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Research Article
7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic EffectsClick to copy article linkArticle link copied!
- Andrew C. KruegelAndrew C. KruegelDepartment of Chemistry, Columbia University, New York, New York 10027, United StatesMore by Andrew C. Kruegel
- Rajendra UpretyRajendra UpretyDepartment of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United StatesMore by Rajendra Uprety
- Steven G. GrinnellSteven G. GrinnellDepartment of Psychiatry, Columbia University, New York, New York 10027, United StatesMore by Steven G. Grinnell
- Cory LangreckCory LangreckDepartment of Pharmacology, Columbia University, New York, New York 10027, United StatesMore by Cory Langreck
- Elizabeth A. PekarskayaElizabeth A. PekarskayaDepartment of Neuroscience, Columbia University, New York, New York 10027, United StatesMore by Elizabeth A. Pekarskaya
- Valerie Le RouzicValerie Le RouzicDepartment of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United StatesMore by Valerie Le Rouzic
- Michael AnsonoffMichael AnsonoffDepartment of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, United StatesMore by Michael Ansonoff
- Madalee M. GassawayMadalee M. GassawayDepartment of Chemistry, Columbia University, New York, New York 10027, United StatesMore by Madalee M. Gassaway
- John E. PintarJohn E. PintarDepartment of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, United StatesMore by John E. Pintar
- Gavril W. PasternakGavril W. PasternakDepartment of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United StatesMore by Gavril W. Pasternak
- Jonathan A. JavitchJonathan A. JavitchDepartment of Psychiatry and Department of Pharmacology, Columbia University, New York, New York 10027, United StatesDivision of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, United StatesMore by Jonathan A. Javitch
- Susruta MajumdarSusruta MajumdarDepartment of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United StatesCenter for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, Missouri 63110, United StatesMore by Susruta Majumdar
- Dalibor Sames*Dalibor Sames*E-mail: [email protected]. (D.S.)Department of Chemistry, Columbia University, New York, New York 10027, United StatesMore by Dalibor Sames
Abstract
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Mitragyna speciosa, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans.
Copyright © 2019 American Chemical Society
Synopsis
Mitragynine is the major active alkaloid of Mitragyna speciosa (kratom). In mice, this compound is converted to an active metabolite, 7-hydroxymitragynine, which mediates its analgesic effect via the mu-opioid receptor.
Introduction
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Mitragyna speciosa, often referred to by the common name kratom, is an evergreen tree native to the tropical jungles of Southeast Asia, where it has been used for at least the last century as a traditional medicine. In its native regions, leaves of the kratom tree are typically consumed as a tea or chewed directly, and are purported to induce stimulant and opioid-like analgesic effects in the user in a dose- and time-dependent manner. These effects have traditionally made kratom popular among agricultural workers, who use the plant to aid in long hours of hard labor. Kratom has also been reported to be useful in ameliorating withdrawal symptoms following cessation of opioid use, and it has achieved some popularity for this use in its native regions. (1−8)
Over the past decade, kratom use has become increasingly popular in the United States (US). Many thousands of US users have reported that consumption of kratom preparations (most often in the form of dried, powdered leaf material) is an efficacious treatment not only for physical pain, but also for mood and anxiety disorders, particularly in cases where other available treatments have either failed or elicited intolerable side effects. (9−13) A significant portion of users have also reported use of kratom as a tool to stop or reduce consumption of prescription or illicit opioids, a potential application that is presently of high interest given the ongoing opioid abuse epidemic in the US. Unfortunately, there have been no controlled clinical studies either examining these alleged therapeutic effects or quantifying any potential risks of kratom use. At the same time, kratom is primarily distributed through unregulated Internet sales and used outside medical supervision. Considering these factors, as well as the reported opioid-like effects and adverse health effects of the plant, the US Drug Enforcement Administration (DEA) and the US Food and Drug Administration (FDA) have both raised concerns that kratom represents a potential drug of abuse and public health threat. (14−16) In September 2016, the DEA announced its intent to place the active compounds found in kratom into Schedule I of the Controlled Substances Act but ultimately decided not to proceed with this action following a large public outcry from the kratom user community, including over 23 000 comments logged in the federal register docket for this issue. (13,17−19) Despite this turn of events, kratom at this time remains in regulatory limbo, with an uncertain future in the US. Accordingly, our laboratories have been working to develop a preclinical profile of kratom’s biological effects, with the hope that such knowledge will prove useful for the development of future therapeutics based on kratom, as well as guide regulatory decision making on the plant itself.
Kratom contains a number of indole alkaloids that are believed to be the primary contributors to its psychoactive effects. Chief among these is mitragynine (Figure 1), which typically constitutes 1–2% of the dry leaf mass and up to approximately two-thirds of the total alkaloid content. (1,5) This compound is joined by 7-hydroxymitragynine (7-OH, Figure 1) in much lower concentrations, typically less than 0.05% of the dried leaf mass. (1,20) The other predominant alkaloids found in kratom leaf are speciogynine, speciociliatine, and paynantheine (each ∼0.2–0.5% of dry leaf mass), but at this time little is known about their pharmacology. (1,5)
Figure 1
Figure 1. Known (Pathway A) and proposed (Pathway B) metabolic transformations of mitragynine.
We have reported that mitragynine and 7-OH are partial agonists of the human μ-opioid receptor (hMOR) in vitro, with 7-OH (EC50 = 34.5 nM; Emax = 47%) being ∼10-fold more potent than mitragynine (EC50 = 339 nM; Emax = 34%). (21) Further, both compounds are known to exhibit opioid-receptor-dependent analgesic effects in rodent models, with 7-OH again being significantly more potent. (6,22−25) At the same time, we have also found that both mitragynine and 7-OH are G protein-biased agonists of the mu-opioid receptor (MOR). (21,25) We have thus classified the kratom alkaloids as “atypical opioids” and have postulated that these compounds may provide a greater therapeutic window between analgesia and classical opioid side effects. For example, other MOR agonists that activate G protein signaling without recruiting the beta-arrestin pathway exhibit attenuated respiratory depression and reduced inhibition of gastrointestinal (GI) transit compared to classical opioids. (26−30) In fact, an early study on the pharmacology of mitragynine demonstrated its superiority compared to the classical opioid codeine in this regard, providing preliminary support for this hypothesis. (24) Similarly, mitragynine pseudoindoxyl, a chemical rearrangement product of 7-OH, has been found to be both G-protein biased and exhibit an improved therapeutic window in mice. (25)
Both methanolic and crude alkaloid extracts of kratom have also demonstrated analgesic properties in rodents. (1) However, it currently remains unsettled which of kratom’s alkaloids are the most important contributors to the analgesic properties of such preparations or to those of the raw leaf. Despite its higher potency, we previously estimated on the basis of preclinical studies that the quantity of 7-OH contained in typical dry kratom leaf preparations is insufficient to induce opioid-like effects directly at typical doses consumed by human subjects. (1) At the same time, examination of the existing literature on the pharmacology of mitragynine revealed a number of unusual observations that complicated our understanding at the outset of the present investigations. First, despite low to moderate oral bioavailability (20–30% in rats), mitragynine has been found in prior investigations to be paradoxically more potent as an analgesic when administered by the oral (p.o.) and intraperitoneal (i.p.) routes compared to the subcutaneous (s.c.) route in rats and mice. (1,24,31) These findings suggested to us the involvement of an active metabolite produced via first-pass metabolism in mediating the analgesic activity of mitragynine. (1) At the same time, our own prior in vitro studies at the mouse mu-opioid receptor (mMOR) had shown that mitragynine acts as either a competitive antagonist or a partial agonist depending on the assay system used, calling into question the ability of this compound to have a direct agonist effect on MOR in rodents and consistent with a metabolite-driven analgesic effect. (21,25) However, mitragynine has also been found to induce analgesic effects when administered intracerebroventricularly (i.c.v), which argued conversely against the involvement of an active metabolite (unless metabolism occurs directly in the brain). (23) Therefore, we set out to further elucidate the pharmacological and metabolic mechanism(s) leading to mitragynine’s analgesic effects.
