1 INTRODUCTION

Kratom (Mitragyna speciosa, Rubiaceae family) is an indigenous tropical tree from Southern East Asia (e.g., Malaysia, Thailand, Laos, Cambodia), which also grows in East-West Africa and Papua New Guinea (Hassan et al., 2013; Kruegel and Grundmann, 2018). This evergreen non-seasonal plant is also known locally with other names, such as Biak-Biak, Ketum, Kakuam, Ithang, Thom, and Mambog (Hassan et al., 2013; Veltri and Grundmann, 2019). It exerts stimulant cocaine-like effects in doses smaller than 5 g and sedative-like effects at higher doses between 5 and 15 g (Cinosi et al., 2015; Eastlack et al., 2020).

Kratom leaves are generally smoked, chewed, or brewed as an herbal decoction (Hassan et al., 2013; Kruegel and Grundmann, 2018). It has been used traditionally for centuries to treat several medical conditions like diarrhea and pain, to mitigate opioid and alcohol withdrawal symptoms, to detoxify from other substances, like cannabis or methamphetamine, to improve sexual desire, and to combat fatigue (Grewal, 1932a; Hassan et al., 2013; Saref et al., 2019a; Singh et al., 2017; Vicknasingam et al., 2010).

Kratom has recently gained popularity as an ethnomedicinal remedy in Western countries, especially in the United States (US), where it is sold online and elsewhere (e.g., gas station, specialty shops) in different formulations, such as tablets, supplements, capsules, or powder (Prozialeck et al., 2012; Tavakoli et al., 2016). Several user-based surveys revealed use to self-treat acute/chronic pain, among other psychiatric conditions, including opioid and substance use disorders (Bath et al., 2020; Coe et al., 2019; Garcia-Romeu et al., 2020; Grundmann, 2017). A case report also referred to its successful use in alleviating COVID-19 related pain (Metastasio et al., 2020).

However, despite this increased scientific interest in kratom, the evidence supporting such self-reported claims is still lacking. It is known that its psychoactive effects are mainly dependent on its major metabolite 7-OH-mitragynine (7HMG) and mitragynine (MG), which together account for 68% of all the alkaloids present in the plant (Hassan et al., 2013; Kruegel and Grundmann, 2018; Shellard, 1974; Takayama, 2004).

Mitragynine (IUPAC name (E)-2-[2S,3S,12bS)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]-quinolizin-2-yl]-3-methoxyprop-2-enoate) is an indole alkaloid Corynanthe-type having a monoterpene portion similarly to yohimbine and the psychedelic substance voacangine (Han et al., 2020; Hassan et al., 2013; Kong et al., 2017a; Ramanathan et al., 2015). It is insoluble in both basic and aqueous solutions but possesses a high solubility in typical organic solvents (e.g., acetone, acetic acid, alcohol, chloroform, and diethyl-ether) (Han et al., 2020; Kong et al., 2017a; Ramanathan et al., 2015). It has intermediate lipophilicity and a high capacity to cross the blood-brain barrier (Yusof et al., 2019).

The compound has been described as a G-protein biased atypical opioid (Faouzi et al., 2020; Gutridge et al., 2020; Raffa et al., 2018) that acts as mu- and delta-opioid receptor agonist (Foss et al., 2020; Matsumoto et al., 1996b, 2006), and kappa-opioid receptor antagonist-like, without β-arrestin recruitment (Kruegel et al., 2016; Todd et al., 2020; Váradi et al., 2016). Mitragynine also possesses a non-opioid action through (α2) adrenergic receptors, adenosine (A2A), dopamine (D2), and serotonin (5-HT2A, 5-HT2C, and 5-HT7) receptors (Harun et al., 2015; Hiranita et al., 2019; Matsumoto et al., 1996a, 1996b, 1997).

The contribution of these receptors in the (acclaimed) effects of kratom has yet to be determined. A drawback is that most of the available data has been collected in users. It derives from online surveys, drug fora, and case reports. Additionally, Ramachandram et al. (2019) reported that the association between the pharmacodynamics and -kinetics of mitragynine in (pre)clinical models had not been studied yet.

Limited evidence has shown that the compound possesses a biphasic elimination pattern after both oral (p.o.) (half-life (T1/2):3–9 h) and intravenous (i.v.) (T1/2:13 h) administration in rodents (Kong et al., 2017b; Ya et al., 2019), and a large volume of distribution when it was administered (i.v.) in dogs (Maxwell et al., 2020). On the other side, mitragynine has been shown to follow a two compartmental model after oral intake in a small sample of kratom users, with a T1/2 of 23.24 ± 16.07 h (Trakulsrichai et al., 2015).

