xerostomia research articles

Xerostomia of Various Etiologies: A Review of the Literature

Affiliations.

• 1 Department of Conservative Dentistry with Endodontics, Medical University of Silesia, Bytom, Poland.
• 2 Conservative Dentistry with Endodontics, Academic Center of Dentistry and Specialist Medicine, Bytom, Poland.
• PMID: 26935515
• DOI: 10.17219/acem/29375

This paper presents the etiopathogenesis, symptomatology, evaluation and treatment of mouth dryness. Xerostomia affects 1-29% of the population, mostly women. It is observed in geriatric patients and in individuals using certain medications, those subjected to radiotherapy of the head and neck region or affected with autoimmune conditions. The main signs of xerostomia include the impression of a dry mouth, problems with food ingestion and dryness of the oral mucosa and skin. Evaluation is based on structured interviews (the Fox test) and determinations of unstimulated and stimulated salivary volume. The signs of xerostomia can be attenuated with saliva substitutes, cevimeline or malic acid. Only palliative treatment of this condition is available at present. Untreated xerostomia significantly impairs the quality of life, which can potentially lead to depression.

Publication types

• Palliative Care
• Predictive Value of Tests
• Quality of Life
• Risk Factors
• Salivary Glands / physiopathology*
• Salivation*
• Treatment Outcome
• Xerostomia / diagnosis
• Xerostomia / etiology*
• Xerostomia / physiopathology
• Xerostomia / psychology
• Xerostomia / therapy

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• Published: 24 January 2022

Xerostomia and hyposalivation in association with oral candidiasis: a systematic review and meta-analysis

• Molek Molek 1 ,
• Florenly Florenly 1 ,
• I. Nyoman Ehrich Lister 2 ,
• Tuka Abdul Wahab 3 ,
• Clarissa Lister 4 &
• Fioni Fioni 2  

Evidence-Based Dentistry ( 2022 ) Cite this article

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Introduction Several studies reported that hyposalivation was associated with a higher prevalence of oral Candida colonisation and oral candidiasis, and despite the correlation between these conditions, no previous systematic review was conducted to examine this relationship in its utmost depth.

Objectives This study aims to investigate the relationship between xerostomia, hyposalivation and oral candidiasis.

Search methods This systematic review and meta-analysis was conducted in February 2021 through an electronic search.

Data sources The electronic search was performed on PubMed, Scopus, Web of Science through Clarivate, Medline through Clarivate and Cochrane Library.

Data selection This systematic review and meta-analysis included cohort, observational nested case-control cohort studies, and studies of other designs providing the number of patients with and without xerostomia or hyposalivation crossed with the number of patients with and without oral candidiasis or oral Candida growth. Studies included were conducted on adult populations with no restriction to sex or race. Included studies should use a reliable diagnostic method for all conditions of interest.

Data extraction Results were obtained from the implementation of the search strategy and managed using the EndNote Web and Rayyan Qatar Computing Research Institute (QCRI). Quantitative data synthesis was performed using the Review Manager 5.4 software.

Results A total of 429 studies were identified by searching the databases, of which nine studies were included for qualitative and quantitative data synthesis. The analysis included 590 xerostomic patients and 697 controls subgrouped into two categories: Candida growth (207 patients and 195 controls) and oral candidiasis (383 patients and 502 controls). The Candida growth subgroup analysis shows that the xerostomic patients are at higher risk for oral Candida growth than controls (OR [95% CI] = 3.13 [2.02-4.86]) and the oral candidiasis subgroup analysis yields that xerostomic patients are at higher risk for developing manifest oral candidiasis than controls (OR [95% CI] = 2.48 [1.83-3.37]).

Conclusion Our study concludes that patients with xerostomia have a higher risk than non-xerostomic control groups of developing oral candidiasis and oral fungal growth. Major inter-study heterogeneity, however, may restrict confidence in the accuracy of our results, and caution should therefore be taken in interpreting the evidence. In caring for patients with hyposalivation, we recommend healthcare professionals consider the possible association between both conditions. Furthermore, we recommend further research with improved methodological qualities and more valid diagnostic methods.

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Faculty of Dentistry, Universitas Prima, Indonesia

Molek Molek & Florenly Florenly

Faculty of Medicine, Universitas Prima, Indonesia

I. Nyoman Ehrich Lister & Fioni Fioni

Faculty of Medicine, Damascus University, Syria

Tuka Abdul Wahab

South West Acute Hospital, Enniskillen, UK

Clarissa Lister

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Dr Molek: searching strategy, methodology and result. Prof Dr I. Nyoman Ehrich Lister: data extraction and statistic analysis. Dr Florenly: filtering studies included and quality appraisal of studies. Dr Tuka Abdul Wahab: introduction, data extraction. Dr Clarissa Lister: filtering studies included and quality appraisal of studies. Dr Fioni: designed/planning/idea of the paper led to submission, team leader, searching strategy, approved the final version, revised manuscript.

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Molek, M., Florenly, F., Lister, I. et al. Xerostomia and hyposalivation in association with oral candidiasis: a systematic review and meta-analysis. Evid Based Dent (2022). https://doi.org/10.1038/s41432-021-0210-2

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• Published: 20 June 2023

The effect of gum chewing on xerostomia and salivary flow rate in elderly and medically compromised subjects: a systematic review and meta-analysis

• Michael W. J. Dodds 1 ,
• Mohamed Ben Haddou 2 &
• Jon E. L. Day 3  

BMC Oral Health volume  23 , Article number:  406 ( 2023 ) Cite this article

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Xerostomia negatively affects quality of life. Symptoms include oral dryness; thirst; difficulty speaking, chewing, and swallowing food; oral discomfort; mouth soft tissue soreness and infections; and rampant tooth decay. The objective of this systematic review and meta-analysis was to investigate if gum chewing is an intervention that results in objective improvements in salivary flow rates and subjective relief from xerostomia.

We searched electronic databases including Medline, Scopus, Web of Science, Embase, Cochrane Library (CDSR and Central), Google Scholar and the citations of review papers (last searched 31/03/23). The study populations included: 1) elderly people with xerostomia (> 60 years old, any gender, and severity of xerostomia), and 2) medically compromised people with xerostomia. The intervention of interest was gum chewing. Comparisons included gum chewing vs. no gum chewing. The outcomes included salivary flow rate, self-reported xerostomia, and thirst. All settings and study designs were included. We conducted a meta-analysis on studies where measurements of unstimulated whole salivary flow rate for both a gum chewing, and no gum chewing intervention (daily chewing of gum for two weeks or longer) were reported. We assessed risk of bias using Cochrane’s RoB 2 and ROBINS-I tools.

