Introduction

Kratom (Mitragyna speciosa Korth.), a tropical evergreen tree native to Southeast Asia, has been used for centuries in traditional medicine, particularly in Thailand, Malaysia, and Indonesia1,2. The leaves of the plant are traditionally consumed by chewing or brewing them as a tea to alleviate fatigue, enhance work productivity, and manage pain1. The plant’s pharmacological effects are primarily attributed to its active alkaloids, mitragynine and 7-hydroxymitragynine, which exert complex, dose-dependent effects, ranging from stimulant-like activity at low doses to opioid-like analgesia at higher doses2,3.

In recent years, kratom has gained significant popularity beyond its traditional contexts, with a growing global user base seeking it for therapeutic and recreational purposes4. This expansion, coupled with a shifting legal landscape, including its decriminalization in Thailand in 2021, has intensified the scientific and regulatory debate surrounding its safety profile. The existing evidence remains fragmented and often contradictory. On the one hand, numerous case reports have suggested a potential link between kratom consumption and organ toxicity, particularly hepatotoxicity and nephrotoxicity5. On the other hand, some systematic reviews and community-based studies, especially among traditional users in Malaysia, have reported no significant alterations in major hematological or biochemical parameters, even with long-term, high-quantity use6.

This conflicting evidence highlights a critical knowledge gap, particularly regarding the long-term physiological effects of traditional consumption patterns in endemic regions. This ambiguity leaves kratom users, health providers, and policymakers without evidence-based guidance and robust data to inform harm-reduction strategies. Southern Thailand, where kratom use is a long-standing cultural practice, presents a unique opportunity to address this gap7. The region provides a valuable setting to compare habitual users and non-users who share a similar demographic and environmental context. A systematic investigation is urgently needed to provide robust, population-based evidence on kratom’s subclinical health impacts, which is essential for informing public health policy, harm-reduction strategies, and clinical guidance for healthcare providers. Furthermore, the relationship between the dose and duration of use and potential physiological changes remains poorly understood4,5.

It should be noted that the participants in this study were recruited as part of a larger community-based health surveillance project in the Nam Phu sub-district. Previous reports from this cohort have focused specifically on lipid profiles8 and metabolic syndrome parameters9. However, the present study investigates entirely distinct physiological parameters that have not been reported elsewhere. Unlike the previous publications, which were restricted to metabolic indices, this study provides a comprehensive analysis of hematological parameters (complete blood count) and clinical chemistry markers specifically related to liver and kidney function. This distinct dataset addresses the need for a broader understanding of the physiological safety profile of traditional kratom users beyond metabolic health.

Therefore, this study aimed to (1) compare key hematological and clinical-chemistry parameters, including liver and kidney function markers, between traditional kratom users and non-users in a large community-based sample in Southern Thailand, and (2) examine the association between the duration and quantity of kratom consumption and these physiological parameters among users.

Materials and methods

Study design and setting

This study utilized data from a large cross-sectional project conducted in the Nam Phu sub-district, Surat Thani province, located in Southern Thailand. The characteristics of the study population and data collection procedures have been described in detail elsewhere8,9. The present study focuses on a novel, in-depth analysis of hematological and a broad range of clinical-chemistry parameters. This area was selected as the community has been permitted to use kratom according to traditional practices under the “Nam Phu Sub-district Charter,” a local community agreement established in 2017. The reporting of this study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines10.

Study participants

The study population consisted of 581 individuals aged 18 years or older who had resided in the Nam Phu sub-district for at least one year. Participants were categorized into two groups: Kratom users, defined as individuals who had used kratom within the past 12 months and were officially registered under the community charter agreement; and non-users, defined as individuals with no history of kratom use within the past 12 months. To control for the potential confounding effect of age, the non-user group was matched to the user group to ensure a similar age structure. Exclusion criteria for all participants included pregnancy, a history of illicit substance use (other than kratom), and the inability to communicate clearly. All participants were fully informed about the study’s objectives and procedures, and written informed consent was obtained prior to their enrollment.

Data collection and measurements

Data were collected through face-to-face interviews using a structured questionnaire administered by trained research staff. The questionnaire gathered information on sociodemographic characteristics, health-related behaviors, medical history, and current medication use. For kratom users, data on the duration of use (in years) and the daily quantity of consumption (in number of leaves) were also collected. Height and weight were measured to calculate the body mass index (BMI).