Results
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Known Metabolites Do Not Explain Analgesic Activity
Given our working hypothesis that an active metabolite might be involved in mediating the analgesic effects of mitragynine, we were interested in identifying metabolites that might exhibit agonist activity at MOR. The metabolites of mitragynine in rat and human urine had been previously studied, revealing a large number of metabolites modified primarily through demethylation at one or more of mitragynine’s three O-methyl groups (Figure 1, Pathway A), followed by either glucuronidation or sulfation of the exposed nucleophile, or oxidative or reductive transformations of the acrylate moiety. (32) Considering previously observed structure–activity relationships (SAR) in the mitragynine scaffold, it was expected that the demethylated metabolites would exhibit similar or lower potency activity at MOR compared to mitragynine. (21) This was confirmed by synthesis of these compounds and testing using in vitro functional assays at hMOR (see Supporting Information, Table S1). Similarly, conjugated metabolites were also expected to be both inactive at MOR and have low penetration of the blood–brain barrier (BBB). Accordingly, when we began our investigation, known metabolites were insufficient to explain the opioid-mediated analgesic activity of mitragynine.
Deuteration of Mitragynine Has Little Effect on Metabolism in Vitro
Our above supposition was further strengthened by findings with a deuterated analogue. On the basis of the reported metabolic pathways of mitragynine, we synthesized an analogue of this compound fully deuterated at each of its three O-methyl groups, mitragynine-d9 (see Supporting Information, Scheme S1), expecting that, through kinetic isotope effects, the metabolism of this derivative would be slowed. Surprisingly, when we examined the stability of mitragynine-d9 head-to-head with its undeuterated counterpart in human liver microsomes (HLM) and mouse liver microsomes (MLM), stability was unchanged (Figure 2A). Therefore, we concluded that demethylation is only a minor pathway of hepatic metabolism (demethylated metabolites may accumulate slowly in the urine or be formed extrahepatically) and that the previously reported metabolites are unlikely to explain the hypothesized role of a hepatically formed metabolite in the analgesic activity of mitragynine.
Figure 2
Figure 2. Decomposition of mitragynine and formation of 7-OH in liver microsomes was quantified by LC-MS/MS. (A) Mitragynine was unstable in both MLM and HLM, while deuteration of all three methyl groups, as in mitragynine-d9, had little effect on microsomal stability. (B) Loss of mitragynine in microsomal preparations was accompanied by formation of 7-OH as a metabolite, and this conversion was more efficient in HLM. There was a strong main effect of species on 7-OH concentration. Two-way ANOVA: F1,30 = 51.66, p < 0.0001. ****p < 0.0001 relative to MLM, **p < 0.01 relative to MLM, *p < 0.05 relative to MLM, ns = p > 0.05 relative to MLM. All data points represent the means of two independent experiments with two incubations per experiment, with error bars representing ± SEM.
Chemistry Suggests a New Site of Metabolism
With known metabolites seemingly unable to explain the observations pointing toward an active metabolite, we began exploring alternative metabolic pathways that might yield such a compound. For inspiration, we turned to known chemical transformations of indole alkaloids, including mitragynine, under oxidative conditions. For example, 2,3-disubstituted indoles are known to undergo functionalization under oxidation/halogenation conditions to afford the corresponding 3-substituted indolenines. (33) Specifically, mitragynine is known to be oxidized by [bis(trifluoroacetoxy)iodo]benzene (PIFA) to give 7-OH (Scheme 1). (6) During our ongoing synthetic explorations of the mitragynine scaffold, we also found that singlet oxygen (21) and potassium peroxymonosulfate (Oxone) were effective oxidants for the conversion of mitragynine into 7-OH (Scheme 1). Therefore, we postulated that the 2–3 indole double bond attacked by these chemical oxidants might also be a site for oxidation by cytochrome P450 enzymes (CYPs) to produce 7-OH as a metabolite (Figure 1, Pathway B). Given the much greater potency of 7-OH as an MOR agonist, we hypothesized that even minor conversion to this product might contribute significantly to mitragynine’s analgesic activity and help to explain the apparent contradictions in the literature.
Scheme 1
Scheme 1. Conversion of Mitragynine to 7-OH by Chemical Oxidants
7-OH is a Mitragynine Metabolite in Vitro
To test our hypothesis, we monitored formation of 7-OH by liquid chromatography-tandem mass spectrometry (LC-MS/MS) during incubation of mitragynine with both HLM and MLM. In both microsome preparations, 7-OH was produced concomitant with disappearance of mitragynine (Figure 2B). Further, 7-OH appeared to be the major metabolite in each case, as the approximate decreases in molar mitragynine concentration from the starting level (2 μM) were accompanied by similar increases in 7-OH concentration. The metabolic conversion was more efficient in HLM, suggesting that an appreciation of interspecies differences is likely to be important for understanding the pharmacology of mitragynine. However, note that our findings conflict with an earlier report, which found that mitragynine was stable in microsomes. (34) The reason for this discrepancy remains unclear at this time, but it may relate to variable metabolic activity of microsome preparations from different sources. Further, we confirmed the low stability of mitragynine in HLM and concomitant formation of 7-OH in an independent laboratory (Biotranex, LLC, data not shown).
7-OH is Resistant to Phase I Metabolism
Having found that 7-OH was indeed formed from mitragynine in vitro, we next assessed whether this compound was itself stable in liver preparations. We found that 7-OH was stable in both HLM and MLM, with more than 90% remaining after 40 min of incubation (Figure S1). This finding that 7-OH was stable to oxidative Phase I metabolism was consistent with its accumulation during microsomal incubations of mitragynine.
Mitragynine and 7-OH are Stable in Plasma
Before proceeding further, we also tested the stability of mitragynine and 7-OH in blood plasma. Both mitragynine and 7-OH were highly stable in mouse plasma (Figure S2), indicating that plasma hydrolysis or other plasma metabolism does not contribute significantly to the biotransformation of these compounds.
Conversion of Mitragynine to 7-OH is Mediated by CYP3A Isoforms in Vitro
We next set out to determine which CYP isoform is responsible for conversion of mitragynine to 7-OH. Mitragynine was incubated in vitro with purified recombinant preparations of the five major human CYP isoforms (CYP3A4, 2C19, 2C9, 1A2, 2D6) alongside a reference substrate of each isoform as positive control. Decomposition of mitragynine was nearly complete in the presence of CYP3A4 (2% remaining at 60 min). In contrast, there was little or no decomposition in the incubations with CYP2C19, 2C9, 1A2, and 2D6 (77%, 99%, 96%, and 82% remaining at 60 min, respectively). The activity of each enzyme preparation was confirmed by nearly complete disappearance of the reference substrates (Figure 3A). During these incubations, the formation of 7-OH was also monitored by LC-MS/MS, revealing that formation of 7-OH was most robust in the presence of CYP3A4, whereas little conversion to 7-OH was observed in the incubations with other CYPs (Figure 3B).
Figure 3
Figure 3. CYP3A4 mediates conversion of mitragynine to 7-OH. (A) Mitragynine was incubated in vitro with recombinant preparations of the five major human CYP isoforms alongside a reference substrate of each isoform as positive control. The relative percent remaining of mitragyine or reference substrate in each incubation was quantified by LC-MS/MS. Disappearance of mitragynine was most rapid in the presence of CYP3A4, whereas incubations with the other isoforms resulted in little or no decomposition. The activity of each preparation was confirmed by the nearly complete disappearance of the corresponding reference substrates. (B) Formation of 7-OH was monitored by LC-MS/MS during incubation of mitragynine with each of the recombinant CYP preparations. CYP3A4 resulted in the most robust conversion to 7-OH. All data points represent the means of two independent experiments with two incubations per experiment, with error bars representing ± SEM.