Nine thousand six hundred and two studies were screened and 0.26% ( n  = 25) met the inclusion criteria for the systematic review. Two of the 25 papers had a high overall risk of bias. Of the 25 papers selected for the systematic review, six met the criteria to be included in the meta-analysis which confirmed a significant overall effect of gum on saliva flow outcomes compared to control (SMD = 0.44, 95% CI: 0.22—0.66; p  = 0.00008; I 2  = 46.53%).

Conclusions

Chewing gum can increase unstimulated salivary flow rate in elderly and medically compromised people with xerostomia. Increasing the number of days over which gum is chewed increases the improvement in the rate of salivation. Gum chewing is linked with improvements in self-reported levels of xerostomia (although it is noted that no significant effects were detected in five of the studies reviewed). Future studies should eliminate sources of bias, standardise methods to measure salivary flow rate, and use a common instrument to measure subjective relief from xerostomia.

Study registration

PROSPERO CRD42021254485.

Peer Review reports

It has been estimated that up to 39% of the non-institutionalised older adult population suffer from xerostomia [ 1 ], with a reported overall prevalence of 21.3% in males and 27.3% in females across ages 20 – 80 years [ 2 ]. Xerostomia is the subjective perception of oral dryness, and is often caused by salivary gland hypofunction resulting in low salivary output. However, it is notable that subjective xerostomia does not always correspond with objective measures of salivary flow rate [ 3 ]. The main factors causing decreased saliva generation include natural outcomes of aging, side effects of medication or medical procedures such as head and neck radiation therapy and haemodialysis, and specific medical or psychiatric conditions such as connective tissue disorders, diabetes, anxiety and depression [ 4 ].

Xerostomia negatively affects the Oral Health Quality of Life index [ 5 ]. Symptoms include sensations of dryness or thirst, difficulty speaking, chewing and swallowing food, oral discomfort, and mouth soft tissue soreness. Xerostomia can also lead to oral infection and increased incidence of dental caries [ 2 ]. One approach to mitigate these symptoms is the use of sugar-free chewing gum which stimulates a strong flow of saliva through the separate and interactive effects of mastication and taste [ 6 ]. It has been used to provide symptomatic relief in patients suffering from xerostomia or salivary gland hypofunction. A Cochrane Collaboration review of topical therapies for dry mouth concluded that chewing gum increased saliva production in those with residual secretory capacity. Chewing gum may be preferred by patients, however, the review found no evidence to suggest the effect is greater or worse in comparison to saliva substitutes [ 7 ]. A more recent integrative review concluded that chewing gum for treatment of thirst resulted in increased salivary flow, xerostomia relief, and thirst reduction [ 8 ]. However, neither of these reviews included a meta-analysis of salivary flow rate data. Therefore, the objective of our systematic review and meta-analysis was to determine whether gum chewing leads to salivation and consequent relief from xerostomia in elderly and medically compromised people. Such evidence could support the development of interventions that address xerostomia and improve quality of life in both healthy and challenged populations.

Protocol registration

The protocol was registered with the international prospective register of systematic reviews (PROSPERO) in accordance with PRISMA-P guidelines (PROSPERO CRD42021254485). The protocol can be accessed at: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=254485 .

Defining the research question

We formulated the research question of the systematic review using PICOS (Population, Intervention, Comparison, Outcome, and Setting) [ 9 ]. The populations studied were: 1) elderly people with xerostomia (> 60 years old, any gender, and severity of xerostomia), and 2) medically compromised people with xerostomia. These populations were not restricted to any geography and included papers from all over the world. The intervention of interest was gum chewing (with or without specific ingredients designed to promote salivation). The comparisons included gum chewing vs. no gum chewing. The outcomes used for study selection included rate of salivation / salivary volume per unit time, xerostomia relief (self-reported, e.g., the Xerostomia Inventory), and thirst. Settings of any type (e.g. laboratory, clinical, nursing home, etc.), study designs of any type (e.g. RCTs including within- and between-subjects’ designs, cross-sectional, etc.) were in scope. Only fully-refereed research studies published in the English language were included. Abstracts and review papers were excluded.

Data sources and searches

We searched the Medline (1946 to 31 st March 2023) and Scopus (1806 to 31 st March 2023), Web of Science, Embase and Cochrane Library (CDSR and Central) databases using the syntax outlined in Table 1 . Additionally, we searched for randomised controlled trials in clinical trials registries ( https://clinicaltrials.gov/ and https://www.isrctn.com/ ), with terms relating to xerostomia, dry mouth, chewing, mastication, gum, salivation, oral hydration, and thirst. Other methods used for identifying relevant research included laddering (manual searching) from references cited in the literature obtained, identifying possible data from conferences attended, and reviewing proprietary information.

Study selection

The papers identified by the searches were independently reviewed by two researchers (JD & MD) to assess them against the inclusion and exclusion criteria of the PICOS statement. A consensus meeting was held to discuss papers where there was disagreement on whether they should, or should not, be included.

Outcomes and variables

For the systematic review, the outcome measures were self-reported xerostomia, salivary flow rates (stimulated and unstimulated), and thirst. For the meta-analysis, the primary outcome measure was unstimulated salivary flow rate (ml / min). Since the immediate effect of chewing sugar-free gum is to increase saliva flow, we determined that unstimulated saliva flow rate would be the preferred outcome measure for the meta-analysis, since this would be more consistent across studies, and would be least influenced by different stimuli used to collect saliva. Furthermore, unstimulated, but not stimulated, salivary flow rate has been found to be significantly correlated with xerostomia symptoms [ 10 ].

Data extraction and quality assessment

Following the selection of papers, the two reviewers independently examined each paper for risk of bias using Cochrane’s RoB 2 (for individually-randomised, parallel-group trials and cross-over trials) [ 11 ] and ROBINS-I tools [ 12 ]. A second consensus meeting was held to decide on the final, agreed, risk of bias.

