Clinical Implications of Kratom (Mitragyna speciosa) Use: a Literature Review

Abstract    Purpose of Review This work aims to provide an up-to-date review of the preclinical and clinical scientific literature on the therapeutic value of kratom to better understand the underlying mechanisms related to its use and inform future therapeutic applications. Recent Findings A growing number of studies, mainly of cross-sectional nature, describe the widespread use of kratom by individuals to self-treat pain, psychiatric symptoms, and substance use disorders (SUD) outside a controlled clinical setting. Preclinical evidence suggests kratom is effective as an analgesic agent and might decrease the self-administration of other drugs. A randomized controlled trial has further supported kratom’s therapeutic value as an analgesic. Investigations in nonclinical samples of long-term kratom users also indicate its therapeutic benefit in managing SUD symptoms (e.g., craving) and long-term or acute symptoms (e.g., withdrawal) for alcohol, opioids, and other illicit drugs. However, episodes of kratom-related intoxications have also been reported, often due to the adulteration and the contamination of kratom products mainly sold online or mixed toxicities when consumed outside clinical and traditional settings. Summary Evidence on the clinical implications of kratom use is still limited and uncertain, with kratom research constantly evolving. Therefore, further randomized trials are needed.


Clinical Background
Over the past decade, kratom (Mitragyna speciosa Korth.) has widely spread from its Eastern native regions (Malaysia, Thailand, and Indonesia) to the West, especially in Europe and the United States (US) [1, 2••]. It is mainly used by white adults (ages 30-50 on average) who are well-educated and employed at least part-time (e.g., [3, 4••]). Estimates of kratom users largely differ, but millions of people have been using this plant in the US where it is federally legal in all the constituent states apart from Alabama, Arkansas, Indiana, Vermont, Wisconsin, and Rhode Island [1, 2••]. Kratom is sold in various formulations (i.e., capsules, resin, tinctures, powder) in headshops and on the internet [1, 2••]. Recent evidence has shown that kratom products are becoming quite popular also in darknet markets [5]. Kratom is used recreationally as a plant-based substance by some users. Its effects are described as psychostimulant in small dosages of up to 5 g of plant material and similar to opioids at higher doses of approximately 5 to 15 g [1,6]. However, its native use in South Asia has been associated with the nonmedical self-treatment of several conditions (i.e., substance use disorder (SUD) symptoms, such as opioid and other drugs' withdrawal, pain, and improving energy) described even in the West, as well as hypertension, stomach ailments, diarrhea, infections, and diabetes, among others [1,7,8].

Preclinical Data
From a pharmacological perspective, mitragynine (MG) is the main lipophilic alkaloid present in kratom. Its psychoactive metabolite 7-hydroxy-mitragynine (7-HMG) is widely studied in preclinical models for its analgesic properties, while few studies have been conducted on the other alkaloids present in the plant. Another alkaloid, speciociliatine, has also been recently studied [9••]. MG possesses a poly-pharmacological profile and a primary opiate receptor activity, with preliminary evidence suggesting the possibility of mu-opioid receptor (MOR) activity without β-arrestin-2 recruitment in the signaling pathway [10•]. Recent evidence has shown that high doses (between 20 and 400 mg/kg) of oral MG do not exert respiratory depression compared to oxycodone in animal models [11]. However, information related to the safety profile of MG is still quite limited. Furthermore, in February 2018, the Food and Drug Administration (FDA) expressed concerns about the abuse potential of MG and 7-HMG contained in unregulated kratom-related products, highlighting that no medical indication has been approved for such herbal supplements [12]. Similar concerns have emerged in Europe, where kratom remains illegal in various countries (e.g., Sweden, Poland, Romania, and Denmark, among others) [13].
With the increasing scientific interest in the balance between kratom's risks and potential therapeutic use, the present paper aims to provide an up-to-date review of the preclinical and clinical scientific literature on this topic to understand the underlying mechanism of kratom use and inform future therapeutic applications. The key objectives of our search were to (a) evaluate evidence suggesting kratom's therapeutic value from a clinical perspective, including both anecdotal information and (pre)clinical evidence; (b) identify the clinical issues/ health hazards linked to kratom use; and (c) understand if any information is available on the clinical consequences of kratom use in naïve users.

