Mitra SpeciosaStudies

Assessing the therapeutic potential and toxicity of Mitragyna speciosa in opioid use disorder

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Mitragyna speciosa Korth. is an evergreen plant native to Southeast Asia. It is commonly known as kratom in the western world and kratom, ketum, or biak-biak in Southeast Asian countries. Kratom is a psychotropic plant from the coffee family, Rubiaceae, and like coffee, brewed tea made from the freshly harvested leaves has been consumed customarily by the native users in Malaysia and Thailand. In the traditional use, it is consumed to treat pain, boost endurance, enhance mood, and to mitigate opioid withdrawal symptoms [1]. Many countries in Southeast Asia have a large Muslim population for whom alcohol is forbidden, so instead, they drink brewed kratom leaf tea recreationally. In the USA, kratom products made from powdered dried leaves or concentrated extracts are formulated into tablets, hard gelatin capsules, powders, liquid shots, and/or energy drinks [2]. The Food and Drug Administration (FDA) executed an import ban on kratom to the United States, yet kratom products are commercially available in gas stations, at local specialty shops, and on e-commerce web portals [3]. Due to the import ban, kratom supplies available in the United States must be acquired through illegitimate channels and some products are being manufactured in unregulated facilities. A report in June of 2019 from the American Kratom Association indicated that 1950 metric tons (1,950,030,482 g) of kratom were being exported to the USA per month with the average consumer using 4.2 g per day (125 g/month) indicating >15 million kratom consumers [4]. Kratom is available in nature and is considered safe in its native setting, having been consumed for centuries. Meanwhile, in developed countries of the Western world, multiple problems are being associated with the use of kratom. This disparity between the traditional use and commercial/manufactured products must somehow be accounted for. In this editorial, we address the challenges associated with kratom use in the Western countries along with the therapeutic potential of the kratom for the treatment of pain and opioid withdrawal.

2. Kratom alkaloids and therapeutic potential

The leaves of Mitragyna speciosa plants have been reported to contain more than 40 major and minor alkaloids including indoles, N(4)-oxides of indoles, oxindoles, and 9-hydroxylated oxindoles. Most of the studied kratom alkaloids have shown prominent activity at central nervous system targets, with mitragynine and 7-hydroxymitragynine receiving the most attention in the scientific literature [5]. Mitragynine is the most abundant alkaloid in kratom, and its content ranges from 0.7–38.7% in traditional and commercial kratom products [2]. According to the literature, mitragynine is primarily responsible for the psychotropic activity of kratom. It governs the therapeutic activity through dual opioid and adrenergic receptor activities, which are well-known targets for pain and opioid use disorder therapy. Mitragynine is a biased and partial mu-opioid receptor agonist (binding affinity (Ki), 161 ± 10 nM). It does not recruit β arrestin-2 signaling pathways and activates about 40% (maximum effect (Emax)) of G-proteins compared to the maximum response of full mu-opioid receptor agonist, DAMGO. Mitragynine is an agonist at alpha1A and D receptors and a competitive antagonist at alpha 1A, B, D, and 2 C adrenergic receptors [5]. Mitragynine is primarily metabolized by cytochrome P-450 (CYP) 3A4 with minor contributions from CYP 2D6 and CYP 2C9 to the O-demethylated and mono-oxidative metabolites. Among the reported metabolites, 9-hydroxycorynantheidine and 7-hydroxymitragynine have showed greater binding affinity (Ki, 105 ± 0.60 and 7.16 ± 0.94 nM) at the mu-opioid receptor than mitragynine [5]. Two independent pre-clinical studies in rodents have shown that mitragynine can reduce opioid self-administration without prominent tolerance, cross-tolerance to opioids, or addiction potential [6,7]. Alternatively, the minor kratom alkaloid, 7-hydroxymitragynine, has shown opioid-mediated abuse and the potential to be addictive. In addition, 7-hydroxymitragynine is an active metabolite of mitragynine and it shows a 22.5-fold increased binding affinity (Ki, 7.2 ± 0.9 nM) over mitragynine at the mu-opioid receptor [5,6]. Due to the higher polar surface area of the molecule, 7-hydroxymitragynine has a more limited ability to cross the blood-brain barrier when compared to mitragynine, and it is further converted to even more potent and efficacious metabolite, mitragynine pseudoindoxyl specifically in human plasma [8,9]. Levels of 7-hydroxymitragynine in Malaysian street samples and other freshly prepared extracts are below the lower limit of quantification (0.01%w/w) of analytical methods, but in commercial kratom products in the United States are present up to 2%w/w [1,10]. According to our experience with freshly prepared kratom samples, 7-hydroxymitragynine is not produced by the plant but rather, oxidation of mitragynine occurs post-harvest during the drying, transportation, and/or manufacturing processes. Levels of 7-hydroxymitragynine in commercial kratom products in the United States are considerably (109–520%) higher than that of kratom preparations in native settings [10]. Substantially high levels of 7-hydroxymitragynine, an alkaloid with abuse potential, in commercial kratom products may be the cause of the harm that has been associated with kratom use in the United States. Moreover, it could possibly explain why some individuals have required treatment for kratom abuse.