In addition to the systematic review, a meta-analysis was conducted on a subset of the selected papers where both a gum chewing intervention was imposed for two or more weeks, and where unstimulated salivary flow rate was measured (ml / min). Data extraction was performed independently by two reviewers (JD & MBH) and the results compared to highlight any potential errors. Data were extracted from the text, tables and figures of each of the papers. Additionally, we also recorded: 1) authors and publication year, 2) sample size (control and intervention), 3) intervention protocol (observation weeks), and 4) outcome data expressed as saliva flow rate. Where the data were reported in graphical form, WebPlotDigitizer [ 13 ] was used to extract the underlying numerical data. Where repeated measures were reported (i.e. multiple observations over a number of weeks), only the outcomes where the intervention had been imposed for two or more weeks were included.

Data synthesis and analysis

A random-effects meta-analysis using standardised mean differences (SMD) was performed using RStudio software (R version 4.1.3 (2022–03-10)) to assess the overall effect of gum chewing on unstimulated salivary flow rate. The data were converted to SMDs (Hedge’s g) and standard errors to obtain 95% confidence intervals (CIs). The following data were used for the calculation of SMDs: 1) mean ± standard deviation, and 2) sample size (n). None of the included studies reported the correlations between trials, thus a 0.5 correlation was assumed for all trials, as per recommendations [ 14 ]. Hedge’s g values of < 0.2, 0.2 ≤ 0.5, 0.5 – 0.8, and > 0.8 were considered to represent very small, small, medium, and large effects respectively [ 15 ]. The I 2 statistic was used to assess the degree of heterogeneity, with values from < 50% indicating low heterogeneity, 50–75% moderate heterogeneity, and > 75% high level of heterogeneity. Heterogeneity between the studies was assessed using graphic exploration with funnel plots.

To assess the stability of the results and investigate the effects of outliers, a “leave one out” approach was conducted. In this approach, studies are removed one by one, and the random effect model is fitted on the remaining studies. Meta-regression was used to investigate whether the duration of the intervention (e.g. how many days participants chewed gum) influenced unstimulated salivary flow rates.

Search results

The search returned a list of 9,602 papers. A summary of the number and types of exclusions is given in Fig.  1 . The two reviewers disagreed over the classification of 40/9,602 papers in their independent reviews (0.76%). A consensus meeting was used to decide on the ultimate inclusion and exclusion of the disputed papers resulting in a final list of 25 publications for the systematic review [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ].

Overview of the systematic review on the effect of gum chewing on xerostomia and salivary flow rate in elderly and medically compromised subjects (as per PRISMA statement)

Characteristics of included studies

Each paper was reviewed to determine the experimental design, the numbers of participants, the outcome measures, and the key results (Table 2 ).

In accordance with the PICOS criteria, all studies involved at least one intervention relating to the chewing of gum and a control condition (generally no chewing). Additionally, in two studies, gum chewing was also compared with sham chewing or a simple oral exercise [ 17 , 26 ]. One study compared gum chewing with the sucking of a lemon-flavoured lozenge [ 34 ]. Five studies compared the effects of gum chewing with the effects of artificial saliva on associated measures of xerostomia [ 30 , 31 , 33 , 34 , 40 ].

The 25 studies included in the systematic review measured a range of different outcome variables. Twenty studies measured stimulated and/or unstimulated saliva flow rate [ 17 , 18 , 19 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 31 , 32 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ], 17 studies measured self-reported xerostomia or symptoms of dry mouth [ 17 , 18 , 19 , 21 , 23 , 24 , 25 , 26 , 27 , 29 , 30 , 31 , 33 , 34 , 37 , 38 , 40 ], seven studies measured thirst [ 16 , 20 , 21 , 26 , 27 , 29 , 31 ], and one study measured mucosal moisture levels [ 22 ]. Of the 19 studies that measured stimulated and/or unstimulated saliva flow rate, 9 found a positive effect of gum chewing [ 17 , 18 , 22 , 24 , 27 , 35 , 36 , 38 , 39 ] and 10 did not detect any effects [ 19 , 23 , 25 , 26 , 28 , 31 , 32 , 34 , 37 , 40 ]. Of the six studies included in the meta-analysis, three found a positive effect of gum chewing on unstimulated saliva flow rate [ 17 , 18 , 36 ], and three did not detect any effects of gum chewing on unstimulated saliva flow rate [ 26 , 31 , 34 ]. Of the 17 studies that measured xerostomia or symptoms of dry mouth, 12 found a positive effect of gum chewing [ 18 , 19 , 21 , 23 , 24 , 25 , 26 , 27 , 30 , 31 , 38 , 40 ] and five did not detect any effects [ 17 , 29 , 33 , 34 , 37 ]. Of the seven studies that measured thirst, six found a positive effect of gum chewing [ 16 , 20 , 21 , 26 , 27 , 31 ] and one did not detect any effects [ 29 ]. The single study that measured mucosal moisture found that chewing hard gum significantly increased mucosal moisture whereas chewing soft gum did not [ 22 ].

There were no results indicating that gum chewing adversely affected levels of self-reported xerostomia or symptoms of dry mouth, thirst, stimulated and/or unstimulated saliva flow rate, or mucosal moisture levels. Seven out of the 24 studies reported minor side effects associated with chewing gum use [ 23 , 24 , 29 , 30 , 33 , 34 , 36 ]. For the most part, the reported frequency of these events was low, and the most common symptoms were jaw pain and gastrointestinal disturbances (gas, nausea), although one study reported a high incidence of complaints of decreased appetite [ 29 ].

Risk of bias

Eleven studies were assessed for risk of bias using the RoB 2 tool for individually-randomised, parallel-group trials [ 11 ] (Fig.  2 ). Of these, one had a low overall risk of bias [ 16 ]; 9 had an uncertain risk of bias [ 17 , 18 , 19 , 20 , 24 , 27 , 28 , 32 , 35 ], and one had a high risk of bias [ 21 ]. Ten studies were assessed for risk of bias using the RoB 2 tool for cross-over trials [ 11 ] (Fig.  3 ). All these studies had an uncertain risk of bias [ 22 , 23 , 26 , 30 , 31 , 33 , 34 , 36 , 37 , 38 ]. Four studies were assessed for risk of bias using the ROBINS-I tool [ 12 ] (Fig.  4 ). Of these, one had a low overall risk of bias [ 39 ]; two had an uncertain risk of bias [ 25 , 29 ], and one had a high risk of bias [ 40 ]. The most prevalent sources of bias arose through incomplete or inadequate reporting on details such as randomisation, blinding, attrition and, in some cases, selective reporting.