Having identified CYP3A4 as the predominant metabolic pathway responsible for hepatic metabolism of mitragynine and concurrent formation of 7-OH using purified enzyme preparations, we next sought to confirm these results in liver microsomes, a more complex system with endogenous expression of relevant enzymes. To that end, mitragynine was incubated with HLM alone and in the presence of the CYP3A inhibitor ketoconazole (1 or 10 μM), the CYP2C19 inhibitor ticlopidine (20 μM), or a combination of the two. Ketoconazole robustly inhibited both decomposition of mitragynine (Figure 4A) and formation of 7-OH (Figure 4B), whereas ticlopidine had little effect. Analogous results were found in MLM (Figure S3). In sum, our findings demonstrate that mitragynine is converted to 7-OH in both mouse and human liver preparations and that this conversion is mediated by CYP3A isoforms (including CYP3A4 in humans).
Figure 4
Figure 4. CYP3A-dependence of 7-OH formation was confirmed in HLM. Disappearance of mitragynine and formation of 7-OH was monitored by LC-MS/MS. (A) In HLM, the CYP3A isoform inhibitor ketoconazole (Ket) dose-dependently attenuated metabolic decomposition of mitragynine. In contrast, the CYP2C19 inhibitor ticlopidine (Tic) had little effect. (B) During incubation of mitragynine with HLM, ketoconazole (and to a small degree, ticlopidine) also inhibited formation of 7-OH. All data points represent the means of two independent experiments with two incubations per experiment, with error bars representing ± SEM.
Mitragynine is Analgesic in Mice Through an MOR-Dependent Mechanism
To build on the preceding results, we hoped to examine whether 7-OH is in fact formed as a metabolite of mitragynine in vivo. Further, we sought to test whether 7-OH, as a metabolite, could be a key mediator of the analgesic effects of mitragynine. However, before proceeding with these experiments, we first set out to confirm the analgesic activity of mitragynine in our own hands and to determine whether these effects are dependent on MOR.
For this purpose, we used the 129 mouse strain, which we found to be sensitive to mitragynine-induced analgesia, consistent with the documented high sensitivity of this strain to opioid agonists. (35,36) Further, genetic knockouts of opioid receptors are available on this genetic background. Dose–response curves were generated for mitragynine administered by both oral (p.o.) and subcutaneous (s.c.) routes using the tail-flick test, a classic rodent model for analgesic activity (Figure 5A). We found that mitragynine was much more potent when administered p.o. (ED50 = 2.1 mg/kg) than when administered s.c. (ED50 = 106 mg/kg), consistent with earlier literature reports. To establish the opioid receptor dependence of these effects, an efficacious analgesic dose of mitragynine (10 mg/kg, p.o.) was administered to MOR knockout (KO), κ-opioid receptor (KOR) KO, and δ-opioid receptor (DOR) KO mice, and to wild-type (WT) mice following pretreatment with the opioid receptor antagonist naloxone (1 mg/kg, s.c.). Both MOR KO and naloxone pretreatment significantly attenuated the analgesic effect of mitragynine, whereas KOR KO and DOR KO had no effect (Figure 5B). Therefore, the analgesic activity of mitragynine was found to be MOR-dependent, consistent with prior literature demonstrating pharmacological blockade of analgesia with the opioid receptor antagonist naloxone. (6,23)
Figure 5
Figure 5. Analgesic activity of mitragynine in 129 mice. (A) Dose–responses of mitragynine and 7-OH in the tail-flick assay at time of maximal analgesic effect (15 min). Mice (n = 5–17 per dose, per treatment; 129S1 strain) were treated with ascending doses of mitragynine or 7-OH by the indicated route of administration in a cumulative dosing procedure, and tail-flick latency was recorded for each animal at 15 min post drug administration (peak analgesic effect). ED50s (95% CI) were as follows: mitragynine, s.c. = 106 (57.4–195) mg/kg; mitragynine, p.o. = 2.05 (1.24–3.38); 7-OH, s.c. = 0.57 (0.19–1.7). The means of each point were calculated as percentage maximal possible effect (%MPE) [(observed latency – baseline latency)/(maximal latency – baseline latency)] × 100. Error bars represent ± SEM. (B) The analgesic effect of mitragynine (10 mg/kg, p.o.) in the tail-flick assay was evaluated 15 min post drug administration in WT, MOR-1 KO, KOR-1 KO, and DOR-1 KO mice, and WT mice following pretreatment with naloxone (1 mg/kg, s.c.), in two independent experiments (n = 5 per group per experiment, n = 10 total per group; 129S6 strain). The analgesic effect of mitragynine was attenuated by naloxone pretreatment and in MOR-1 KO, while the effect was found intact in KOR-1 KO and DOR-1 KO mice. One-way ANOVA: F4,45 = 19.90, p < 0.0001. ****p < 0.0001 relative to WT, ns = p > 0.05 relative to WT. All values are expressed as the mean ± SEM. (C) The analgesic effect of 7-OH (1 mg/kg, s.c.) in the tail-flick assay was evaluated 15 min post drug administration in WT, MOR-1 KO, KOR-1 KO, and DOR-1 KO mice, and WT mice following pretreatment with naloxone (1 mg/kg, s.c.), in two independent experiments (n = 5 per group per experiment, n = 10 total per group; 129S6 strain). The analgesic effect of 7-OH was attenuated by naloxone pretreatment and in MOR-1 KO, while the effect was found intact in KOR-1 KO and DOR-1 KO mice. One-way ANOVA: F4,45 = 101.7, p < 0.0001. ****p < 0.0001 relative to WT, *p < 0.05 relative to WT. All values are expressed as the mean ± SEM.
7-OH is a Potent Analgesic in Mice Acting Through an MOR-Dependent Mechanism
Before further exploring our hypothesis that 7-OH is a key active metabolite of mitragynine, we also wanted to confirm the potent analgesic activity reported for this compound. A dose–response curve was generated for 7-OH in 129 mice using the tail-flick assay (Figure 5A). Consistent with previous reports, (22,25) it was found that 7-OH was a highly potent analgesic (ED50 = 0.6 mg/kg, s.c.), ∼fivefold more potent than p.o. mitragynine. This high potency was consistent with our hypothesis that 7-OH formed as a metabolite, even in small quantities, could be responsible for mediating much of mitragynine’s analgesic activity. Both MOR KO and naloxone pretreatment significantly attenuated the analgesic effects of 7-OH, whereas the analgesic effect was retained in KOR KO and DOR KO animals (Figure 5C). Therefore, the analgesic activity induced by 7-OH was also MOR dependent. We note that the reason for the slight enhancement of analgesia in KOR KO and DOR KO animals remains unclear, but some prior literature has suggested that blockade of DOR may enhance MOR-dependent analgesia. (37) Further, any potential antagonism of KOR or DOR by mitragynine or 7-OH, as has been suggested by in vitro studies, (21) would not be expected to contribute to analgesic effects directly, since antagonists of these receptors are not known to be analgesic on their own. Thus, our findings are consistent with agonism of MOR as the primary mechanism of analgesia for both compounds.
Conversion of Mitragynine to 7-OH also Occurs in Vivo
Having profiled the analgesic effects of mitragynine and 7-OH in mice, we next set out to confirm that the metabolic conversion that we had previously observed in vitro also occurred in living animals. Mice (129S1) were treated with mitragynine (10 mg/kg, s.c.), and plasma and brain samples were collected at 15 and 60 min and analyzed by LC-MS/MS for mitragynine and 7-OH. Both mitragynine (Figure 6A) and 7-OH (Figure 6B) were detected at both time points in both plasma and brain, confirming that 7-OH is indeed formed as a metabolite of mitragynine in vivo and that it enters the brain. These results also permitted a preliminary assessment of the BBB penetration of the two alkaloids by comparison of plasma to whole brain concentrations. By this metric, mitragynine brain penetration was very high (∼1:1 brain/plasma), whereas 7-OH brain penetration was more modest (∼1:5 brain/plasma). However, note that this estimation does not account for tissue binding and, thus, does not necessarily reflect free concentrations of drug.