The questionnaire was developed based on a literature review and validated for content validity by five experts using the Index of Item-Objective Congruence (IOC). Only items with an IOC index ≥ 0.5 were included in the final version. The English version of the questionnaire is provided as “Supplementary File S1”.

Laboratory procedures

Participants were instructed to fast for 12 h overnight before blood sample collection. On the morning of the appointment, a 3-ml sample of venous blood was drawn by a certified medical technologist at the Ban Yang Ung Health Promoting Hospital. The samples were then transported to the laboratory unit of Ban Na San Hospital, which is accredited by the Medical Technology Council of Thailand, for analysis within one hour of collection. For hematological analysis, a complete blood count (CBC) was performed using an automated hematology analyzer (Nihon Kohden Cell Counter, models 7222 and 8222). Concurrently, clinical-chemistry parameters, including liver function tests, kidney function tests, and blood glucose/HbA1c levels were analyzed using an automated chemistry analyzer (Dimension EXL 200).

Statistical analysis

All data were analyzed using SPSS version 30.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics, including means, standard deviations (SD), frequencies, and percentages, were used to summarize the baseline characteristics of the study participants. Bivariate analyses were conducted to compare the two groups. The Independent Samples t-test was used for continuous variables (e.g., hematological and biochemical parameters), while the Chi-square test was used for categorical variables (e.g., sex, smoking status). Furthermore, analysis of covariance (ANCOVA) was used to compare the mean hematological and clinical-chemistry parameters between kratom users and non-users, as well as among kratom users stratified by duration and quantity of use, after controlling for potential confounding variables. Covariates included in the adjusted model were age, sex, body mass index (BMI), current smoking status, and current alcohol consumption. A p-value of < 0.05 was considered statistically significant for all tests.

Results

Sociodemographic characteristics and health behaviors

A total of 581 participants were included in the final analysis, comprising 285 kratom users and 296 non-users. The sociodemographic characteristics and health behaviors of the participants are presented in Table 1. The mean age of the two groups was nearly identical (55.8 ± 11.4 vs. 55.7 ± 12.0 years, p = 0.963). However, significant baseline differences were observed for several key variables. The kratom user group had a significantly higher proportion of males (78.6% vs. 29.7%, p < 0.001) and a lower mean BMI (23.1 ± 3.9 vs. 25.2 ± 4.8 kg/m2, p < 0.001).

Table 1 Sociodemographic characteristics and health behaviors of participants, stratified by kratom use.
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Regarding health behaviors, kratom users reported significantly higher rates of current smoking (54.0% vs. 13.2%, p < 0.001) and current alcohol consumption (26.0% vs. 7.8%, p < 0.001). Conversely, non-users were more likely to engage in regular exercise (38.5% vs. 28.1%, p = 0.008). A history of cannabis and methamphetamine use was also more prevalent in the kratom user group. No significant differences were found in the use of prescribed medications for hypertension or diabetes between the groups.

Comparison of hematological parameters

The comparison of hematological parameters is shown in Table 2. In the unadjusted analysis, kratom users exhibited significantly higher mean values for white blood cells (WBC), red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC), and significantly lower platelet counts (all p < 0.05).

Table 2 Comparison of hematological parameters between kratom users and non-users.
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However, after adjusting for age, sex, BMI, current smoking, and current alcohol consumption, all of these differences became non-significant (p > 0.05). Importantly, the mean values for all hematological parameters in both groups fell within the normal reference ranges.

Comparison of clinical-chemistry parameters

The comparison of key clinical-chemistry markers for liver and kidney function is detailed in Table 3. Liver Function: In the unadjusted analysis, users showed slightly higher alkaline phosphatase levels (p = 0.022) and lower albumin levels (p = 0.008). However, after adjustment for confounders, no statistically significant differences were observed for any liver function markers, including AST, ALT, alkaline phosphatase, bilirubin, or plasma proteins (all p > 0.05). Kidney Function: A significant association was found with markers of renal function. In the adjusted model, kratom users had significantly lower serum creatinine levels (adjusted mean, male: 0.89 vs. 0.99 mg/dL, p < 0.001) and consequently a significantly higher estimated glomerular filtration rate (eGFR) (adjusted mean: 95.42 vs. 91.55 mL/min/1.73m2, p = 0.002) compared to non-users. Glycemic Control: There were no significant differences in fasting blood glucose or HbA1c between the two groups in either the unadjusted or adjusted analyses.