Risk of bias summary using the revised Cochrane risk of bias tool for randomised trials (RoB 2). Five domains are reported: D1 (randomisation process); D2 (deviations from the intended interventions); D3 (missing outcome data); D4 (measurement of the outcome) and D5 (selection of the reported result). ‘ + ’ low risk of bias; ‘!’ some concerns, and ‘- ‘ high risk of bias

Risk of bias summary using the revised Cochrane risk of bias tool for cross-over trials (RoB 2). Six domains are reported: D1 (randomisation process); DS (bias arising from period and carryover effects); D2 (deviations from the intended interventions); D3 (missing outcome data); D4 (measurement of the outcome) and D5 (selection of the reported result). ‘ + ’ low risk of bias; ‘!’ some concerns, and ‘- ‘ high risk of bias

Risk of bias summary using the revised Cochrane risk of bias tool for non-randomised studies—of Interventions (ROBINS-I). Seven domains are reported: D1 (confounding); D2 (selection of participants into the study); D3 (classification of interventions); D4 (deviations from intended interventions); D5 (missing data); D6 (measurement of outcomes) and D7 (selection of the reported result). ‘ + ’ low risk of bias; ‘!’ some concerns, and ‘- ‘ high risk of bias

One study did not counterbalance the order in which treatments were imposed [ 22 ], and six studies had some concerns over selection bias [ 17 , 25 , 30 , 31 , 36 , 40 ] as they reported insufficient detail to fully explain how participants were selected for inclusion in the trial (Table 2 ). Ten studies were judged to have some concerns over the blinding of participants and personnel [ 17 , 19 , 22 , 25 , 27 , 29 , 30 , 31 , 36 , 40 ]. Whilst the blinding of participants is not possible with a gum chewing intervention, study personnel should have been blinded where possible. In many cases, blinding of study personnel was not reported which resulted in some concerns over bias. Thirteen studies were judged to have some concerns over bias due absent or unreported blinding of outcome assessment [ 17 , 19 , 22 , 25 , 26 , 27 , 29 , 30 , 31 , 34 , 36 , 37 , 40 ]. Three studies were judged to have some concerns over bias due to incomplete outcome data [ 22 , 26 , 38 ]. In these cases it was not possible to determine whether all the participants recruited had completed the study. Levels of attrition (if present) were not reported, and degrees of freedom were not quoted to indirectly ascertain the sample sizes present in the analysis. Nine studies were judged to have some concerns over bias due to selective reporting [ 17 , 22 , 23 , 25 , 27 , 29 , 36 , 37 , 40 ]. In most cases, this risk arose through the partial reporting of either the objective (e.g. saliva flow rates) or subjective (e.g. self-reported relief from xerostomia) outcome measures. Four studies were judged to have some concerns over bias due to other sources [ 17 , 19 , 23 , 25 ]. These sources included imbalanced groups [ 19 ], potentially confounded treatments [ 17 ], unclear statistical analysis [ 23 ] and saliva collection protocols [ 23 , 25 ].

Effect of gum chewing on unstimulated rate of salivation

Six studies contained data suitable for inclusion in the meta-analysis (Table 3 ). Three of these studies were of patients undergoing dialysis [ 18 , 26 , 31 ], one was of an elderly population [ 17 ], one was of patients with rheumatism [ 36 ], and one was a population of patients with diagnosed xerostomia / hyposalivation [ 34 ].

Each of the studies had some overall concerns over bias. It was decided to include these studies because the primary outcome measure (salivary flow rate) was less likely to be biased by factors such as blinding of participants and personnel than subjective measures such as self-reports. However, this assumption was tested through sensitivity analysis and measures of heterogeneity.

The meta-analysis results are presented in the forest plot in Fig.  5 . There was a significant overall effect of gum on saliva flow outcomes compared to control (SMD = 0.44, 95% CI: 0.22—0.66; p  = 0.00008; I 2  = 46.53%). The effect is small but certain, heterogeneity is average but less than 50%.

Forest plot

Heterogeneity

Heterogeneity between the studies was assessed using graphic exploration with funnel plots in Fig.  6 .

Funnel plot

The results show that nearly all the studies are inside the funnel. One study, however, has a large SMD and lies outside the triangle as it has a large mean difference.

Sensitivity analysis

To assess the stability of the results and outlier analysis using a “leave one out” approach was conducted. In this approach studies were removed one by one, and the random effect model was fitted on the remaining studies. Figure  7 shows that the results remain stable for both the effect direction and magnitude.

Effect of duration of gum chewing on unstimulated salivary flow rate

Because of the moderate heterogeneity, we used meta-regressions to investigate how the duration of the chewing intervention influenced unstimulated salivary flow rate. The results show significant decrease in heterogeneity when I 2 is less than 1%. The results show also that the rate of salivation increased by 0.06 standard deviations per week ( p  < 0.001).

The bubble plot shows the estimated regression slope, as well as the effect size of each study (Fig.  8 ). To indicate the weight of a study, the bubbles have different sizes, with a greater size representing a higher weight.