Figure 6
Figure 6. Conversion of mitragynine to 7-OH was confirmed in vivo in 129S1 mice using LC-MS/MS. (A) Mitragynine was detected in both the plasma and brains of mice treated with mitragynine (10 mg/kg, s.c.). n = 4 per time point for plasma; n = 8–9 per time point for brain. (B) At the same time, 7-OH was also detected in the plasma and brains of the same animals, but at lower concentrations.
It is interesting to note the differences between our findings in vitro in microsome preparations and those in vivo. In microsomes, we found that 7-OH was a major hepatic metabolite. In contrast, in mice, 7-OH was found to be only a minor metabolite in terms of relative concentrations, with a mitragynine/7-OH ratio in plasma of ∼15:1 or more (dependent on time point). This suggests both inherent differences between the metabolic activity of in vitro and in vivo systems, as well as additional hepatic or extrahepatic routes of mitragynine and/or 7-OH metabolism not well accounted for by in vitro microsome preparations.
7-OH Contributes to the Analgesic Activity of Mitragynine as a Metabolite
Having shown that 7-OH was indeed a metabolite of mitragynine in mice, we last examined whether the concentration of this metabolite formed in vivo might be sufficient to contribute to mitragynine’s opioid-mediated analgesic effects. To demonstrate this, we planned an experiment in which the brain concentration of 7-OH observed as a metabolite following administration of an analgesic dose of mitragynine would be compared to the brain concentration of 7-OH observed following direct administration of an equianalgesic dose of 7-OH. Under these conditions, we hypothesized that 7-OH concentrations would be similar if this metabolite was in fact playing a significant role in mediating the analgesic effects of mitragynine. In testing this hypothesis, we chose to administer both compounds by the s.c. route, as we found that it was difficult to obtain reliable dose–response curves for p.o. 7-OH, likely as a result of variable p.o. absorption of the compound. Thus, s.c. administration was necessary to allow the PK of mitragynine and 7-OH to be compared following the same route of administration, which was desirable from the standpoint of consistency.
Equianalgesic doses of mitragynine (140 mg/kg, s.c.) and 7-OH (0.7 mg/kg, s.c.) were selected based on the previously obtained dose–response curves (∼1.3-fold ED50, Figure 5A). Mice (129S1) were treated with the selected doses, and analgesic activity was confirmed at 15 min in the tail-flick assay. As expected, there was no significant difference in tail-flick latency between the two groups (Figure 7A). Immediately after determination of tail-flick latency, mice were sacrificed, and brain samples were collected for analysis. There was no significant difference in the mean brain concentration of 7-OH found in the mitragynine group (formed as metabolite) compared to that found in the 7-OH group (from direct administration) (Figure 7B), consistent with 7-OH being the primary mediator of central analgesic activity in both cases. At the same time, very brain high concentrations (16.6 ± 2.7 μM; mean ± standard error of the mean (SEM)) of mitragynine were observed in the mitragynine-treated animals, while minimal concentrations (0.097 ± 0.012 μM; mean ± SEM) were observed in the 7-OH-treated animals (Figure 7C). This 170-fold difference in mitragynine brain concentration between the two groups had no significant effect on analgesia (Figure 7A), despite the fact that the mitragynine brain concentration in the mitragynine-treated group was ∼50-fold higher than the compound’s binding affinity for mMOR (0.23 μM (21)). Accordingly, we conclude that 7-OH formed as a metabolite is sufficient to explain the opioid-mediated analgesic activity of mitragynine and that the parent compound does not make a significant contribution to its own analgesic activity in mice.
Figure 7
Figure 7. 7-OH formed as a metabolite is sufficient to explain mitragynine’s analgesic effect in 129S1 mice. (A) Selected doses of mitragynine (140 mg/kg, s.c.) and 7-OH (0.7 mg/kg, s.c.) were equianalgesic at 15 min in the tail-flick assay and induced ∼50% MPE. n = 10 per treatment. Two-tailed t test, t(18) = 0.66, p = 0.52. ns = p > 0.05. (B) 7-OH was detected in the brains of the same animals at 15 min (sacrifice and sample collection immediately after tail-flick), and there was no difference in mean brain concentration between the two treatments. n = 9 for mitragynine, n = 10 for 7-OH. Two-tailed t test, t(17) = 1.19, p = 0.25. ns = p > 0.05. (C) Mitragynine was detected in the brains of the same animals at 15 min, and there was a significant difference between the two treatments, with a 170-fold higher brain concentration of mitragynine in the animals directly treated with this drug compared to those treated with 7-OH. n = 10 for mitragynine, n = 6 for 7-OH (four values below the lower limit of quantitation, 5 ng/g, were excluded from analysis). Two-tailed t test, t(13) = 4.88, p = 0.0003. ***p < 0.001. All bars represent mean ± SEM.
Although it does not appear to play an important role in mediating analgesia, the above observation of small quantities of mitragynine formed as a metabolite of 7-OH in vivo was surprising to us. We did not expect to observe this reductive metabolic process, which is effectively the reverse of the observed oxidative metabolism of mitragynine to 7-OH. However, prior literature had indeed reported the partial conversion of 7-OH to mitragynine in vitro in liver microsomes and simulated gastric fluid. (34) The exact mechanism of this transformation remains unclear at this time.
Discussion
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In the present report, we provide evidence that hepatic formation of 7-OH as a metabolite is important in mediating the analgesic activity (and presumably other MOR-mediated effects) of mitragynine, the major active alkaloid of the kratom plant. The analgesic effects of mitragynine and 7-OH each depended on activation of MORs. Further, the analgesia induced by mitragynine appears to depend largely on formation of 7-OH as a metabolite and not on the parent compound. Accordingly, the pharmacological profile of mitragynine may mirror that of 7-OH under certain circumstances, assuming appropriate dose corrections are made to account for the efficiency of conversion to this active metabolite in the system under study. It should be mentioned that during the preparation of this manuscript, other groups separately reported the formation of 7-OH as a metabolite of mitragynine in vitro and in rats, but the mechanistic significance of this finding was not established through pharmacological studies. (38,39) Here we confirmed these concurrent research findings and provided the essential in vivo link demonstrating the pharmacological relevance of 7-OH.
Our results highlight the critical need to consider metabolic pathways and interspecies differences when interpreting preclinical data on kratom or attempting translation of such to man. For example, greater or lesser conversion (relative to mice) of mitragynine to 7-OH in a given species would be expected to increase or decrease, respectively, the potency of mitragynine’s opioid activity in that species. At the same time, if similar metabolic conversion is required for the expression of opioid agonist activity in humans, there exists the possibility that metabolic saturation at high doses might provide a built-in ceiling to the opioid effects of kratom, improving the inherent safety of this material. In fact, preliminary evidence of such metabolic saturation can be inferred from the present results, where the 7-OH brain concentration (0.157 μM) at 15 min after a high dose (140 mg/kg, s.c.) of mitragynine was only around sixfold higher than that (0.027 μM) formed from a 14-fold lower dose (10 mg/kg, s.c.). However, full PK profiles at multiple doses will be needed to confirm the existence of such a phenomenon. Likewise, metabolic differences between individuals will need to be considered, and some individuals may be more sensitive to the opioid agonist effects of kratom by virtue of more efficient CYP3A metabolism.
Indeed, here we demonstrated that 7-OH is formed from mitragynine in HLM and that this conversion appears more efficient compared to that in MLM. Accordingly, we expect that 7-OH will also be observed as a metabolite in humans. This hypothesis is supported by a post-mortem toxicological report from a kratom-associated fatality, where mitragynine and 7-OH were quantified in the blood and urine of the decedent. (40) Interestingly, the mitragynine/7-OH ratios found in blood and urine were ∼7:1 and ∼1.5:1, respectively. It is our opinion that such high relative concentrations of 7-OH compared to mitragynine would be impossible to achieve in the circulation through direct absorption of the minimal quantities of 7-OH found in kratom leaf preparations and commercial extracts, where the mitragynine/7-OH ratio is typically greater than 50:1. Instead, assuming no adulteration of the ingested material, the high concentrations of 7-OH observed in this case support the hypothesis that 7-OH is also formed as an important metabolite in humans. PK studies will ultimately be required to elucidate the importance of 7-OH as a mitragynine metabolite in man.