Table 3 Comparison of clinical-chemistry parameters (liver and kidney function) between kratom users (n = 285) and non-users (n = 296).
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Stratified analysis by duration and quantity of use

To control for potential confounders, an ANCOVA was conducted, adjusting for age, BMI, sex, smoking, and drinking history (Table 4). After adjusted comparison, long-term users (≥ 5 years) exhibited significantly lower levels of glucose (p < 0.001), HbA1c (p = 0.017), total protein (p = 0.023), albumin (p < 0.001), total bilirubin (p = 0.035), and direct bilirubin (p = 0.016) compared to short-term users (< 5 years). Quantity of Use (Table 5): After adjustment for potential confounders (age, BMI, sex, smoking, and alcohol drinking), significant differences were observed in renal function markers and serum protein levels. Users consuming higher quantities of kratom leaves exhibited significantly lower levels of creatinine (p = 0.004), BUN (p = 0.028), and albumin (p = 0.027) compared to those with lower consumption. No significant differences were observed for other hematological or liver function parameters across the quartiles of use.

Table 4 Comparison of key hematological and clinical-chemistry parameters among kratom users, stratified by duration of use, after adjustment for potential confounders.
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Table 5 Key hematological and clinical-chemistry parameters among kratom users, stratified by daily quantity of use.
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Sex-stratified analysis

Male participants (Table 6): In the male-only analysis, after adjusting for potential confounders, significant differences persisted in renal function markers. Male kratom users exhibited significantly lower creatinine levels (p < 0.001) and higher eGFR (p < 0.001) compared to male non-users. However, the previously observed differences in BUN and HbA1c were no longer statistically significant after adjustment.

Table 6 Comparison of hematological and clinical-chemistry parameters between male kratom users and male non-users.
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Female participants (Table 7): After adjusting for potential confounders, the associations with renal function markers observed in males were not present. However, significant differences persisted for specific hematological and biochemical parameters. Female kratom users exhibited significantly lower Red Cell Distribution Width (RDW) (p = 0.017) and serum albumin levels (p = 0.003) compared to female non-users.

Table 7 Comparison of hematological and clinical-chemistry parameters between female kratom users and female non-users.
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Discussion

In this large-scale, cross-sectional study conducted among a traditional kratom-using community in Southern Thailand, we found no evidence of clinically significant hematological or hepatic abnormalities associated with chronic kratom use after robust adjustment for confounding variables. However, our analysis revealed a complex and statistically significant association with markers of renal function and body composition, specifically lower serum creatinine, a consequently higher eGFR, and a lower BMI in kratom users. These findings challenge simplistic narratives of kratom’s physiological effects and highlight the critical importance of accounting for lifestyle and demographic factors in evaluating its health impacts.

Our unadjusted data initially suggested numerous differences in hematological indices between users and non-users, a finding consistent with some previous reports that have noted minor alterations in blood parameters11. However, a key finding of our study is that these associations lost statistical significance after adjusting for covariates, most notably sex, BMI, and smoking status. This powerfully demonstrates that lifestyle and demographic factors, rather than kratom use itself, are likely the primary drivers of these previously observed hematological variations. This underscores the critical need for multivariable adjustment in observational studies of substance use, as failure to do so can lead to spurious conclusions.

Similarly, while some case reports have raised concerns about kratom-induced hepatotoxicity12,13, our study found no significant differences in any liver enzyme markers (AST, ALT, ALP) or bilirubin levels between users and non-users in the adjusted analysis. Our findings align with other large-scale community-based studies in Malaysia, which also failed to detect significant liver injury in traditional, long-term users14. Furthermore, the general lack of adverse findings in our study is congruent with a prior report from this dataset which associated traditional kratom use with a favorable metabolic profile, including a reduced likelihood of metabolic syndrome9, likely attributable to the combined effects of increased physical activity in this manual-laborer population and the potential appetite-suppressing properties of kratom alkaloids. This suggests that within the context of traditional use, the risk of overt liver damage may be low, and that previously reported cases of hepatotoxicity might be idiosyncratic reactions, related to adulterants, or result from non-traditional patterns of use15.

A principal finding of this study is the association between kratom use and lower serum creatinine and higher eGFR, which persisted after multivariable adjustment. It is imperative to interpret this finding with caution. A conclusion of “improved kidney function” would be an over-interpretation of our cross-sectional data. Instead, we propose that the observed lower serum creatinine is likely attributable to differences in body composition.