The metabolism of mitragynine has been described to be mainly hepatic in both human microsomes (Kamble et al., 2019) and preclinical models (Ya et al., 2019), and it would be mediated by cytochrome P450 (CYP450) (Basiliere and Kerrigan, 2020; Hanapi et al., 2013; Kong et al., 2011), which may also be involved in potential drug-drug interaction.

Serious adverse events, including fatalities (Corkery et al., 2019; Wong and Mun, 2020), have been reported only in Western countries, mainly when kratom is used in recreational settings. Suggested reasons are extreme high dose, and co-administration of benzodiazepines, amphetamines, or ethanol, or the presence of adulterants, like the synthetic O-desmethyl tramadol (Anwar et al., 2016; Corkery et al., 2019; Kronstrand et al., 2011; Olsen et al., 2019). Other serious events have been associated with chronic kratom use (Alsarraf et al., 2019; Anwar et al., 2016; Grundmann, 2017; Schimmel and Dart, 2020) and include the risk of addiction, dependence, and withdrawal (Singh et al., 2018c; Veltri and Grundmann, 2019).

The Food and Drug Administration (FDA) and the US Drug Enforcement Administration (DEA) considered these kratom-related reports as dangerous and consequently proposed to place the plant in Schedule I of the Controlled Substances Act (CSA) in 2016 (Eastlack et al., 2020; Grundmann, 2017; Henningfield et al., 2018). However, since a broad public opposition reversed this action, kratom is still legal at the federal level in the US, with many users claiming its therapeutic potential, in the absence of sufficient clinical evidence.

Given this background, the current systematic review aims to investigate whether kratom has potential medical benefits based on preclinical and clinical studies measuring acute and chronic effects on behavior and other clinical outcomes. The second aim was to investigate possible safety issues in humans. The medical applications of kratom reported by users in traditional and non-traditional settings were used to define this review's search strings.

2 MATERIALS AND METHODS 2.1 Data sources and search strategy

A literature search was performed using the PubMed and the Medline database to identify the scientific publications related to kratom's potential therapeutic utility and safety, as investigated in (pre)clinical research. The search, which was carried out between April and August 2020, consisted of assessing titles and abstracts using both Medical Subject Headings, or subheadings (MeSH) and free-text terms. The choice of search terms was informed by recent high-quality reviews, papers, and online surveys that reported anecdotal data related to kratom's benefits in treating pain, psychiatric symptoms and conditions, and several other medical applications (e.g., hypertension, inflammatory conditions, diabetes).

The query's search strings included a combination of substance [1] and symptoms/condition [2] strings; both included the Boolean command 'OR', and they were combined with 'AND'. The terms used in [1] were kratom, mitragynine, mitragyna, Mitragyna speciosa. The terms used in [2] were: ADD, addiction, ADHD, affective disorders, analgesia, analgesic, analgesics, anorexia, anthelmintic, antidepressant, anti-inflammatory, antimalarial, antinociceptive, anxiety, anxiolytic, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, blood pressure, cough, dependence, depression, diabetes, diarrhea, diarrheal disease, fever, gastric, infection, inflammation, mood disorders, “muscle AND relaxation”, opioid use disorder, pain, psychosis, psychotic disorders, stress, stress disorders post traumatic, substance-related disorders, treatment-resistant depression, withdrawal. Terms in this string were combined with ‘OR’. No period restrictions were applied. This search led to 224 hits and was updated on November 2020, to identify records that could have potentially been published during the preparation of this paper for submission. This search gave 7 additional articles.

2.2 Inclusion/exclusion criteria

Taking into account the review method and the aim of this study, exclusion criteria were the following: (1) non-original research articles or publications not pertinent or not potentially related to the aims, including those mainly focused on methods of identification in biological samples or sold products, chemistry and physicochemical properties, pharmacology, including pharmacodynamic and pharmacokinetic properties, toxicology or other topics (fatalities, harm reduction, legal status); (2) review, commentaries, or other surveys of the literature; (3) case series and case reports because of their high potential of bias in the study designs; (4) data in humans derived from online surveys.

Studies were included if they met all of the following criteria: (1) preclinical study, in vitro or in vivo, investigating the pharmacology or toxicology potentially related to the review aim, and (2) any clinical outcome providing sufficient scientific evidence of kratom, mitragynine, mitragyna and related or derivative compounds, that would support the traditional medical uses or anecdotal benefits reported by users.