It is interesting to note the apparent parallel of mitragynine to codeine, a classical opioid that depends on metabolic conversion to the active metabolite morphine by CYP2D6 for inducement of opioid effects. (41) Accordingly, individuals with genetic mutations leading to abnormally high or low activity of CYP2D6 are more or less sensitive to codeine, respectively. (41) However, life-threatening respiratory depression with codeine is rare even in cases of intentional overdose, potentially due to metabolic saturation. (42) Considering that preclinical studies have found mitragynine to induce less respiratory depression than codeine, (24) which is itself relatively safe compared to other classical opioids, we hypothesize that severe respiratory depression or death induced through an opioid mechanism following oral mitragynine (or kratom) consumption is likely to be rare. Consistent with this hypothesis, mitragynine has been found to have low toxicity in mice when administered orally (LD50 > 400 mg/kg). (31,43) Further, the active metabolite 7-OH has itself been found to be a partial, G protein-biased agonist at MOR, signaling properties that are hypothesized to lead to improved respiratory safety among MOR agonists. (21,25) Overall, these considerations are consistent with the limited reports of kratom overdose deaths (44 in total for all time as of 2017, despite millions of worldwide users) (14) in comparison to all opioid overdose deaths (∼50 000 in 2017 alone). (44) However, such hypotheses must be confirmed in humans before definitive conclusions are reached regarding the respiratory safety of mitragynine or kratom.
Metabolic processes are also likely to be an important determinant of the abuse liability of kratom and its alkaloids. It has recently been found in two independent studies that mitragynine does not support self-administration (SA) in rats, while 7-OH is self-administered. (45,46) We suspect that this apparent contradiction may be explained, at least in part, by the metabolic effects reported here. Mitragynine has been shown to be more potent (in terms of analgesic effects) in rats by the p.o. route (24) versus the intravenous (i.v.) route used in the reported self-administration studies, thus complicating appropriate dose selection and challenging the relevance of i.v. SA studies for assessing the abuse liability of p.o. mitragynine (or kratom). Further, the likely necessity of metabolic conversion of mitragynine to 7-OH for the induction of opioid agonist effects might result in a temporal dissociation between drug administration and experience of rewarding effects, further complicating the interpretation of SA studies. Lastly, certain individuals with enhanced or deficient CYP3A4 activity may experience greater or lesser reinforcing effects following mitragynine (or kratom) consumption depending on the extent of conversion to 7-OH. Again, a comparison to codeine is warranted, as the abuse liability of this compound has been found to depend on formation of active metabolites and vary depending on interindividual differences in CYP metabolic efficiency. (47) There also remains the possibility that mitragynine exerts a buffering effect on the opioid agonist activity of its 7-OH metabolite, either through direct competitive antagonism at MOR or through other as-yet-unknown pharmacological mechanisms. Ultimately, only controlled clinical trials will be able to definitively resolve these issues for mitragynine.
In addition to interspecies metabolic differences, the in vitro pharmacology of mitragynine at the opioid receptors is also species-dependent and complicates the translation of the present results to humans. For example, we have previously shown in an in vitro assay that mitragynine acts as a competitive antagonist at the mMOR but as a weak partial agonist at the hMOR. (21) Accordingly, in humans, mitragynine itself might contribute to its own analgesic effects directly via the parent compound, in contrast to the present mouse study, where most of the analgesic effects appeared to be induced through the 7-OH metabolite. The interplay between mitragynine and 7-OH in mediating kratom’s purported analgesic effects will thus require further exploration in humans.
Lastly, it is important to mention that extracts of the kratom plant have been found to both inhibit and induce various CYP enzymes. (48,49) Accordingly, it remains a possibility that the mixture of compounds contained in the plant or its extracts may present a distinct opioid pharmacology compared to isolated mitragynine, by virtue of interference of other chemical species with the hepatic conversion of mitragynine to 7-OH. Thus, additional study of metabolic drug–drug interactions among kratom compounds will also be necessary.
Conclusion
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We have found that the opioid pharmacology of mitragynine is complicated by the important role of an active metabolite, 7-OH, in mediating its activity. This apparent requirement for metabolic activation is consistent with the higher analgesic potency of mitragynine administered orally versus parenterally in animals. Further, it suggests a possible explanation for the seemingly improved safety profile of mitragynine compared to classical opioid agonists. However, the critical involvement of hepatic metabolism also complicates our understanding of mitragynine’s pharmacology and introduces the possibility of interindividual variability in the compound’s potential therapeutic effects and side effects. We believe mitragynine and related compounds have great potential as future therapeutics, but metabolic processes must be carefully considered as the field continues to advance.
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscentsci.9b00141.
Opioid functional activity of desmethyl metabolites, additional microsome and plasma stability experiments, formation of 7-OH in mouse microsomes, synthetic scheme and procedures for preparation of deuterated analogues, biological procedures (PDF)
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Author Information
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- Dalibor Sames - Department of Chemistry, , , , Columbia University, New York, New York 10027, United States;
http://orcid.org/0000-0001-6911-2260;
- Andrew C. Kruegel - Department of Chemistry, , , , Columbia University, New York, New York 10027, United States;http://orcid.org/0000-0002-9156-8755
- Gavril W. Pasternak - Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States;http://orcid.org/0000-0003-0060-6996
A.C.K. and R.U. contributed equally to this work.
Acknowledgments
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This work was generously supported by the National Institute on Drug Abuse (R01DA046487 and R21DA045884), the American Kratom Association, and the Hope for Depression Research Foundation. S.M. also received support from the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (W81XWH-17-1-0256) and acknowledges National Cancer Institute Cancer Center Support Grant No. P30 CA008748. We also thank Dr. B. Fowler (Dept. of Chemistry, Columbia Univ.) for HRMS analysis.
References
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This article references 49 other publications.
- 1Kruegel, A. C.; Grundmann, O. The Medicinal Chemistry and Neuropharmacology of Kratom: A Preliminary Discussion of a Promising Medicinal Plant and Analysis of Its Potential for Abuse. Neuropharmacology 2018, 134, 108– 120, DOI: 10.1016/j.neuropharm.2017.08.026Google Scholar1The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuseKruegel, Andrew C.; Grundmann, OliverNeuropharmacology (2018), 134 (Part_A), 108-120CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu-opioid receptors and competitive antagonists at kappa- and delta-opioid receptors. Furthermore, both alkaloids are G protein-biased agonists of the mu-opioid receptor and therefore, may induce less respiratory depression than classical opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex pharmacol. profile of raw kratom exts., although characterization of effects at these other targets remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-hydroxymitragynine used in animal studies can be related to single doses of raw kratom plant commonly consumed by humans, permitting preliminary interpretation of expected behavioral and physiol. effects in man based on this preclin. data and comparison to both anecdotal human experience and multiple epidemiol. surveys. Kratom exposure alone has not been causally assocd. with human fatalities to date. However, further research is needed to clarify the complex mechanism of action of the Mitragyna alkaloids and unlock their full therapeutic potential.