Methods
An exploratory literature search was performed between May 2022 and January 2023 in PubMed, Medline, Google Scholar, ScienceDirect, and Cochrane. "Kratom", "mitragynine", and "Mitragyna speciosa" were used as keywords to carry out the databases' searches. We excluded all the duplicates and commentaries. Studies considered recent as published within the past 5 years were considered for analysis. Particular attention was given to all the (pre)clinical studies also if published outside this timeframe as limited clinical evidence is available.

Anecdotal Information
There is an ongoing debate in the scientific community to understand the complex profile of kratom and its alkaloids regarding safety, health issues, and potential medical benefits. Anecdotal data, mainly from its native countries, suggest it has therapeutic value as an aid in several domains. Data from qualitative reports, e.g., social media analyses [14,15] and large-scale surveys (e.g., [16••, 17••]), all document its widespread reported use in nonmedical settings for treating pain such as that related to the coronavirus disease 2019 (COVID-19) [18], cancer, multiple sclerosis, neuropathy and trigeminal neuralgia, fibromyalgia, headache, rheumatoid arthritis, and other inflammatory conditions (i.e., lupus, osteoarthritis, inflammatory bowel disease, complex regional pain syndrome, Ehlers-Danlos syndrome) [2 ••, 19]. Kratom use has also been reported as a substitute in nonmedical settings for dangerous drugs (i.e., methamphetamine, benzodiazepines, or heroin) or to mitigate the withdrawal from opioids, alcohol, and other illicit substances [20••, 21], especially among opioid poly-drug users [22]. Other underlying motivations for kratom intake include the improvement of sexual performance [23], coping strategies for negative emotional states [24], ameliorating psychiatric symptoms (i.e., anxiety, depression, insomnia, attention deficit hyperactivity disorder (ADHD), and post-traumatic stress disorder (PTSD) [e.g., 4••, 16••], and the enhancement of sociability, energy, and focus [14]. A recent case even reported its use in post-COVID insomnia [25].

Preclinical Evidence
Evidence emerging from the initial preclinical findings supports the anecdotal reports that kratom can be beneficial in treating pain and mental health-related conditions [26 ••]. In vitro and/or in vivo studies have shown that kratom and its alkaloids exert analgesic/ antinociceptive effects as suggested by the increased latency of an antinociceptive response in the hot plate or tail-flick tests or in the model of inflammatory pain induced by acetic acid (27, 28••). Anti-allodynic efficacy in neuropathic pain has also been described [29••, 30•). Moreover, some preclinical models have suggested kratom's antidepressant, anxiolytic, stressmitigating [31••, 32•, 33] and antipsychotic effects [34•]. It has also emerged that kratom and its alkaloids exert gastroprotective, anti-inflammatory [35••, 36], antibacterial [37], antioxidant, antimutagen, and anticancer actions [38]. A recent preclinical study showed, for instance, that MG and speciociliatine acted as chemo-sensitizers for cisplatin and inhibited cell proliferation of nasopharyngeal carcinoma, malignant cancer [9••]. In another current study, MG has been shown to inhibit the enzyme acetylcholinesterase (AChE) involved in Alzheimer's disease [39••]. It might also exert a lipolytic effect [40••] and antidiabetic action by inhibiting other biological enzymes (α-glucosidase, pancreatic lipase) when combined with the diabetes-2 drug (α-glucosidase inhibitor) acarbose [41••]. Preclinical evidence has also suggested its potential in treating (i) alcohol use disorder, alcohol withdrawal, and alcohol-seeking behavior, with a large therapeutic window (e.g., [42, 43 ••]); (ii) dependence and withdrawal from opioids (e.g., [28••, 44••]) without anxiogenic symptoms [45] and by improving simultaneously cognitive performance [46••]; and (iii) craving and addiction from methamphetamine [47] (for an overview of preclinical evidence and anecdotal data providing some evidence suggesting kratom's therapeutic potential, see also Table 1). In light of the anecdotal and preclinical findings, little data is available on kratom's therapeutic potential.