2.3 Study selection

All procedures were performed according to PRISMA guidelines (Moher et al., 2009). The selection was conducted in two stages: an initial screening of titles and abstracts against the inclusion criteria to identify potentially relevant papers, followed by screening the full papers assessed for eligibility. The selection was discussed in a small team of four (EP, ET, JR, KK).

2.4 Data extraction

When a record reported a combination of review-relevant and -irrelevant data, only the former was included. Based on the included articles' content, the review was organized in the following categories: (pre)clinical evidence related to potential therapeutic use in pain, withdrawal and dependence, and other medical conditions, and therapeutic application or safety issues in humans.

3 RESULTS 3.1 Studies description

In total, 63 studies met the eligibility criteria. After an initial screening, 17 were removed, as they focused on Mitragyna genus per se or on kratom pharmacology and toxicology data and thus not relevant for this review. Additional studies (29) were included in the analysis as a further assessment of relevant citations emerged. Overall, 75 records were deemed relevant to this systematic review (details of the selection process are shown in Figure 1). These included 18 studies performed in humans, and 57 preclinical studies, that were mainly in vivo studies with a brief observation period, with nine having a more extended observation period (Cheaha et al., 2015; Grewal, 1932b; Harun et al., 2020; Hassan et al., 2020; Khor et al., 2011; Kumarnsit et al., 2006, 2007a; Meepong and Sooksawate, 2019; Wilson et al., 2020), and other nine were in vitro (Abdul Aziz et al., 2012; Fakurazi et al., 2013; Ghazali et al., 2011; Goh et al., 2014; Grewal, 1932b; Jamil et al., 2013; Juanda et al., 2019; Parthasarathy et al., 2009; Yuniarti et al., 2020). Since six preclinical studies gave evidence for two potential therapeutic uses, the related content will be described in each specific section of the results.

PRISMA flowchart depicting the selection and review process that resulted in 75 articles for inclusion in the current review

3.2 (Pre)clinical evidence of potential therapeutic use 3.2.1 Pain

Twenty-three in vivo (mice, rats, or dogs) studies provided evidence for kratom's potential therapeutic use in the treatment of acute pain (Carpenter et al., 2016; Criddle, 2015; Fakurazi et al., 2013; Hiranita et al., 2019; Idid et al., 1998; Macko et al., 1972; Matsumoto et al., 1996a, 1996b, 2004, 2005, 2006, 2008; Mossadeq et al., 2009; Reanmongkol et al., 2007; Sabetghadam et al., 2010, 2013; Shamima et al., 2012; Stolt et al., 2014; Takayama et al., 2002; Thongpradichote et al., 1998; Wilson et al., 2020) and chronic pain (Foss et al., 2020; Matsumoto et al., 2014). The antinociceptive effects of the studied preparations were shown in the different models of acute thermal or mechanical stimulus-induced pain, and neuropathic pain, after administration via a range of routes (p.o., i.p., i.v., or i.c.v.).

The studied preparations were Mitragyna speciosa (MS) aqueous or methanol or alkaloid extracts (Carpenter et al., 2016; Criddle, 2015; Mossadeq et al., 2009; Reanmongkol et al., 2007; Sabetghadam et al., 2010, 2013), lyophilized kratom tea (LKT) (Wilson et al., 2020), mitragynine alone (Carpenter et al., 2016; Criddle, 2015; Fakurazi et al., 2013; Foss et al., 2020; Hiranita et al., 2019; Idid et al., 1998; Macko et al., 1972; Matsumoto et al., 1996a, 1996b; Shamima et al., 2012; Thongpradichote et al., 1998), or mitragynine + paynantheine (Stolt et al., 2014), and its synthetic derivatives MG Pseudoindoxyl (Takayama et al., 2002) and [(E)-methyl 2-(3-ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-methoxyindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate] (MGM-9) (Matsumoto et al., 2008), or 7HMG (Matsumoto et al., 2004, 2005, 2006), and its derivatives (E)-methyl 2-((2S,3S,7aS,12aR,12bS)-3-ethyl-7a-hydroxy-8-methoxy-1,2,3,4,6,7,7a,12,12a,12b-decahydroindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (MGM-15) and (E)-methyl 2-((2S,3S,7aS,12aR,12bS)-3-ethyl-9-fluoro-7a-hydroxy-8-methoxy-1,2,3,4,6,7,7a,12,12a,12b-decahydroindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (MGM-16) (Matsumoto et al., 2014).