- 2Adkins, J. E.; Boyer, E. W.; McCurdy, C. R. Mitragyna Speciosa, a Psychoactive Tree from Southeast Asia with Opioid Activity. Curr. Top. Med. Chem. 2011, 11 (9), 1165– 1175, DOI: 10.2174/156802611795371305Google Scholar2Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activityAdkins, Jessica E.; Boyer, Edward W.; McCurdy, Christopher R.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2011), 11 (9), 1165-1175CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. Mitragyna speciosa Korth. (Rubiaceae) is a tree that is commonly found in Southeast Asia. Leaves from this tree have been traditionally been used for both their stimulant properties as well as an opium substitute. The tree/leaves are currently illegal in four countries, but is currently legal and widely available in the United States. To date over 40 compds. have been isolated from the leaves. The major alkaloid found within the crude ext., mitragynine, has been the subject of many pharmacol. studies. In addn. to the pharmacol. studies, two total syntheses of mitragynine have been published as well as general structure-activity relationships with respect to opioid activity.
- 3Prozialeck, W. C.; Jivan, J. K.; Andurkar, S. V. Pharmacology of Kratom: An Emerging Botanical Agent with Stimulant, Analgesic and Opioid-like Effects. J. Am. Osteopath. Assoc. 2012, 112 (12), 792– 799Google Scholar3Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effectsProzialeck Walter C; Jivan Jateen K; Andurkar Shridhar VThe Journal of the American Osteopathic Association (2012), 112 (12), 792-9 ISSN:.Kratom (Mitragyna speciosa) is a plant indigenous to Thailand and Southeast Asia. Kratom leaves produce complex stimulant and opioid-like analgesic effects. In Asia, kratom has been used to stave off fatigue and to manage pain, diarrhea, cough, and opioid withdrawal. Recently, kratom has become widely available in the United States and Europe by means of smoke shops and the Internet. Analyses of the medical literature and select Internet sites indicate that individuals in the United States are increasingly using kratom for the self-management of pain and opioid withdrawal. Kratom contains pharmacologically active constituents, most notably mitragynine and 7-hydroxymitragynine. Kratom is illegal in many countries. Although it is still legal in the United States, the US Drug Enforcement Administration has placed kratom on its "Drugs and Chemicals of Concern" list. Physicians should be aware of the availability, user habits, and health effects of kratom. Further research on the therapeutic uses, toxic effects, and abuse potential of kratom and its constituent compounds are needed.
- 4Singh, D.; Narayanan, S.; Vicknasingam, B. Traditional and Non-Traditional Uses of Mitragynine (Kratom): A Survey of the Literature. Brain Res. Bull. 2016, 126, 41– 46, DOI: 10.1016/j.brainresbull.2016.05.004Google Scholar4Traditional and non-traditional uses of Mitragynine (Kratom): A survey of the literatureSingh, Darshan; Narayanan, Suresh; Vicknasingam, BalasingamBrain Research Bulletin (2016), 126 (Part_1), 41-46CODEN: BRBUDU; ISSN:0361-9230. (Elsevier)The objective of the paper was to highlight the differences in the traditional and non-traditional users of kratom in the South East Asian and Western contexts. A literature survey of published kratom studies among humans was conducted. Forty published studies relevant to the objective were reviewed. Apart from the differences in the sources of supply, patterns of use and social acceptability of kratom within these two regions, the most interesting finding is its evolution to a recreational drug in both settings and the severity of the adverse effects of kratom use reported in the West. While several cases of toxicity and death have emerged in the West, such reports have been non-existent in South East Asia where kratom has had a longer history of use. We highlight the possible reasons for this as discussed in the literature. More importantly, it should be borne in mind that the individual clin. case-reports emerging from the West that link kratom use to adverse reactions or fatalities frequently pertained to kratom used together with other substances. Therefore, there is a danger of these reports being used to strengthen the case for legal sanction against kratom. This would be unfortunate since the experiences from South East Asia suggest considerable potential for therapeutic use among people who use drugs. Despite its addictive properties, reported side-effects and its tendency to be used a recreational drug, more scientific clin. human studies are necessary to det. its potential therapeutic value.
- 5Takayama, H. Chemistry and Pharmacology of Analgesic Indole Alkaloids from the Rubiaceous Plant, Mitragyna Speciosa. Chem. Pharm. Bull. 2004, 52 (8), 916– 928, DOI: 10.1248/cpb.52.916Google Scholar5Chemistry and pharmacology of analgesic indole alkaloids from the Rubiaceous plant, Mitragyna speciosaTakayama, HiromitsuChemical & Pharmaceutical Bulletin (2004), 52 (8), 916-928CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)A review. The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochem. studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compds. were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of mitragynine, the major constituent of this plant, and its analogs were found in in vitro and in vivo expts. and the mechanisms underlying the analgesic activity were clarified. The essential structural features of mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacol. evaluation of the natural and synthetic derivs. Among the mitragynine derivs., 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.
- 6Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi, N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto, L. T.; Watanabe, K.; Murayama, T.; Horie, S. Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands. J. Med. Chem. 2002, 45 (9), 1949– 1956, DOI: 10.1021/jm010576eGoogle Scholar6Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid LigandsTakayama, Hiromitsu; Ishikawa, Hayato; Kurihara, Mika; Kitajima, Mariko; Aimi, Norio; Ponglux, Dhavadee; Koyama, Fumi; Matsumoto, Kenjiro; Moriyama, Tomoyuki; Yamamoto, Leonard T.; Watanabe, Kazuo; Murayama, Toshihiko; Horie, SyunjiJournal of Medicinal Chemistry (2002), 45 (9), 1949-1956CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mitragynine is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compd., synthesis of some derivs., evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compds. for μ-, δ-, and κ-receptors were detd. in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivs. of mitragynine, i.e., mitragynine pseudoindoxyl (I) and 7-hydroxymitragynine, were found as opioid agonists with higher potency than morphine in the expt. with guinea pig ileum. In addn., I induced an analgesic activity in the tail flick test in mice.
- 7Raffa, R. B.; Beckett, J. R.; Brahmbhatt, V. N.; Ebinger, T. M.; Fabian, C. A.; Nixon, J. R.; Orlando, S. T.; Rana, C. A.; Tejani, A. H.; Tomazic, R. J. Orally Active Opioid Compounds from a Non-Poppy Source. J. Med. Chem. 2013, 56 (12), 4840– 4848, DOI: 10.1021/jm400143zGoogle Scholar7Orally Active Opioid Compounds from a Non-Poppy SourceRaffa, Robert B.; Beckett, Jaclyn R.; Brahmbhatt, Vivek N.; Ebinger, Theresa M.; Fabian, Chrisjon A.; Nixon, Justin R.; Orlando, Steven T.; Rana, Chintan A.; Tejani, Ali H.; Tomazic, Robert J.Journal of Medicinal Chemistry (2013), 56 (12), 4840-4848CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The basic science and clin. use of morphine and other opioid drugs are based almost exclusively on the exts. or analogs of compds. isolated from a single source, the opium poppy (Papaver somniferum). However, it now appears that biol. diversity has evolved an alternative source. Specifically, at least two alkaloids isolated from the plant Mitragyna speciosa, mitragynine ((E)-2-[(2S,3S)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[3,2-h]quinolizin-2-yl]-3-methoxyprop-2-enoic acid Me ester; 9-methoxy coryantheidine; MG) and 7-hydroxymitragynine (7-OH-MG), and several synthetic analogs of these natural products display centrally mediated (supraspinal and spinal) antinociceptive (analgesic) activity in various pain models. Several characteristics of these compds. suggest a classic opioid mechanism of action: nanomolar affinity for opioid receptors, competitive interaction with the opioid receptor antagonist naloxone, and two-way analgesic cross-tolerance with morphine. However, other characteristics of the compds. suggest novelty, particularly chem. structure and possible greater sepn. from side effects. We review the chem. and pharmacol. properties of these compds.