Evidence from Clinical Studies
The discussion on the clinical implications of kratom use has been further enriched by the findings derived from some observational studies carried out in a traditional context (Malaysia or Thailand) among long-term/daily kratom users drinking daily several glasses of kratom juice/tea (between 2 and 6) [48, 49, 50, 51••]. In these cases, the estimated daily dose of MG ranges between 76 and 434 mg [52,53], with no data on other alkaloids. Some of these studies have reported the association between long-term kratom use and health issues. This includes kratom's impact on visual episodic memory and alteration of cholesterol level [54,55], early stage of renal injury [50], dependence (which affects physical well-being if severe; [48,56]), and craving with physical and psychological withdrawal symptoms [58,59]. Such symptoms last about 3 days but are less severe than those described in the West or those related to classical opioids [57,58,59,60]. However, until now, there is no evidence of kratom-related psychosis, social functioning alterations, long-term cognitive or biochemical/endocrinological impairment [53,54,61,62,63]. Furthermore, preliminary clinical data suggest kratom's therapeutic potential as (i) an analgesic agent, with a randomized controlled trial (RCT) in kratom users showing enhanced pain tolerance after drinking kratom without any significant negative health consequences [51 ••], and (ii) a form of harm reduction, with kratom being reported to reduce regular drug (heroin, methamphetamine, amphetamine) use, opioids adverse effects, and HIV risk behaviors among illicit and opiates drug users [64,65,66]. Some evidence has also suggested that kratom possesses a favorable lipid profile and might be protective against metabolic syndrome, coronary heart, or cerebrovascular disease [63,67,68]. However, this data is in contrast with the slight increase in serum lipids linked to a higher frequency of kratom use reported by Leong Bin Abdullah et al. [69]. Finally, two studies evaluated the pharmacokinetic profile of MG in humans and suggest that it follows a two-compartment model with a 1-day terminal half-life [70••, 71]. As reported by the authors, such beneficial pharmacokinetic properties might be useful for its potential use as a medication (for a summary of clinical studies conducted on kratom users, see Table 2).

Clinical Issues/Health Hazards Linked to Kratom Use
An evaluation of kratom's clinical implications should also consider the reported kratom-related negative clinical consequences. A large number of case reports and case series have been questioning kratom's safety profile, especially when ingested outside controlled settings. Issues raised include the risks of kratom dependence or addiction with withdrawal symptoms, cases of neonates with abstinence syndrome born from mothers with or without kratom withdrawal, and neurological and psychiatric manifestations [76][77][78]. Recent evidence has reported episodes of mental and psychological distress, especially when kratom is used with nonmedical opioids and methamphetamine [79]. Other negative consequences to be investigated further include endocrinological damages, dermatological manifestations, electrolytic and kidney alterations, hepatic and gastrointestinal injuries, and respiratory and cardiological health hazards (e.g., [80][81][82][83]). Concerning kratom's effects on cardiological functioning, data is still inconsistent. Trakulsrichai et al. [70••] found a temporary increase in pulse rate and blood pressure in kratom users, and Leong Bin Abdullah et al. [73] described a condition of sinus tachycardia without alterations of QTc intervals. However, in another study, kratom use has been associated with a dose-dependent prolonged QTc interval [49], highlighting the need for more investigation on the cardiological impact of kratom use. The serotonin syndrome, the autonomic nervous system dysfunction, an undifferentiated shock, conditions of multi-organ dysfunction [84][85][86], overdoses, and fatalities (e.g., [87,88] must also be considered (for a summary of the main kratom-related toxicities and their clinical presentations, see Table 3).
While in Asia kratom has been used with a limited number of associated health hazards [25,108], most of the safety issues have been reported in the West, mainly among users ingesting kratom on a daily basis in combination with other drugs, such as prescription medicines (e.g., antipsychotic, antidepressant, and hypnotic drugs, among others) and psychoactive substances (e.g., amphetamine, methamphetamine, cyclopropyl fentanyl, opioids, ethanol) [76,88,108]. Unscheduled contaminants/adulterants in kratom products (e.g., propyl-hexedrine, phenyl-ethylamine, O-desmethyltramadol, hydrocodone, and morphine) [90, 96 •, 97•, 100], microbes (e.g., Salmonella, M. incognita), and toxic metals (lead and nickel) [109••, 110••, 111••] have also been found responsible for toxicities. Furthermore, MG was identified as a contributing factor to some fatalities [112]. More recently, a survey has suggested that kratomrelated side effects might depend on the doses [113]. Thus, it is possible to hypothesize that low doses of kratom might come with smaller risks in the absence of other substances responsible for drug-drug interaction. Suggested therapeutic potential [57] To investigate constipation prevalence k-use related and fatigue severity during k-use cessation (1) Observational design (retrospective study) Semi-structured questionnaire/kuse for opioid withdrawal, increase energy, to substitute heroin, to reduce risk behaviors (e.g., sexual practices, injecting illicit substances, sharing the injecting equipment)

