TABLE 1.
Summary of reviewed literature.
| Author (year) | Study design, sampling, and sample size | Sample size calculation (Yes/No) | Objectives | Outcome measures | Findings | Limitations |
|---|---|---|---|---|---|---|
| Lu et al. (2014) | In vitro study with hiPSC-CMs | — | To investigate the cardiotoxicity of mitragynine and its analogs by studying their effects on hERG and APD | (1) IKr | (1) Mitragynine, paynantheine, speciogynine, and speciociliatine suppressed IKr in hiPSC-CMs in a dose-dependent manner | (1) hiPSC-CMs contain different subtypes of cardiomyocytes |
| (2) hiPSC-CMs are immature and embryonic-like compared to adult cardiomyocytes | ||||||
| (2) ICa,L | (2) Mitragynine significantly prolonged APD, which induced prolonged QTc and with the potential of causing torsades de pointes | |||||
| (3) APD | (3) Mitragynine did not cause synthesis or trafficking defects of hERG | |||||
| Tay et al. (2019) | In vitro study with hERG1a/1b-transfected HEK293 cells | — | To determine the mechanisms of mitragynine-induced inhibition on hERG1a/1b current | The effects of mitragynine on: (1) hERG1a/1b expression | (1) Mitragynine inhibited the cardiac IKr current in a concentration-dependent manner | (1) Used transfected HEK293 cells instead of cardiomyocytes |
| (2) hERG1-cytosolic chaperones’ interaction | ||||||
| (2) Mitragynine had no inhibitory or induction effects on the mRNA expression of hERG1a and hERG1b | ||||||
| (3) Mitragynine reduced fully glycosylated (fg) hERG1a but upregulated both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes | ||||||
| (4) In conclusion, mitragynine may impair hERG1a trafficking by preventing proper hERG1a channel protein folding through the plasma membrane of transfected HEK293 cells | ||||||
| Aggarwal et al. (2018) | Case report | — | — | — | A 26-year-old man: (a) History: presented with cardiorespiratory arrest after ingesting an unknown quantity of kratom 24 h previously; no prior medical illness or regularly prescribed medication | (1) The patient consumed a standard dose of codeine |
| (b) Clinical findings: cardiorespiratory arrest with ventricular arrhythmia | (2) Serum mitragynine and 7-HMG were not measured | |||||
| (c) Investigations | ||||||
| (i) Urine toxicology: the presence of codeine (of which the patient had taken a standard dose just prior to admission) | ||||||
| (ii) Other findings: imminent cerebral herniation in CT brain scan | ||||||
| (d) Outcome: the patient died 12 h after initial ROSC | ||||||
| Abdullah et al. (2019) | Case report | — | — | — | A 35-year-old man: (a) History: presented with cardiorespiratory arrest and a history of taking kratom in powdered form as a tea numerous times daily; history of polysubstance abuse; used kratom as self-prescribed medication for opioid dependence | (1) The kratom powder that the patient consumed could have been adulterated |
| (b) Clinical findings: cardiovascular, gastrointestinal, and respiratory examinations were otherwise unremarkable; a neurological examination revealed only evidence of cardiorespiratory arrest | (2) Serum mitragynine and 7-HMG were not assessed | |||||
| (c) Investigations | ||||||
| (i) Arterial blood gas: respiratory acidosis, liver function test: liver impairment | ||||||
| (ii) Cardiac enzyme analysis: high creatinine kinase (4,000 U/L) and troponin I (0.37 μ/L) | ||||||
| (iii) ECG findings were normal and an echocardiogram only indicated a recent cardiac arrest | ||||||
| (iv) Other investigations were unremarkable and a urine drug screen upon admission was negative for any drugs | ||||||
| (d) Outcome: patient survived and recovered from opioid withdrawal symptoms 8 days after admission | ||||||
| ELJack et al. (2020) | Case report | — | — | — | A 24-year-old man: (a) History: presented with cardiorespiratory arrest with a history of continually using illicit substances, particularly kratom, but had abstained from opioid use for approximately 1 year; history of polysubstance abuse but no history of medical illness prior to the incident | (1) Serum mitragynine and 7-HMG were not assessed |