- 8Suhaimi, F. W.; Yusoff, N. H. M.; Hassan, R.; Mansor, S. M.; Navaratnam, V.; Müller, C. P.; Hassan, Z. Neurobiology of Kratom and Its Main Alkaloid Mitragynine. Brain Res. Bull. 2016, 126, 29– 40, DOI: 10.1016/j.brainresbull.2016.03.015Google Scholar8Neurobiology of Kratom and its main alkaloid mitragynineSuhaimi, Farah W.; Yusoff, Nurul H. M.; Hassan, Rahimah; Mansor, Sharif M.; Navaratnam, Visweswaran; Muller, Christian P.; Hassan, ZurinaBrain Research Bulletin (2016), 126 (Part_1), 29-40CODEN: BRBUDU; ISSN:0361-9230. (Elsevier)Kratom or its main alkaloid, mitragynine is derived from the plant Mitragyna speciosa Korth which is indigenous to Southeast Asian countries. This substance has become widely available in other countries like Europe and United States due to its opium- and coca-like effects. In this article, we have reviewed available reports on mitragynine and other M. speciosa exts. M. speciosa has been proven to have a rewarding effect and is effective in alleviating the morphine and ethanol withdrawal effects. However, studies in human revealed that prolonged consumption of this plant led to dependence and tolerance while cessation caused a series of aversive withdrawal symptoms. Findings also showed that M. speciosa exts. possess antinociceptive, anti-inflammatory, anti-depressant, and muscle relaxant properties. Available evidence further supports the adverse effects of M. speciosa prepns., mitragynine on cognition. Pharmacol. activities are mainly mediated via opioid receptors as well as neuronal Ca2+ channels, expression of cAMP and CREB protein and via descending monoaminergic system. Physicochem. properties of mitragynine have been documented which may further explain the variation in pharmacol. responses. In summary, current researchs on its main indole alkaloid, mitragynine suggest both therapeutic and addictive potential but further research on its mol. effects is needed.
- 9Grundmann, O. Patterns of Kratom Use and Health Impact in the US—Results from an Online Survey. Drug Alcohol Depend. 2017, 176, 63– 70, DOI: 10.1016/j.drugalcdep.2017.03.007Google Scholar9Patterns of Kratom use and health impact in the US-Results from an online surveyGrundmann OliverDrug and alcohol dependence (2017), 176 (), 63-70 ISSN:.BACKGROUND: Kratom preparations have raised concerns of public health and safety in the US. Investigation into the demographics, perceived beneficial and detrimental effects of Kratom as well as common doses and purposes of its use are important to properly evaluate its potential health impact. METHODS: An anonymous cross-sectional online survey was conducted in October 2016 of 10,000 current Kratom users through available social media and online resources from the American Kratom Association. A total of 8049 respondents completed the survey. RESULTS: Kratom is primarily used by a middle-aged (31-50 years), middle-income ($35,000 and above) population for purposes of self-treating pain (68%) and emotional or mental conditions (66%). Kratom preparations present with a dose-dependent effect with negative effects, which were primarily gastrointestinal related including nausea and constipation, mainly presenting at high (5g or more/dose) and more frequent (22 or more doses/week) dosing. CONCLUSIONS: Kratom shows a dose-dependent opioid-like effect providing self-reported perceived beneficial effects in alleviating pain and relieving mood disorders. Kratom was primarily used for self-treatment of pain, mood disorders, and withdrawal symptoms associated with prescription opioid use.
- 10Swogger, M. T.; Hart, E.; Erowid, F.; Erowid, E.; Trabold, N.; Yee, K.; Parkhurst, K. A.; Priddy, B. M.; Walsh, Z. Experiences of Kratom Users: A Qualitative Analysis. J. Psychoact. Drugs 2015, 47 (5), 360– 367, DOI: 10.1080/02791072.2015.1096434Google Scholar10Experiences of Kratom Users: A Qualitative AnalysisSwogger Marc T; Hart Elaine; Yee Kaila; Parkhurst Kimberly A; Priddy Brittany M; Erowid Fire; Erowid Earth; Trabold Nicole; Walsh ZachJournal of psychoactive drugs (2015), 47 (5), 360-7 ISSN:0279-1072.Kratom (Mitragyna speciosa) is a psychoactive plant that has been used since at least 1836 in folk medicine in Southeast Asian countries. More recently, kratom has become widely available in the West and is used for both recreational and medicinal purposes. There has, however, been little scientific research into the short- and long-term effects of kratom in humans, and much of the information available is anecdotal. To supplement the increasing scientific understanding of kratom's pharmacology and research into its effects in animals, we report the results of a qualitative analysis of first-hand descriptions of human kratom use that were submitted to, and published by, a psychoactive substance information website (Erowid.org). Themes that emerged from these experience reports indicate that kratom may be useful for analgesia, mood elevation, anxiety reduction, and may aid opioid withdrawal management. Negative response themes also emerged, indicating potential problems and unfavorable "side" effects, especially stomach upset and vomiting. Based on our analyses, we present preliminary hypotheses for future examination in controlled, quantitative studies of kratom.
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- 20Ponglux, D.; Wongseripipatana, S.; Takayama, H.; Kikuchi, M.; Kurihara, M.; Kitajima, M.; Aimi, N.; Sakai, S. A New Indole Alkaloid, 7α-Hydroxy-7H-Mitragynine, from Mitragyna Speciosa in Thailand. Planta Med. 1994, 60 (6), 580– 581, DOI: 10.1055/s-2006-959578Google Scholar20A new indole alkaloid, 7α-hydroxy-7H-mitragynine, from Mitragyna speciosa in Thailand.Ponglux, Dhavadee; Wongseripipatana, Sumphan; Takayama, Hiromitsu; Kikuchi, Masae; Kurihara, Mika; Kitajima, Mariko; Aimi, Norio; Sakai, Shin-ichiroPlanta Medica (1994), 60 (6), 580-1CODEN: PLMEAA; ISSN:0032-0943. (Thieme)7α-Hydroxy-7H-mitragynine (I) was isolated from M. speciosa. I was synthesized from mitragynine by treatment with iodosobenzene diacetate in MeCN.
- 21Kruegel, A. C.; Gassaway, M. M.; Kapoor, A.; Váradi, A.; Majumdar, S.; Filizola, M.; Javitch, J. A.; Sames, D. Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. J. Am. Chem. Soc. 2016, 138 (21), 6754– 6764, DOI: 10.1021/jacs.6b00360Google Scholar21Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor ModulatorsKruegel, Andrew C.; Gassaway, Madalee M.; Kapoor, Abhijeet; Varadi, Andras; Majumdar, Susruta; Filizola, Marta; Javitch, Jonathan A.; Sames, DaliborJournal of the American Chemical Society (2016), 138 (21), 6754-6764CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is assocd. with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacol. properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analog 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (-)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich-Michael reaction sequence as the key transformation. Pharmacol. evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chem. transformations developed in the total synthesis allowed the elucidation of previously unexplored structure-activity relationships (SAR) within the Mitragyna scaffold. Mol. docking studies, in combination with the obsd. chem. SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids.
- 22Matsumoto, K.; Horie, S.; Ishikawa, H.; Takayama, H.; Aimi, N.; Ponglux, D.; Watanabe, K. Antinociceptive Effect of 7-Hydroxymitragynine in Mice: Discovery of an Orally Active Opioid Analgesic from the Thai Medicinal Herb Mitragyna Speciosa. Life Sci. 2004, 74 (17), 2143– 2155, DOI: 10.1016/j.lfs.2003.09.054Google Scholar22Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosaMatsumoto, Kenjiro; Horie, Syunji; Ishikawa, Hayato; Takayama, Hiromitsu; Aimi, Norio; Ponglux, Dhavadee; Watanabe, KazuoLife Sciences (2004), 74 (17), 2143-2155CODEN: LIFSAK; ISSN:0024-3205. (Elsevier Science Inc.)Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa. The authors previously reported the morphine-like action of mitragynine and its related compds. in the in vitro assays. In the present study, the authors investigated the opioid effects of 7-hydroxymitragynine, which is isolated as its novel constituent, on contraction of isolated ileum, binding of the specific ligands to opioid receptors and nociceptive stimuli in mice. In guinea-pig ileum, 7-hydroxymitragynine inhibited elec. induced contraction through the opioid receptors. Receptor-binding assays revealed that 7-hydroxymitragynine has a higher affinity for μ-opioid receptors relative to the other opioid receptors. Administration of 7-hydroxymitragynine (2.5-10 mg/kg, s.c.) induced dose-dependent antinociceptive effects in tail-flick and hot-plate tests in mice. Its effect was more potent than that of morphine in both tests. When orally administered, 7-hydroxymitragynine (5-10 mg/kg) showed potent antinociceptive activities in tail-flick and hot-plate tests. In contrast, only weak antinociception was obsd. in the case of oral administration of morphine at a dose of 20 mg/kg. It was found that 7-hydroxymitragynine is a novel opioid agonist that is structurally different from the other opioid agonists, and has potent analgesic activity when orally administered.