According to the evidence included in our analysis, mitragynine's analgesic effect was similar to classical opioids oxycodone and morphine (MOR) (Carpenter et al., 2016; Criddle, 2015). When combined with MOR in long-term treatment, the analgesic effect was more pronounced (Fakurazi et al., 2013). Further, it was described as more potent and relatively safer than the MS alkaloid extract (Sabetghadam et al., 2013). Wilson et al. (2020) also found LKT's analgesic effect similar to MOR, with relatively fewer negative effects (Wilson et al., 2020). 7HMG, a partial mu- and delta-opioid receptors agonist, was described as more potent than MOR (Matsumoto et al., 2004, 2006), with a minor intestinal transit inhibition (Matsumoto et al., 2006). However, it was also found responsible for a locomotor activity increase in a dose-dependent manner (Matsumoto et al., 2008) and producing cross-tolerance to MOR (Matsumoto et al., 2005, 2008). Among its derivatives, authors found MGM-16 to have a superior potency as an opioid agonist in comparison to both MGM-15 and 7HMG (Foss et al., 2020; Matsumoto et al., 2014), and Matsumoto et al. (2008) reported MGM-9 to have higher potency, with lower adverse effects, whether compared to MOR and 7HMG (Matsumoto et al., 2008).

Further, four studies (Fakurazi et al., 2013; Macko et al., 1972; Mossadeq et al., 2009; Wilson et al., 2020) showed that kratom also exerts other therapeutic effects besides analgesic properties, including applications in opioid withdrawal, described in more detail below.

3.2.2 Withdrawal and dependence

Twelve in vivo studies (mice, rats or zebrafish) and two in vitro studies provided evidence for kratom so potential therapeutic use in the treatment of both opioid (Cheaha et al., 2017; Fakurazi et al., 2013; Harun et al., 2020; Hassan et al., 2020; Hemby et al., 2019; Jamil et al., 2013; Khor et al., 2011; Meepong and Sooksawate, 2019; Wilson et al., 2020; Yue et al., 2018) and alcohol use disorders (Cheaha et al., 2015; Gutridge et al., 2020; Kumarnsit et al., 2007a; Vijeepallam et al., 2019), as shown by the effects of the studied preparations (kratom extracts, LKT, mitragynine and other alkaloids; p.o. or i.p. or i.v. or intragastrically) in models of induced withdrawal, drug consumption/replacement, and dependence.

Among the extracts, the MS alkaloid (Cheaha et al., 2015) and aqueous extract (Kumarnsit et al., 2007a) attenuated ethanol withdrawal. The methanol extract was found to reduce the ethanol-seeking behavior (Vijeepallam et al., 2019), and both extracts (with or without 7HMG) and alkaloids (e.g., paynantheine, speciogynine, mitragynine, 7HMG) diminished alcohol intake (Gutridge et al., 2020). LKT (Wilson et al., 2020) and mitragynine were reported to lessen morphine withdrawal (Cheaha et al., 2017; Harun et al., 2020; Khor et al., 2011), with Hassan et al. (2020) suggesting that this mitragynine effect may resemble that produced by methadone and buprenorphine (Hassan et al., 2020). Additionally, mitragynine attenuated morphine dependence as well (Hemby et al., 2019; Jamil et al., 2013; Meepong and Sooksawate, 2019), and Yue et al. (2018) demonstrated a reduction by the compound of response rates in the model of heroin-induced Conditioned Place Preference (CPP) (Yue et al., 2018). Further, Fakurazi et al. (2013) found that mitragynine possesses the potential to reduce morphine tolerance in a chronic morphine administration model, defined by transcription factor cAMP response element binding (CREB)'s activation and the consequent increase in cAMP level's expression (Fakurazi et al., 2013).

3.2.3 Other medical conditions

Twenty-two (15 in vivo in mice, rats or frogs, rabbits and cats, 7 in vitro) studies, plus four previously described to report also effects in pain (Macko et al., 1972; Mossadeq et al., 2009) and withdrawal or dependence (Khor et al., 2011; Kumarnsit et al., 2007a), provided evidence for kratom's potential therapeutic use in the treatment of some conditions.

Both mitragynine and MS extracts (p.o. or i.p.) were found to produce several effects including gastroprotective action (Chittrakarn et al., 2018), inhibition of acid gastric secretion (Tsuchiya et al., 2002), and anti-inflammatory (Aziddin et al., 2005; Chittrakarn et al., 2018; Macko et al., 1972; Mossadeq et al., 2009), stress mitigating (Hazim et al., 2011; Khor et al., 2011; Vázquez López et al., 2017), anxiolytic-like (Hazim et al., 2014; Khor et al., 2011; Moklas et al., 2013) and antidepressant-like effects (Idayu et al., 2011; Kumarnsit et al., 2007a, 2007b), anorectic action (Chittrakarn et al., 2008; Grewal, 1932b; Kumarnsit et al., 2006, 2007b), antimutagen/anticancer (Ghazali et al., 2011; Goh et al., 2014), antioxidant (Goh et al., 2014; Grewal, 1932b; Parthasarathy et al., 2009; Yuniarti et al., 2020), and muscle relaxant effect (Chittrakarn et al., 2010). The extract had a more significant action in terms of muscle relaxation when compared to mitragynine (Chittrakarn et al., 2010).