| (b) Clinical findings: physical examination revealed unremarkable findings | (2) Likely co-exposure of kratom and other substances | |||||
| (c) Investigations | ||||||
| (i) Cardiovascular investigation: ventricular fibrillation (polymorphic ventricular tachycardia) and incomplete right bundle branch block in ECG | ||||||
| (ii) Transthoracic echocardiography: normal | ||||||
| (iii) Other investigation: indicative of tissue and organ hypoperfusion due to cardiac arrest | ||||||
| (iv) Serum and urine toxicology screening: no evidence of any illicit drug use or medication overdose | ||||||
| (d) Outcome: Patient fully recovered and was extubated 2 days after his hospital presentation | ||||||
| Sheikh et al. (2021) | Case report | — | — | — | A 44-year-old man: (a) History: presented with cardiorespiratory arrest and a history of consuming kratom daily as an energy supplement, co-administered with an energy drink; otherwise, no history of underlying medical illnesses | (1) No assessment of serum mitragynine and 7-HMG |
| (b) Clinical findings: unremarkable | (2) Co-exposure of kratom and other substances | |||||
| (c) Investigations | ||||||
| (i) Cardiovascular investigation: multiple episodes of ventricular fibrillation and later prolonged QT interval and intraventricular conduction block in ECG | ||||||
| (ii) Chest x-ray: pulmonary vascular congestion | ||||||
| (iii) Emergency cardiac catheterization, ECG (no left ventricular abnormalities), cardiac MRI, and serum troponin were all normal | ||||||
| (d) Outcome: Patient fully recovered | ||||||
| Anwar et al. (2016) | (1) Retrospective survey | — | Not mentioned | (1) Single exposure versus multiple exposures | Cardiovascular finding: (1) Common adverse cardiovascular effects were tachycardia (25%) and hypertension (11.7%) | (1) Unverified reports |
| (2) Sample size: 660 reports of kratom exposure | (2) Common substances co-administered with kratom | Other findings: (1) Isolated kratom exposure was reported in 64.8% of cases | (2) Unknown health backgrounds in cases | |||
| (3) Symptoms and signs of kratom exposure | (2) Common co-administered substances included ethanol, other botanicals, benzodiazepines, narcotics, and acetaminophen | (3) Serum mitragynine and 7-HMG levels not available | ||||
| (4) Factors associated with outcomes’ severity | (3) Multiple exposures (kratom co-administration with other substances) increased the risk of a severe outcome compared to a single exposure | |||||
| Post et al. (2019) | (1) Retrospective survey | — | To analyze reports of kratom exposure to the US NPDS from 2011 to 2017 | (1) Single exposure vs. multiple exposures by age group | Cardiovascular finding: (1) Adverse cardiovascular effects: tachycardia (21.4%), hypertension (10.1%), conduction defects (2.8%), chest pain (including non-cardiac pain; 2.6%), hypotension (1.8%), bradycardia (1.2%), and cardiac arrest (0.4%) | (1) Unverified reports |
| (2) Sample size: 1,807 reports of kratom exposure | (2) Trend of kratom exposure from 2011 to 2017 | Other findings: (1) 65% of cases reported involved only kratom exposure | (2) Unknown health backgrounds in cases | |||
| (3) Clinical features and medical outcomes associated with kratom exposure | (2) 11 kratom-related deaths were reported with only two cases associated with isolated kratom exposure | (3) Serum mitragynine and 7-HMG levels not available | ||||
| Davidson et al. (2021) | (1) Retrospective survey | — | To analyze reports of kratom exposure with abuse potential to the US NPDS and Thai RPC from 2011 to 2017 | (1) Characteristics of kratom exposure | Cardiovascular findings: (1) Adverse cardiovascular effects and outcomes: tachycardia (30.4%) and hypertension (12.4%) | (1) Unverified reports |