Clinical Consequences of Kratom Use in Naïve Users
Limited information is available regarding kratom quantity used and clinical consequences in naïve users. Very few clinical reports of toxicity have been recorded among individuals using kratom alone and/or for the first time [77,105]. With no clinical studies conducted among such populations, doubts remain about its safety. More rigorous research on the clinical, pharmacodynamic, and pharmacokinetic aspects of kratom and MG is needed to clarify the therapeutically useful or risky doses of kratom in humans.

Discussion and Conclusion
With kratom research rapidly evolving, the most updated evidence on the clinical implications of kratom use has been reviewed in this work. Despite the growing amount of anecdotal self-reported evidence suggesting the therapeutic value of kratom in treating acute/chronic pain and psychiatric disorders, including SUD, in nonmedical settings, various studies report episodes of acute intoxications or the development of dependence linked to the heavy chronic use in such settings. Interestingly, most of the safety concerns derive from Western (nonnative) countries, where kratom use frequently occurs in combination with other substances. Furthermore, kratom products are advertised online or elsewhere with captivating marketing strategies providing misleading or no information about the ingredients, dosage, type, and alkaloids, among others. These aspects make it difficult to determine the dose-response relationship and/or the causal relation with kratom exposure. On the contrary, most of the investigations that we found in native countries, mainly of cross-sectional nature, provide encouraging data on the potential therapeutic value of kratom, also supported by the initial preclinical evidence. Despite these discrepancies, it remains a priority to determine the dose of MG and other alkaloids that can be considered safe and clinically useful in medical treatment. Such insight might contribute to kratom's risk assessment and give additional information to clinicians and regulatory agencies willing to recognize kratom as an agent for the treatment of pain, mental health, and other chronic/benign health conditions. Finally, controlled and longitudinal studies under careful clinical supervision, including healthy and naïve individuals and/or participants who consume other drugs or medicines outside the traditional context, will further contribute to the development of kratom research and provide a better understanding of the underlying clinical, pharmacological, and toxicological mechanisms necessary to inform future therapeutic applications of kratom. Funding Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement.

Author Contribution
Data Availability All the information that was used is presented in the tables and in the manuscript.

Conflict of Interest
The authors declare no competing interests.

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.  [86,104] Multi-organ dysfunction (e.g., rhabdomyolysis, lethargy, confusion, transient hearing loss, right lower extremity swelling, diffuse body aches, fatigue, generalized weakness, compartment syndrome, acute kidney injury, liver dysfunction, cardiomyopathy) [107] Intentional overdose and suicide attempt/suspected Fanconi syndrome from cadmium toxicity exacerbated by heavy kratom use [85] Undifferentiated shock and extreme elevation of procalcitonin/nausea, vomiting, weakness, and dizziness