Further, only mitragynine was found to have also dose-dependent anthelmintic activity (Abdul Aziz et al., 2012), antitussive (Macko et al., 1972), paramoecia killing action, anti-hypertensive, and anesthetic effects (Grewal, 1932b), while MS extracts showed to exert antibacterial (Juanda et al., 2019; Parthasarathy et al., 2009), bodyweight decreasing and dose-dependent antidiarrheal (Chittrakarn et al., 2008), antipsychotic-like (Vijeepallam et al., 2016), antipyretic effects (Salleh et al., 2011) and facilitation of learning (Senik et al., 2012).

For a complete overview, see Table 1.

TABLE 1. Preclinical studies Author Research Question Studied Compound (Dose, Route) Positive Control (Dose, Route) SAL/VEH Animal, Tissue Type, Groups (Sample Size) Clinical Model Test/Measures Antinociceptive Effects Carpenter et al. (2016) Comparison on thermal nociception between MS articles and opioid agonists MG (30 mg/kg, i.p.) MSE (300 mg/kg, i.p.) MS alkaloids fraction (75 mg/kg, i.p.) MOR (10 mg/kg, i.p.) Oxycodone (3 mg/kg, i.p.) N/Y Sprague Dawley rats, 6 (9–10) Acute thermal pain HPT/Increase in latencies to perform an antinociceptive response MG (100 mg/kg, p.o.) MSE (300 mg/kg, p.o.) Oxycodone (6 mg/kg, p.o.) // Sprague Dawley rats, 4 (8–9) // // Criddle (2015) Comparison between MS articles and opioid agonists MG (30 mg/kg, i.p.) MSE (300 mg/kg, i.p.) MS alkaloids fraction (75 mg/kg, i.p.) MOR (10 mg/kg, i.p.) Oxycodone (3 mg/kg, i.p.) N/Y Sprague-Dawley rats, 6 (10) Acute thermal pain HPT/Increase in latencies to perform an antinociceptive response MG (100 mg/kg, p.o.) MSE (300 mg/kg, p.o.) Oxycodone (6 mg/kg, p.o.) // Sprague Dawley rats, 4 (8–10) // // Fakurazi et al. (2013)a Enhancement of MG's analgesic action in combination with MOR MG (15, 25 mg/kg, i.p.) MOR + MG (5 mg/kg + 15, 25 mg/kg, i.p.) MOR (5 mg/kg, i.p.) Y/N ICR mice, 6 (7) Acute thermal pain HPT/Increase in latencies to perform an antinociceptive response Foss et al. (2020) Effect on neuropathic pain MG (1, 5, 10 mg/kg, i.p.) ND (ND) N/Y Male Sprague-Dawley rats, 4 (7–8) Allodynia oxaliplatin (6 mg/kg i.p.) induced; locomotor activity Mechanical sensitivity test/Reduction of paw withdrawal threshold; % of ambulatory counts in the VEH (0) MG (30 mg/kg, i.p.) ND (ND) // Male Sprague-Dawley rats, 2 (7) // % of ambulatory counts in the VEH (−) Hiranita et al. (2019) Effect on schedule-controlled responding and antinociception MG (3.2, 5.6, 10, 17.8, 32, 56 mg/kg, i.p.) ND (ND) N/Y Sprague-Dawley rats, 2 (16) Operant procedures for food reinforcement; acute thermal pain Multiple cycles fixed ratio 10 schedules of food delivery/Reduction of schedule-controlled responding; HPT/Increase in latencies to perform an antinociceptive response (like MOR) MG + MOR (3.2, 5.6, 10, 17.8, 32, 56 mg/kg + 3.2, 5.6, 10, 17.8, 32, 56 mg/kg, i.p.) ND (ND) // // // Multiple cycle fixed ratio 10 schedule of food delivery (0), HPT (0) (MG 17.8 mg) Idid et al. (1998) Comparison of antinociceptive effect between MG, paracetamol and MOR MG (200 mg/kg, p.o.) MOR (5 mg/kg, p.o.) paracetamol (100 mg/kg, p.o.) N/Y Albino mice, 4 (6) Pain; acute