3. Toxicity

According to the FDA’s Adverse Event Reporting System (FAERS) database, there are 497 kratom associated serious cases, including 356 deaths, reported over the last ten years. After carefully studying the FAERS database, it was observed that in the overwhelming majority of cases kratom was not administered alone and rather other prescription drugs were co-ingested along with the kratom products [11]. Two kratom alkaloids, mitragynine (Ki, 1.1 μM) and corynantheidine (Ki, 2.8 μM), are moderately potent CYP2D6 inhibitors. In the case of co-administration of kratom products, mitragynine can competitively inhibit the CYP2D6 mediated metabolism of concomitantly administered drugs and may lead to serious toxic events [12]. This is especially significant for the western population due to the availability of concentrated organic extracts which contain very high levels of mitragynine compared to the traditional preparations. Differences in the plasma concentrations of mitragynine between native kratom users from Thailand (Cmax, 0.05–0.26 μM) and autopsy samples in the United States (Cmax, up to 8.8 μM) are evidence for the plausibility of mitragynine-mediated herb–drug interactions leading to serious adverse events [13,14]. Apart from the high mitragynine content in some commercial kratom products in the United States, adulteration with illicit substances (i.e. O-desmethyltramadol, phenylethylamine, morphine, and hydrocodone), contamination with Salmonella, and toxic levels of heavy metals have also been reported [15]. An adulterated kratom blend spiked with O-desmethyltramadol, Krypton, led to at least nine deaths in Sweden (https://pubmed.ncbi.nlm.nih.gov/21513619/). According to a case report in the USA, a fitness instructor died due to the consumption of adulterated kratom containing phenylethylamine which led to a fatal intracerebral hemorrhage (https://link.springer.com/article/10.1007/s13181-019-00741-y). Due to the poorly regulated environment around dietary supplements in the USA, these non-conformances in some kratom products come as no surprise and may also contribute to the toxicity that has been reported. Most recently, reports have emerged of infants born with neonatal abstinence syndrome, purportedly due to their mothers who were self-treating their opioid dependence with kratom. Systematic studies are warranted to understand the effects of kratom alkaloids in utero; meanwhile, pregnant and childbearing age females should take noted precautions when using kratom products.

4. Expert opinion

Mitragyna speciosa has been ingested by the natives of Southeast Asia for centuries with no major casualties reported, but in the western world, there have been multiple kratom-associated poison control center calls, emergency room admissions, and deaths. Furthermore, there have been users of kratom in the United States that have had to seek professional help to ween from their use, sometimes being under the care of addiction treatment specialists. Major differences in kratom consumption habits, product types, and adulteration may be responsible for the harm and fatalities in the United States. There are reports that individuals with opioid use disorder are using kratom as replacement therapy. There are others that are misusing kratom with other drugs to reach a ‘legal high.’ Due to the potential likelihood of herb–drug interactions, this behavior may provide the explanation for some of the harm reported with kratom use in the USA. Herbal products are not always safe; therefore, responsible use of kratom products is required. But responsible use must also come with the appropriate regulations in the industry starting from the growing practices, collections of the leaves, and raw material chain-of-custody documentation, appropriate testing results, and GMP packaging of the finished products. Additionally, minor kratom alkaloids with strong three-dimensional structural similarities to mitragynine and 7-hydroxymitragynine could also interact with opioid and/or adrenergic receptors (along with other drug targets); therefore, kratom products should not only be standardized for mitragynine and 7-hydroxymitragynine content but also for other minor alkaloids that may be biologically active and reach the blood or brain after oral ingestion. Systematic, controlled studies are required to understand the pharmacokinetic and pharmacodynamic profile of each alkaloid, to explore their therapeutic potential individually and their roles in the combined pharmacology of kratom products. The natural product works like a symphony orchestra where each alkaloid may have a critical role in the overall outcome. Isolation and testing of individual alkaloids are like removing one instrument from the orchestra at a time and listening to it ‘full blast’ to determine the contribution it makes. This is a cautionary statement, because one alkaloid should not be considered as the whole plant. Kratom (Mitragyna speciosa) at the appropriate dose and formulation, may be a key aid in the fight to manage or even overt the opioid epidemic. Unfortunately, at higher doses it may become a serious threat to society especially with the concentrated and/or adulterated products that are utilized to achieve a ‘legal high.’ The questionable quality of the available kratom products should be improved with local farming of kratom trees or legitimization of the kratom import channels and processes. Like other food supplements, kratom products should be standardized for alkaloidal content, microbial contamination, pesticides, heavy metals, residual solvents, benzo(a)pyrene, and aflatoxins, along with the proper labeling requirements. Apart from standardized kratom leaf extracts, mitragynine appears to have great potential to be developed as a treatment for pain, opioid use disorder, and opioid withdrawal due to its combined pharmacology at opioid and adrenergic receptors, without any demonstrated addiction potential to date in pre-clinical animal studies. Advanced pharmacokinetic, safety, and toxicity studies are warranted to optimize the dose and dosage regimen of mitragynine as well as kratom preparations.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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