum parthenium; syn. Chrysanthemum parthenium(L.) Pers., Pyrethrum parthenium Sm.)Gastrointestinal upset [42,43], nervousness, insomnia [44], and possible allergic responses in those sensitive to chrysanthemums, daisies,or marigolds. Potential cross-reactivity with other members of the Compositae family [45]. In cross-sectional survey (n = 1818), twocases of potential clinically significant interactions with anticoagulant/antiplatelet agents identified [37].Flaxseed (common flax, linseed, Linum usitatissimum) Rarely, flaxseed (not oil form) has caused gastrointestinal distress [46-50]. A double-blind placebo-controlled trial suggested there maybe increased episodes of mania and hypomania in people with bipolar disorder [46]Garlic (Allium sativum) Breath and body odour, and allergic reactions [51]. Excess use associated with spontaneous epidural hematoma [52]. Potentialreactions include bleeding and hypoglycemia (likely not clinically significant) [53]. In cross-sectional survey (n = 1818), 25 cases ofpotential clinically significant interactions with anticoagulant/antiplatelet agents identified [37]Ginkgo (Ginkgo biloba) Surveillance studies (> 10,000 people), found 1.69% incidence of symptoms such as headache and gastrointestinal complaints [54].Bleeding indicated in a few case reports [55]. May cause allergic hypersensitivity, including Stevens-Johnson syndrome [56-58]. In cross-sectional survey of 1818 patients, 20 cases of potential clinically significant interactions with anticoagulant/antiplatelet agents identified[37]. Infrequent mild gastrointestinal discomfort has been reported when Ginkgo is taken with selective serotonin reuptake inhibitors(SSRIs) [59]. May interact with thiazides [60,61], and nifedipine [62,63]Ginseng (American, Asian, Chinese, Korean red; Panax ginseng,Panax spp. including P. ginseng and P. quinquefolius)Long-term use of Panax and American ginseng associated with skin rash, itching, diarrhea, sore throat, loss of appetite, excitability,anxiety, depression, or insomnia [53,64]. Few reports of headache, fever, dizziness/vertigo, blood pressure changes, chest pain, difficultmenstruation, heart palpitations, leg swelling, nausea, vomiting, manic episodes in bipolar disorder, or Stevens-Johnson syndrome (mayhave been due to product contaminants) [53]. High intake of American ginseng may result in hypoglycemia in people with/withoutdiabetes [65]. May interact with anticoagulants/antiplatelets [66,67], diabetes medications [37], digoxin [68], estrogenic agents [69-71],furosemide [72], monoaminergic agents [73-75], nifedipine [76]Ginseng (American, Asian, Chinese, Korean red; Panax ginseng,Panax spp. including P. ginseng and P. quinquefolius)Long-term use of Panax and American ginseng associated with skin rash, itching, diarrhea, sore throat, loss of appetite, excitability,anxiety, depression, or insomnia [53,64]. Few reports of headache, fever, dizziness/vertigo, blood pressure changes, chest pain, difficultmenstruation, heart palpitations, leg swelling, nausea, vomiting, manic episodes in bipolar disorder, or Stevens-Johnson syndrome (mayhave been due to product contaminants) [53]. High intake of American ginseng may result in hypoglycemia in people with/withoutdiabetes [65]. May interact with anticoagulants/antiplatelets [66,67], diabetes medications [37], digoxin [68], estrogenic agents [69-71],furosemide [72], monoaminergic agents [73-75], nifedipine [76]Melatonin (N-acetyl-5-methoxytryptamine) May worsen depression and irritability. Sedative medications (CNS depressants) and benzodiazepines interact with melatonin [77]Omega-3 Fatty Acids, Alpha-Linolenic Acid Caution indicated for those with diabetes as may increase blood glucose, at risk of bleeding, or with high LDL levels [78-85]. Mayinteract with anticoagulants/antiplatelets [80,86-90]DavisonandKaplanBMCComplementaryandAlternativeMedicine2013,13:80Page6of10http://www.biomedcentral.com/1472-6882/13/80Table 3 Descriptions of potential adverse events for non-nutrient based NHPs used by sample based on database search of reported adverse events foreach NHP (Continued)Valerian (Valeriana officinalis) Mild impairments in concentration, processing, fatigue (less pronounced than with benzodiazepines) [91-95], dizziness, and headache[96,97]. Drug “hangover” and “withdrawal” effect has been reported with high doses [96]. Delirium, ameliorated by benzodiazepines,indicated in one case report [98]. Some develop a “paradoxical reaction” leading to nervousness, and use for longer than 2 monthsmay result in insomnia [53]. Rare reports of hepatotoxicity with some preparations that include valerian [99] but may have been due toother components. May interact with CNS depressants [91,92,100]. In cross-sectional survey (n = 1818), 15 cases of potential clinicallysignificant interactions with sedatives identified [37]. One case of SSRI use and valerian (with alcohol) indicated mental status changes[101]aBased on database searches of MEDLINE, EMBASE, PsychINFO, the Cochrane Library, CINAHL, NAPRALERT, MedEffect™ Canada, International Pharmaceutical Abstracts, CISCOM, and HerbMed for each NHP used in thesample including common and scientific names, synonyms and the primary active constituents of the NHP.DavisonandKaplanBMCComplementaryandAlternativeMedicine2013,13:80Page7of10http://www.biomedcentral.com/1472-6882/13/80The potential health risk associated with intakes abovethe LOAELs (i.e., skin flushing, mild diarrhea) in a fewof the participants is relatively minor. Niacin intake ex-cesses may be due to people receiving pharmacologicaldoses (i.e., 1 to 3 grams daily) to manage serum choles-terol levels as per Canadian lipid guidelines [55]; at least31 participants had high blood cholesterol levels. Wepreviously reported in this same sample that there was apattern of correlations between some nutrient intakes(even above the ULs) and overall mental health based onGAF scores [106], suggesting that these individuals mayhave been benefiting from the additional nutrients. Wealso note that the DRIs are based on healthy populationsand may have limited applicability to persons with men-tal health conditions. For example, lithium in pharmaco-logical doses would certainly be contraindicated in healthypopulations, but in individuals with bipolar disorderhigher amounts of this mineral are standard treatment.While there was potential for more severe adverse reac-tions from non-nutrient based NHPs, some of these prod-ucts are also used as sources for conventional drugs [52].The modest sample size may be interpreted as a limita-tion. However, unlike the large population surveys onNHP use, our study collected detailed data (e.g., types,dose, frequency, nutrients from food plus supplements),verified mental health diagnosis, and conducted an assess-ment of potential for adverse events. The sample was com-prised of mainly females, individuals with a mental healthcondition that were generally high functioning, and residedin an urban region which may limit the generalizability offindings. In addition, it cannot be determined how wellMDABC membership reflects the population of all individ-uals with mood disorders. The prevalence of NHP use inthis study may be overstated as the region in which thedata was collected is reported to have a higher propor-tion of alternative medicine practices compared to otherCanadian provinces [10]. The prevalence estimate for po-tential adverse effects may be conservative as data is lack-ing about interactions of NHPs with each other and withfoods, and many surveillance systems are passive and con-tain incomplete data (e.g., a specific dose level that led toan adverse effect). Conversely, the potential for adverseevents may be overstated as the information obtainedtended to be based on anecdotal reports and not prospect-ive data that specifically documents harms.ConclusionsSince NHP use among individuals with mood disordersis prevalent, health care providers may best serve theseclients by becoming more knowledgeable about theircharacteristics. Further research on the safety of NHPsincluding their impact on the course and prognosis ofmental health conditions is also of relevance.AbbreviationsBCNS: British Columbia Nutrition Survey; CI: Confidence Interval;LOAEL: Lowest Observed Adverse Effect Level; NHP: Natural Health Product;mcg: Micrograms; mg: Milligrams; UL: Tolerable Upper Intake Level.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsKMD and BJK designed the study and planned its coordination and datacollection. KMD carried out the data collection as part of her PhDdissertation, under the supervision of BJK. Both authors worked on writingthe manuscript. Both authors read and approved the final manuscript.Authors’ informationKMD carried out this study as part of her requirement for a PhD in theFaculty of Medicine, University of Calgary, under the supervision of BJK,and is currently a postdoctoral research fellow (Chronic ConditionSelf-Management) in the School of Population and Public Health at theUniversity of British Columbia. BJK is a Professor in the Faculty of Medicineat the University of Calgary who studies nutrition in relation to mentaldevelopment and function.AcknowledgementsThe authors thank their funding source, The Danone Research Institute. Thesecond author also thanks the Alberta Children’s Hospital Research Institutefor ongoing support. We also acknowledge the assistance of the MoodDisorders Association of British Columbia for providing support staff, officespace and assistance with recruitment.Funding and supportFinancial Support for this project was obtained from The Danone ResearchInstitute, which played no role in carrying out the study, analyzing theresults, or influencing publication.Author details1Department of Community Health Sciences, University of Calgary, Calgary,AB, Canada. 2University of British Columbia, School of Population and PublicHealth, 2206 East Mall, Vancouver BC V6T 1Z3, Canada. 3Department ofPaediatrics, University of Calgary, Calgary, AB, Canada.Received: 17 October 2012 Accepted: 27 March 2013Published: 9 April 2013References1. Health Canada: Natural Health Products. Ottawa: Health Canada; 2012.Retrieved: www.hc-sc.gc.ca/dhp-mps/prodnatur/index-eng.php.2. 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Can J Psychiatry2012, 57(2):85–92.doi:10.1186/1472-6882-13-80Cite this article as: Davison and Kaplan: Nutrient- and non-nutrient-basednatural health product (NHP) use in adults with mood disorders:prevalence, characteristics and potential for exposure to adverse events.BMC Complementary and Alternative Medicine 2013 13:80.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitDavison and Kaplan BMC Complementary and Alternative Medicine 2013, 13:80 Page 10 of 10http://www.biomedcentral.com/1472-6882/13/80


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