Meta-regression bubble plot

The objective of this systematic review and meta-analysis was to investigate if gum chewing is associated with objective improvements in saliva output and subjective relief from xerostomia. Xerostomia is a condition with multiple possible aetiologies, including use of prescribed and over-the-counter medications, recreational drug use, rheumatic or autoimmune conditions, such as Sjögren’s syndrome, and radiation therapy for head and neck cancers [ 4 ]. Other associated causes include primary and secondary effects of aging [ 41 ], stress [ 42 ], and the multifactorial effects of chronic haemodialysis [ 43 ]. The physiological, neurological and cellular control of saliva secretion is complex and therefore susceptible to disruption at various levels of control. In addition, there is no consistent correlation between the subjective symptoms of xerostomia and objective measures of salivary gland function (i.e., saliva flow rates [ 3 ]). Owing to the heterogeneity of aetiological factors and the disconnect between objective and subjective measures, xerostomia is not a diagnosis or single disease entity, and certain therapeutic approaches may not be applicable to all sufferers. Both chronic haemodialysis and aging can result in salivary gland hypofunction and xerostomia due to multiple factors, including glandular fibrosis, medication use and fluid restriction [ 41 , 43 ]. In contrast, Sjögren’s syndrome and radiation therapy are conditions in which the cellular secretory mechanism is irreversibly damaged and likely not responsive to stimuli such as chewing gum. However, it is apparent from several studies included in this review that stimulation of salivary flow using chewing gum has the potential to improve either subjective symptoms or objective measures of salivary output regardless of aetiology, so we elected not to constrain the breadth of the review by limiting the analysis to specific known aetiologies of xerostomia. The meta-analysis allowed assessment of the objective outcome of unstimulated whole saliva flow rate in six studies, including three conducted on kidney dialysis patients [ 18 , 26 , 31 ], one on subjects with self-reported xerostomia due to different medical conditions [ 34 ], one on older adults over 65 [ 17 ], and one on rheumatic patients with dry mouth [ 36 ]. Although we could not confirm that the effect of mastication or chewing gum is independent of the aetiology of the condition, we would argue the results of the meta-analysis suggests that where the effect is multifactorial (dialysis, aging), the effect of chewing was more apparent than in the studies that included patients with autoimmune conditions [ 34 , 36 ] and/or post-radiation therapy [ 34 ].

• Systematic review

In accordance with the commentaries made by other reviewers [ 8 ], a large proportion of the studies reviewed included patients under dialysis [ 18 , 21 , 23 , 26 , 27 , 29 , 30 , 31 ], or with specific conditions such as cancer [ 19 , 25 , 33 ], heart disease [ 16 ], or rheumatism [ 36 ]. The extent to which the aetiology of xerostomia in such studies can be compared with other studies where participants were recruited due to a history of dry mouth [ 20 , 24 , 34 , 37 , 38 , 39 , 40 ] or by age [ 17 , 22 , 28 , 32 , 35 ] remains uncertain. However, chewing gum is unlikely to have an impact on xerostomia where salivary gland tissue has been ablated by radiation therapy or other catastrophic medical/surgical causes. In accordance with this proposition, the two studies of patents being treated for head, neck or oral cancers in the present review were unable detect a significant effect of gum chewing on unstimulated saliva flow rate [ 19 , 25 ]. In these cases, emerging treatments such as salivary gland regeneration, repair, or replacement may be more appropriate therapies [ 44 , 45 ].

Historically, a number of questionnaires have been developed to measure the presence and severity of xerostomia [ 46 ]. Initially Fox et al. (1987) defined nine questions related to xerostomia which predicted low saliva flow rates [ 3 ]. Later, the 11-item Xerostomia Inventory (XI) was proposed by Thomson et al. (1999) to develop valid multi-item method of measuring the symptoms of xerostomia which includes the wide range of xerostomia symptoms in a single quantitative measure [ 47 ]. An associated instrument was also proposed by Torres et al. (2002) which was based on 10 questions [ 48 ]. Other instruments have been developed for specific populations. For example, to measure quality of life in patients with head and neck cancer, measurements related to dry mouth / xerostomia are also included in the EORTC QLQ-H&N35 questionnaire developed by Bjordal et al. [ 49 ].

Of the studies that measured saliva flow rates, 13 studies also collected self-reported xerostomia data (e.g. xerostomia inventory [ 21 , 26 , 27 , 31 ], EORTC QLQ-H&N35 questionnaires [ 19 , 25 ], symptoms of dry mouth questionnaire [ 17 , 24 ] or other questionnaire-based instruments [ 34 , 40 ], visual analogue scales [ 18 , 23 , 38 ], and interviews [ 37 ]). There was insufficient data to conduct a meta-analysis to investigate whether increases in the rate of salivation were associated with self-reported relief from xerostomia. We had hoped to conduct a meta-analysis on self-reported data, however, the types of index used across the studies were inconsistent. It is recommended that experts align on a common instrument for future studies to allow direct comparison and meta-analysis.

Garcia et al. [ 8 ] reviewed 12 studies on the effect of chewing gum on thirst in healthy and unhealthy adults. Five of these studies found that chewing gum increased salivary flow [ 25 , 27 , 37 , 38 , 50 ]. Seven studies found that chewing gum increased xerostomia relief [ 26 , 27 , 30 , 31 , 33 , 34 , 37 ], and four studies found that chewing gum increased thirst reduction [ 26 , 27 , 30 , 31 ]. Garcia et al. [ 8 ] concluded that gum chewing resulted in increased salivary flow, xerostomia relief, and thirst reduction.

• Meta-analysis

The reported effects of gum chewing on saliva flow rate across the individual studies of the systematic review were ambiguous. Nine of the 19 studies that measured stimulated and/or unstimulated saliva flow rate found a positive effect whereas 10 studies did not detect an effect (see Results section). In the absence of reported power analyses it is uncertain whether the numbers of participants were sufficient to detect an effect. However, meta-analysis can provide a more precise estimate of the effect of treatment or outcomes than any individual study contributing to the pooled analysis [ 51 ].

To the best of our knowledge, this is the first time meta-analysis has been applied to assessment of the effect of chewing gum as an intervention for dry mouth. A meta-analysis was neither included in the integrative review conducted by Garcia et al. [ 6 ], nor the Cochrane Collaboration review [ 7 ]. A recent review on the efficacy of malic acid mouth sprays on xerostomia and salivary flow rates included meta-analysis of flow rate data and, showed a significant effect of the treatment on unstimulated saliva flow rates [ 52 ] and, in the present review, our meta-analysis confirmed a small, statistically significant effect of mastication on unstimulated rate of salivation in challenged populations. An average level of heterogeneity was present in the results and the funnel plot suggested some publication bias might have been present. A meta-regression found that the duration of the intervention influences the changes in salivation rate, with longer periods of chewing being associated with higher rates of salivation (in the range 2 – 12 weeks).

Our meta-analysis could be criticised for including studies that had some concerns over the overall risk of bias. However, in many cases the potential sources of bias were a lack of reporting on issues such as blinding (which is acknowledged to be difficult / impossible in studies of gum chewing) and randomisation. To address these issues, we investigated the potential impacts of any potential biases through sensitivity analysis and by examining the levels of heterogeneity. The sensitivity analysis confirmed that no one study was leveraging the outcome and that the results remained stable for both the effect direction and magnitude.