| (2) Sample size: 928 reports of kratom exposure | (2) Trend of kratom exposure from 2011 to 2017 | Other findings: (1) Thailand registered a higher prevalence of co-exposure of kratom with other substances than the United States | (2) Unknown health backgrounds in cases | |||
| (3) Single exposure vs. multiple exposures | (2) The United States reported more co-ingestion with other sedatives than Thailand | (3) Serum mitragynine and 7-HMG levels not available | ||||
| (4) Prevalence of co-ingested substances | (3) Five out of six reported deaths were associated with the co-ingestion of kratom and other substances | (4) Kratom dosing and formulation not available | ||||
| (5) Common clinical effects of kratom exposure | ||||||
| (6) Factors associated with death and ICU admission | ||||||
| Corkery et al. (2019) | (1) Retrospective survey | — | To examine the nature of death reportedly associated with kratom exposure across the United Kingdom, United States, Europe, and Thailand until 2019 | (1) The main characteristics of deaths associated with kratom use | Cardiovascular finding: (1) Frequency of cardiovascular findings in deaths solely attributed to kratom: n = 9, 5.8% | (1) Questionable quality of some data sources |
| (2) Sample size: 156 kratom-related mortality cases | (2) Serum mitragynine and 7-HMG levels among patients who had died | (2) Frequency of cardiovascular findings in deaths attributed to kratom combined with other substances: n = 18, 11.5% | ||||
| (3) Frequency of kratom exposure only and co-exposure | (3) Frequency of cardiovascular findings in deaths in which kratom’s role was unclear: n = 5, 3.2% | |||||
| (4) Main causes of death and autopsy reports associated with kratom exposure only and co-exposure | Other findings: (1) Exposure to kratom alone constitutes 23% of death cases while polysubstance use was reported in 87% of death cases | |||||
| (2) Serum mitragynine levels in mortality cases were as follows | ||||||
| (a) Death solely attributed to kratom (mean = 0.398 mg/L, range 0.0035–0.890 mg/L; n = 3) | ||||||
| (b) Death attributed to kratom combined with other substances (mean = 0.8903 mg/L, range 0.00089–16.000 mg/L; n = 62) | ||||||
| Leong Abdullah et al. (2021) | (1) Analytical, cross-sectional study | Yes | To investigate the prevalence of ECG abnormalities generally and QTc intervals particularly among regular kratom users versus non-kratom-using control participants | (1) Kratom use characteristics | (1) Kratom users (8%) had significantly higher odds of sinus tachycardia than control participants (1%); no significant difference was found in other ECG abnormalities | (1) Cross-sectional design |
| (2) Snowball sampling | (2) Resting ECG | (2) An age during one’s first experience of kratom consumption of >18 years old, a consumption duration of > 6 years, and daily kratom juice consumption quantity of one to four glasses significantly increased one’s odds of a borderline QTc interval (QTc = 431–450 ms) but not of a prolonged QTc interval (QTc >450 ms) | (2) No female participants | |||
| (3) Sample size: regular kratom users (n = 100) vs. non-drug-using control participants (n = 100) | (3) Participants were recruited from a single state in Peninsular Malaysia | |||||
| (4) Serum mitragynine analysis was not performed | ||||||
| (5) Used Bazett’s formula to calculate QTc intervals |
Note: hiPSC-CMs = human-induced pluripotent stem cell-derived cardiomyocytes, hERG = human ether-a-go-go-related gene, APD = action potential duration, IKr = rapid delayed rectifier potassium current, ICa,L = L-type calcium current, hERG1a/1b = the human ether-a-go-go-related gene 1a/1b current, HEK293 cells = hERG1a/1b-transfected human embryonic kidney 293 cells, Hsp90 = heat shock protein 90, , 7-HMG = 7-hydroxymitragynine, ECG = electrocardiogram, NPDS = National Poison Data System, RPC = Ramathibodi Poison Center, ROSC = return of spontaneous circulation, MRI = magnetic resonance imaging, and CT = computerized tomography.