Serum creatinine concentration is fundamentally a product of muscle metabolism, and directly proportional to muscle mass16. Although we did not directly measure lean body mass (e.g., via dual-energy X-ray absorptiometry), the kratom-using cohort had a significantly lower BMI compared to non-users. While BMI is not a perfect surrogate for muscle mass17, it is reasonable to infer that the lower body mass in users correlates with reduced muscle mass, thereby resulting in lower baseline creatinine production. Consequently, the calculated higher eGFR likely reflects this physiological difference rather than a direct pharmacological enhancement of renal clearance by kratom. This observation is consistent with a previous analysis from this cohort9. While our analysis adjusted for BMI, we acknowledge that residual confounding from unmeasured differences in lean body mass may persist18.

In our analysis utilizing self-reported consumption, we observed a significant dose-dependent relationship regarding renal function markers and serum protein. Specifically, higher consumption quantities were associated with progressively lower levels of creatinine, BUN, and albumin (Table 5). This inverse relationship aligns with the hypothesis of altered body composition or nutritional status in heavy users, given that BUN and albumin are sensitive markers of protein metabolism19. Conversely, we did not observe a linear dose–response relationship for the majority of other hematological or liver function biomarkers. This finding must be interpreted within the context of measurement limitations. The use of number of leaves as a unit of exposure is a semi-quantitative measure and lacks the precision of pharmacokinetic data (e.g., blood mitragynine concentrations). Variations in leaf size and alkaloid content, along with recall bias, introduce inherent noise to this variable20. Therefore, the absence of a statistical association for these other parameters does not definitively rule out dose-dependent physiological effects that might be detected with more precise exposure metrics. Nevertheless, even with these limitations, the observation that mean values for all groups remained within normal reference ranges, coupled with the lack of overt toxicity markers, provides reassurance regarding the safety profile of traditional use patterns.

We acknowledge the significant sex disparity between the user and control groups, which reflects the cultural demographics of traditional kratom use in this region. To address the potential for residual confounding by sex, we conducted sex-stratified analyses. Crucially, as shown in Table 6, the association with altered renal markers (lower creatinine and higher eGFR) remained highly statistically significant (p < 0.001) in the male-only cohort. This consistency demonstrates that the primary findings are not artifacts of sex imbalance in the total population, but represent robust associations within the principal user demographic.

Strengths

The present study has several notable strengths that enhance the validity of its findings. First, a key strength is the study’s large sample size, recruited from a community of traditional kratom users in an endemic region of Southern Thailand. This provides a robust assessment of long-term, culturally integrated use, a context rarely captured in the existing literature. Second, the inclusion of a non-user control group from the same community, which was frequency-matched for age, minimizes potential confounding from demographic and environmental factors. Finally, a primary strength is our use of multivariable statistical models to adjust for a comprehensive set of crucial covariates, including sex, BMI, smoking, and alcohol consumption. This robust adjustment allowed for a nuanced interpretation of kratom’s physiological correlates, distinguishing them from the effects of lifestyle factors.

Limitations

First, the primary limitation is the cross-sectional design, which, by its nature, captures exposure and outcome data at a single point in time and fundamentally precludes the establishment of a temporal sequence or definitive causal inference. Second, data on the duration and quantity of kratom use were based on self-reports, which may be subject to recall bias. Third, although our statistical models adjusted for crucial confounders, the potential for residual and unmeasured confounding remains. Fourth, the small sample size of female kratom users (n = 61) limits the statistical power and generalizability of the sex-stratified findings. Fifth, we did not directly measure lean body mass. Although BMI was used as a proxy for body size, it may not perfectly reflect muscle mass, limiting our ability to definitively attribute low creatinine levels solely to reduced muscle mass. Finally, the kratom products consumed by participants were not chemically analyzed, so variations in alkaloid potency or the presence of adulterants could not be assessed. Furthermore, we lacked pharmacokinetic data (e.g., blood mitragynine concentrations) to corroborate self-reported usage, which limits the precision of our dose–response analysis.

Conclusion

In conclusion, this study provides compelling evidence that in a real-world, traditional-use setting, chronic kratom consumption is not associated with clinically significant hepatic or hematological toxicity after accounting for crucial confounding factors. The observed association with altered renal markers is most plausibly explained by differences in body composition rather than a direct effect on kidney function. Our findings provide a nuanced perspective on the safety profile of traditional kratom use, suggesting the physiological impact is more subtle and multifaceted than previously reported. Prospective, longitudinal studies are urgently needed to confirm these findings and to delineate the true, long-term causal impact of kratom on renal and metabolic health.