Variation in the methodologies used in the individual studies included in the meta-analysis could have influenced the direction and effect size detected. For example, it is possible that differences in how the chewing intervention was imposed (e.g. type and flavour of gum, frequency and duration of chewing, etc.). In addition, the methodologies used to measure saliva flow rates could have influenced the outcome. A range of different chewing gums were used across the studies included in the systematic review. However, in the meta-analysis, the gum chewing interventions were more consistent. Five studies used commercially available gums sweetened with aspartame or sorbitol or xylitol [ 7 , 32 , 33 , 34 , 53 ], and one used a prototype gum produced specifically for the study (no medicinal additives) [ 17 ]. Ozen et al. (2021), Bots et al. (2005b) and Fan et al. (2013) [ 18 , 26 , 30 ] required participants to chew for 10 min, six times per day and when their mouth felt dry or they were thirsty. Kim et al. [ 17 ] required participants to chew for 10 min, two times per day. Stewart et al. [ 34 ] instructed participants to chew ad libitum in accordance with the manufacturer’s instructions, and Risheim & Arneberg [ 36 ] instructed participants to chew for 30 min, two times per day on days 1–4 of the intervention, and five times per day on days 5–14 of the intervention.

The systematic review found that the protocols used to measure the unstimulated rate of salivation were reasonably consistent across the studies included in the meta-analysis [ 17 , 18 , 26 , 30 , 34 , 36 ]. All of the studies, with the exception of one [ 36 ], reported that participants were requested to refrain from eating and drinking pre-sampling. However, the time specified ranged from 30 min [ 18 ], to either one hour [ 17 , 26 , 30 ] or two hours [ 34 ] pre-sampling. In addition to restricting the consumption of food and drink, four studies also required participants to refrain from smoking [ 17 , 26 , 30 , 34 ], and four studies required participants refrain from any oral hygiene activity such as tooth brushing [ 18 , 26 , 30 , 34 ]. Three studies used a total saliva collection period of 5 min [ 17 , 26 , 30 ], whereas one used a period of 10 min [ 34 ], and another 3 min [ 36 ]. In Bots et al. [ 30 ], participants were required to rinse their mouth with tap water to alleviate thirst and xerostomia. The temperature of the water was not specified. Measurements of saliva flow rate appear to be largely unaffected by collection time, but Gill et al. (2016) found 60% of the participants had a higher saliva flow rate after rinsing with water at a temperature of 10 °C compared with water at 20 and 30 °C [ 54 ]. In many cases it was not clear at which time of day the saliva samples were collected or whether this was standardised between collection sessions. It has been found that there are significant circadian rhythms in unstimulated saliva flow rate [ 55 ]. It is possible that the small variations in the saliva collection protocols may have introduced variability into the data which, in turn, may have influenced the size of effect detected. Navazesh and Kumar (2008) described techniques for measuring unstimulated and stimulated salivary flow, including a five-minute collection time for unstimulated saliva and refraining from eating, drinking, smoking and chewing gum for one hour before collection [ 56 ]. Consistent use of these methods in future studies would facilitate easier comparisons between studies.

In a study of 191 participants (aged 18–65 years) it was found that a history of frequent gum chewing was associated with higher unstimulated salivary flow rate [ 57 ] and, in an earlier study, healthy subjects instructed to chew gum regularly for eight weeks showed increased unstimulated saliva flow rates [ 58 ]. Gueimonde et al. (2016) found twice daily gum chewing progressively increased unstimulated saliva flow rates in 52 subjects over three months, becoming significant after two months compared to baseline [ 24 ]. This makes gum chewing an attractive alternative to pharmaceutical options, either prescription or ‘over the counter’, that may be less palatable, have side-effects, or are simply not as convenient to use. There also remains the intriguing possibility that functional stimulation of the salivary glands by increased mastication over time can increase either the basal (unstimulated) saliva flow rate or stimulated flow rate, at least in subjects without physical damage to, or loss of, the acinar cells. This was suggested by the results of the meta-analysis in the present study but is also in other studies not included in this analysis. For example, Guiemonde et al. [ 24 ] reported that the mean unstimulated saliva flow rate in healthy subjects with hyposalivation increased steadily in all subjects for three months of twice-daily chewing gum use and remained at the higher level for a month following cessation of the chewing regimen. Similarly, in a study of institutionalised, frail elderly subjects who chewed gum two times a day for 12 months, Simons et al. [ 35 ] demonstrated significant incremental increases in stimulated salivary flow rates in gum chewing subjects.

Limitations of the review and meta-analysis

A key limitation of any systematic review and meta-analysis is that of publication bias. There is a preference to publish studies that have statistically significant results despite the clinical significance of studies that do not detect significant results. In addition heterogeneity in study design, population, intervention, or outcome measures can make it challenging to draw a definitive conclusion about the effectiveness of the intervention being studied. The quality of studies included can vary, which can affect the overall quality of the review (although this can be managed to an extent through the use of risk of bias tools). Meta-analyses are typically based on summary data, making it challenging to control for confounding factors that may influence the results. Therefore, it is essential to interpret the results with caution, considering the potential sources of bias and confounding that may have affected the results.

Chewing sugar-free gum is one of many options available to manage xerostomia and symptoms of dry mouth. Our review and that of other authors suggests that chewing sugar-free gum provides relief from xerostomia, and that chewing gum daily over a period of two or more weeks increases the rate of unstimulated salivation. As xerostomia negatively affects a large proportion of both the non-institutionalised older adult population (39%), and of the general population (21.3% in men and 27.3% in women), interventions involving gum chewing offer potential to improve Oral Health Quality of Life (especially in challenged populations). Sugar-free gum is low cost, readily available, safe, is not a drug, has minimal side-effects, and is generally preferred by users to other options, such as artificial salivas. However, additional work is required to unequivocally define the relationships between gum chewing, increased salivation rate and self-reported relief from xerostomia. Progress in this regard has been hampered by a lack of standardisation on the instruments used to measure self-reported xerostomia. We also recommend that future studies clearly differentiate chronic effects of chewing on salivary flow rates from the acute effects of chewing, and if possible measure both stimulated and stimulated salivary flow rates using standardised techniques as described by Navazesh and Kumar [ 56 ].

Availability of data and materials

All data generated or analysed during this study are included in this published article.

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The authors are grateful to Dr. Heleen van de Weerd (Director, Cerebrus Advies BV, Netherlands) for her comments on the manuscript.

This review and meta-analysis was sponsored by Mars Wrigley.

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M.D. conceptualised the study. J.D. and M.D. elaborated the methods of the study. J.D., M.D. and M.B.H. extracted and analysed the data. M.B.H. conducted the meta-analysis. J.D. wrote the first draft of the manuscript, and M.D. and J.D. revised and prepared the final version for submission. All authors have read and agreed to the published version of the manuscript.

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Dodds, M.W.J., Haddou, M.B. & Day, J.E.L. The effect of gum chewing on xerostomia and salivary flow rate in elderly and medically compromised subjects: a systematic review and meta-analysis. BMC Oral Health 23 , 406 (2023). https://doi.org/10.1186/s12903-023-03084-x

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Xerostomia is an underrecognized adverse effect of immunotherapy (IO) that can significantly impact patients’ quality of life by leading to poor nutritional status, dental caries, and oral candidiasis. The purpose of this case series was to describe the onset, severity, clinical course, and management of IO-induced xerostomia.

This was a retrospective case series conducted at an outpatient cancer center. Data collection was conducted via chart review. The severity of dry mouth symptoms was graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Six patients with advanced solid tumors who received a PD-1 inhibitor or PD-1/CTLA-4 inhibitor combination therapy were evaluated. The median time to onset of xerostomia was 4.5 months overall, though symptoms developed sooner in patients who received IO as subsequent-line therapy (median = 1.9 months). All patients developed other immune-related adverse events (IRAEs) such as hypothyroidism. Five patients (83%) had grade 2 dry mouth symptoms, and similarly, 5 patients eventually required prescription medications such as sialogogues and topical or systemic corticosteroids to alleviate symptoms. Two patients (33%) required interruptions in IO. All 3 patients who received cevimeline noticed improvement in symptoms, and one patient who received prednisone dosed at 1 mg/kg/day tapered over 5 weeks also experienced significant relief.

While the optimal management of IO-induced xerostomia has not yet been established by national guidelines, increased awareness can prompt faster initiation of supportive care measures that can prevent significant discomfort and poor oral intake. Thoughtful use of over-the-counter topical agents, sialogogues, corticosteroids, and treatment interruptions can help improve tolerability of this adverse effect.

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Oral mucositis—case series of a rare adverse effect associated with immunotherapy

Xerostomia in patients with advanced cancer: a scoping review of clinical features and complications

MASCC/ISOO clinical practice guidelines for the management of mucositis: sub-analysis of current interventions for the management of oral mucositis in pediatric cancer patients

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All pertinent data are reported within this case series. No software or custom codes were used to analyze data for this case series.

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Hannah Bustillos, Amy Indorf, Laura Alwan, John Thompson & Lindsey Jung

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Bustillos, H., Indorf, A., Alwan, L. et al. Xerostomia: an immunotherapy-related adverse effect in cancer patients. Support Care Cancer 30 , 1681–1687 (2022). https://doi.org/10.1007/s00520-021-06535-9

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DOI : https://doi.org/10.1007/s00520-021-06535-9

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Saliva, or spit, is made by the salivary glands and is very important for a healthy mouth. It moistens and breaks down food, washes away food particles from the teeth and gums, and helps people with swallowing. In addition, saliva contains minerals such as calcium and phosphate that help keep teeth strong and fight tooth decay.

Dry mouth, also called xerostomia (ZEER-oh-STOH-mee-ah), is the condition of not having enough saliva to keep the mouth wet. Dry mouth can happen to anyone occasionally—for example, when nervous or stressed. However, when dry mouth persists, it can make chewing, swallowing, and even talking difficult. Dry mouth also increases the risk for tooth decay or fungal infections in the mouth because saliva helps keep harmful germs in check.

Dry mouth is not a normal part of aging. If you think you have dry mouth, see your dentist or doctor to find out why your mouth is dry.

There are several possible causes of dry mouth:

• Side effects of some medicines. Hundreds of medicines can cause the salivary glands to make less saliva. For example, medicines for high blood pressure, depression, and bladder-control issues often cause dry mouth.
• Disease.  Sjögren's disease, HIV/AIDS, and diabetes can all cause dry mouth.
• Radiation therapy. The salivary glands can be damaged if they are exposed to radiation during cancer treatment.
• Chemotherapy and immunotherapy. Drugs used to treat cancer can make saliva thicker, causing the mouth to feel dry.
• Nerve damage. Injury to the head or neck can damage the nerves that tell the salivary glands to make saliva.

Brochure for patients covering the causes of dry mouth and the importance of saliva to oral health.

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Symptoms of dry mouth include:

• A sticky, dry feeling in the mouth.
• Trouble chewing, swallowing, tasting, or speaking.
• A burning or itchy feeling in the mouth or throat.
• A dry feeling in the throat.
• Cracked lips.
• A dry, rough, red, ‘hairy’, or deeply fissured/cracked appearance.
• Mouth sores.
• Recurrent infections of the mouth or the throat.
• Bad breath.

Your doctor or dentist will review your medical history and ask about any medications you take. He or she may also suggest blood tests or a test that measures how much saliva you produce.

Depending on the cause of your dry mouth, your health care provider can recommend appropriate treatment. For example, if medication is causing dry mouth, the doctor or dentist may advise changing medications or adjusting the dosages, or may prescribe a saliva substitute. Your health care provider may also suggest the use of artificial saliva or other special products to prevent stickiness and keep your mouth wet.

There are also self-care steps you can take to help ease dry mouth, such as drinking plenty of water, chewing sugarless gum, and avoiding tobacco and alcohol. Good oral care at home and regular dental check-ups will help keep your mouth healthy.

You can relieve dry mouth symptoms by:

• Drinking plenty of water, 8 to 12 cups per day (64–96 ounces or 2-3 liters).
• Sipping water or a sugarless drink during meals. This will make chewing and swallowing easier. It may also improve the taste of food.
• Avoiding or limit drinks with caffeine, such as coffee, tea, and some sodas. Caffeine can dry out the mouth and lead to dehydration.
• Chewing sugarless gum or suck on sugarless hard candy to stimulate saliva flow; citrus, cinnamon, or mint-flavored candies are good choices. Some sugarless chewing gums and candies contain xylitol and may help prevent cavities. 
• Being aware that spicy or salty foods may cause pain or a burning sensation in a dry mouth.
• Not using tobacco or alcohol. They dry out the mouth.
• Using a humidifier at night.
• NIH MedlinePlus Magazine – Summer 2020 TV personality Carrie Ann Inaba talks about her experience with Sjögren's disease; NIDCR shares the latest research on Sjögren’s and answers questions about dry mouth, a common symptom.
• MedlinePlus: Dry Mouth The NIH National Library of Medicine's collection of links to government, professional, and non-profit/voluntary organizations with information on dry mouth.
• Sjögren’s Foundation The Sjögren’s Foundation educates patients and their families about Sjögren’s, increases public and professional awareness of the condition, and encourages research into new treatments and a cure.
• Quit Smoking  from the Centers for Disease Control and Prevention.

Fact sheet on dry mouth and how to get relief.

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Fact sheet on maintaining oral health for a lifetime.

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Dry Mouth Research from NIDCR

• Turning the Tap Back On
• Your Mouth on a Chip
• Mimicking Mother Nature to Grow an Artificial Gland
• Pioneering Gene Therapy for Dry Mouth

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Kratom: unsafe and ineffective.

Users swear by kratom for mood enhancement and fatigue reduction, but safety issues and questions about its effectiveness abound.

If you read health news or visit vitamin stores, you may have heard about kratom, a supplement that is sold as an energy booster, mood enhancer, pain reliever and antidote for opioid withdrawal. However, the truth about kratom is more complicated, and the safety problems related to its use are concerning.

Kratom is an herbal extract that comes from the leaves of an evergreen tree (Mitragyna speciosa) grown in Southeast Asia. Kratom leaves can be chewed, and dry kratom can be swallowed or brewed. Kratom extract can be used to make a liquid product. The liquid form is often marketed as a treatment for muscle pain, or to suppress appetite and stop cramps and diarrhea. Kratom is also sold as a treatment for panic attacks.

Kratom is believed to act on opioid receptors. At low doses, kratom acts as a stimulant, making users feel more energetic. At higher doses, it reduces pain and may bring on euphoria. At very high doses, it acts as a sedative, making users quiet and perhaps sleepy. Some people who practice Asian traditional medicine consider kratom to be a substitute for opium.

Some people take kratom to avoid the symptoms of opioid withdrawal and because kratom may be bought more easily than prescription drugs.

Kratom is also used at music festivals and in other recreational settings. People who use kratom for relaxation report that because it is plant-based, it is natural and safe. However, the amount of active ingredient in kratom plants can vary greatly, making it difficult to gauge the effect of a given dose. Depending on what is in the plant and the health of the user, taking kratom may be very dangerous. Claims about the benefits of kratom can't be rated because reliable evidence is lacking.

Side effects and safety concerns

Although people who take kratom believe in its value, researchers who have studied kratom think its side effects and safety problems more than offset any potential benefits. Poison control centers in the United States received about 1,800 reports involving use of kratom from 2011 through 2017, including reports of death. About half of these exposures resulted in serious negative outcomes such as seizures and high blood pressure. Five of the seven infants who were reported to have been exposed to kratom went through withdrawal. Kratom has been classified as possibly unsafe when taken orally.

Kratom has a number of known side effects, including:

• Weight loss
• Chills, nausea and vomiting
• Changes in urine and constipation
• Liver damage
• Muscle pain

Kratom also affects the mind and nervous system:

• Hallucinations and delusion
• Depression and delusion
• Breathing suppression
• Seizure, coma and death

Kratom takes effect after five to 10 minutes, and its effects last two to five hours. The effects of kratom become stronger as the quantity taken increases. In animals, kratom appears to be more potent than morphine. Exposure to kratom has been reported in an infant who was breastfed by a mother taking kratom.

Many of the problems that occur with pain medications happen when these drugs are used at high doses or over a long period of time. It's not known exactly what level of kratom is toxic in people, but as with pain medications and recreational drugs, it is possible to overdose on kratom.

Research shows little promise

At one time, some researchers believed that kratom might be a safe alternative to opioids and other prescription pain medications. However, studies on the effects of kratom have identified many safety concerns and no clear benefits.

Kratom has been reported to cause abnormal brain function when taken with prescription medicines. When this happens, you may experience a severe headache, lose your ability to communicate or become confused.

In a study testing kratom as a treatment for symptoms of opioid withdrawal, people who took kratom for more than six months reported withdrawal symptoms similar to those that occur after opioid use. Too, people who use kratom may begin craving it and require treatments given for opioid addiction, such as naloxone (Narcan) and buprenorphine (Buprenex).

Kratom also adversely affects infant development. When kratom is used during pregnancy, the baby may be born with symptoms of withdrawal that require treatment.

In addition, substances that are made from kratom may be contaminated with salmonella bacteria. As of April 2018, more than 130 people in 38 states became ill with Salmonella after taking kratom. Salmonella poisoning may be fatal, and the U.S. Food and Drug Administration has linked more than 35 deaths to Salmonella-tainted kratom. Salmonella contamination has no obvious signs, so the best way to avoid becoming ill is to avoid products that may contain it.

Kratom is not currently regulated in the United States, and federal agencies are taking action to combat false claims about kratom. In the meantime, your safest option is to work with your doctor to find other treatment options.

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• Kruegel AC, et al. The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology. In press. Accessed May 2, 2018.
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• Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, M.D., on FDA advisory about deadly risks associated with kratom. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584970.htm. Accessed April 17, 2018.
• Voelker R. Crackdown on false claims to ease opioid withdrawal symptoms. JAMA. 2018;319:857.
• Post S. Kratom exposures reported to United States poison control centers: 2011-2017. Clinical Toxicology. Published online February 20, 2019.
• Drug Enforcement Administration. Kratom—drug fact sheet. https://www.dea.gov/sites/default/files/2020-06/Kratom-2020.pdf. Accessed January 26, 2022.
• Therapeutic Research Center. Kratom. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1513. Accessed January 26, 2022.
• Umbehr G, et al. Acute liver injury following short-term use of the herbal supplement kratom. JAAPA. 2022;35:39.
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