- 23Matsumoto, K.; Mizowaki, M.; Suchitra, T.; Takayama, H.; Sakai, S.; Aimi, N.; Watanabe, H. Antinociceptive Action of Mitragynine in Mice: Evidence for the Involvement of Supraspinal Opioid Receptors. Life Sci. 1996, 59 (14), 1149– 1155, DOI: 10.1016/0024-3205(96)00432-8Google Scholar23Antinociceptive action of mitragynine in mice: evidence for the involvement of supraspinal opioid receptorsMatsumoto, Kinzo; Mizowaki, Maho; Suchitra, Thongpradichote; Takayama, Hiromitsu; Sakai, Shin-ichiro; Aimi, Norio; Watanabe, HiroshiLife Sciences (1996), 59 (14), 1149-1155CODEN: LIFSAK; ISSN:0024-3205. (Elsevier)Mitragynine is a major alkaloidal constituent extd. from the young leaves of Mitragyna speciosa Korth. (Rubiaceae). The authors investigated an antinociceptive activity of i.p. and intracerebroventricular (i.c.v.) injection of this alkaloid by the tail-pinch and hot-plate tests in mice, and evaluated the mechanisms of the action using naloxone, an opioid receptor antagonist. Mitragynine (5.0-30 mg/kg, i.p. and 1.0-10 μg/mouse, i.c.v.) exerted a dose-dependent antinociceptive activity which was maximal at 15-45 min after injection in the tail-pinch and hot-plate tests, but it did not induce a morphine-like behavioral change. The antinociceptive actions of i.p. mitragynine were completely abolished by both s.c. (2 mg/kg) and i.c.v (10 μg/mouse) naloxone. The action of i.c.v. mitragynine (10 μg/mouse) was also antagonized by i.c.v. naloxone (10 μg/mouse). These results indicate that mitragynine itself can induce antinociception by acting in the brain, and that the supraspinal opioid systems are at least partly involved in the antinociceptive action of mitragynine in mice.
- 24Macko, E.; Weisbach, J. A.; Douglas, B. Some Observations on the Pharmacology of Mitragynine. Arch. Int. Pharmacodyn. thérapie 1972, 198 (1), 145– 161Google Scholar24Pharmacology of mitragynineMacko, E.; Weisbach, J. A.; Douglas, B.Archives Internationales de Pharmacodynamie et de Therapie (1972), 198 (1), 145-61CODEN: AIPTAK; ISSN:0003-9780.Mitragynine-HCl (SKF 12711A) (I-HCl) [36455-45-5] or mitragynine ethanedisulfonate (SKF 12711J) [36455-46-6] exhibited analgesic and antitussive properties in animals. Unlike the narcotic analgesics, I had little effect on gastric mobility, failed to produce excitement in cats, was not antagonized by nalorphine, and had only weak respiratory depressant activity in anesthetized animals.
- 25Váradi, A.; Marrone, G. F.; Palmer, T. C.; Narayan, A.; Szabó, M. R.; Le Rouzic, V.; Grinnell, S. G.; Subrath, J. J.; Warner, E.; Kalra, S.; Hunkele, A.; Pagirsky, J.; Eans, S. O.; Medina, J. M.; Xu, J.; Pan, Y.-X.; Borics, A.; Pasternak, G. W.; McLaughlin, J. P.; Majumdar, S. Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2. J. Med. Chem. 2016, 59 (18), 8381– 8397, DOI: 10.1021/acs.jmedchem.6b00748Google Scholar25Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2Varadi, Andras; Marrone, Gina F.; Palmer, Travis C.; Narayan, Ankita; Szabo, Marton R.; Le Rouzic, Valerie; Grinnell, Steven G.; Subrath, Joan J.; Warner, Evelyn; Kalra, Sanjay; Hunkele, Amanda; Pagirsky, Jeremy; Eans, Shainnel O.; Medina, Jessica M.; Xu, Jin; Pan, Ying-Xian; Borics, Attila; Pasternak, Gavril W.; McLaughlin, Jay P.; Majumdar, SusrutaJournal of Medicinal Chemistry (2016), 59 (18), 8381-8397CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacol. Herein, we report the pharmacol. and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [35S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is assocd. with opioid side effects. Addnl., 3 developed analgesic tolerance more slowly than morphine, showed limited phys. dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.
- 26Schmid, C. L.; Kennedy, N. M.; Ross, N. C.; Lovell, K. M.; Yue, Z.; Morgenweck, J.; Cameron, M. D.; Bannister, T. D.; Bohn, L. M. Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics. Cell 2017, 171 (5), 1165– 1175e13, DOI: 10.1016/j.cell.2017.10.035Google Scholar26Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid AnalgesicsSchmid, Cullen L.; Kennedy, Nicole M.; Ross, Nicolette C.; Lovell, Kimberly M.; Yue, Zhizhou; Morgenweck, Jenny; Cameron, Michael D.; Bannister, Thomas D.; Bohn, Laura M.Cell (Cambridge, MA, United States) (2017), 171 (5), 1165-1175.e13CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Biased agonism has been proposed as a means to sep. desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compds. spanning a wide range of signaling bias. We find that β-arrestin-biased compds., such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression.
- 27Soergel, D. G.; Subach, R. A.; Burnham, N.; Lark, M. W.; James, I. E.; Sadler, B. M.; Skobieranda, F.; Violin, J. D.; Webster, L. R. Biased Agonism of the μ-Opioid Receptor by TRV130 Increases Analgesia and Reduces on-Target Adverse Effects versus Morphine: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Volunteers. Pain 2014, 155 (9), 1829– 1835, DOI: 10.1016/j.pain.2014.06.011Google Scholar27Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteersSoergel, David G.; Subach, Ruth Ann; Burnham, Nancy; Lark, Michael W.; James, Ian E.; Sadler, Brian M.; Skobieranda, Franck; Violin, Jonathan D.; Webster, Lynn R.Pain (2014), 155 (9), 1829-1835CODEN: PAINDB; ISSN:0304-3959. (Elsevier B.V.)Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclin. models suggest that differential activation of signaling pathways downstream of these receptors dissocs. analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single i.v. injections of the biased ligand TRV130 (1.5, 3, or 4.5 mg), placebo, or morphine (10 mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiog., clin. lab. values), and analgesia (cold pain test) vs. placebo. Other measures included respiratory drive (minute vol. after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5 mg) elicited higher peak analgesia (105, 116 s latency vs 75 s for morphine, P < .02), with faster onset and similar duration of action. More subjects doubled latency or achieved max. latency (180 s) with TRV130 (3, 4.5 mg). Respiratory drive redn. was greater after morphine than any TRV130 dose (-15.9 for morphine vs. -7.3, -7.6, and -9.4 h * L/min, P < .05). More subjects experienced severe nausea after morphine (n = 7) than TRV130 1.5 or 3 mg (n = 0, 1), but not 4.5 mg (n = 9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less redn. in respiratory drive and less severe nausea. This demonstrates early clin. translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.
- 28Raehal, K. M.; Schmid, C. L.; Groer, C. E.; Bohn, L. M. Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance. Pharmacol. Rev. 2011, 63 (4), 1001– 1019, DOI: 10.1124/pr.111.004598Google Scholar28Functional selectivity at the μ-opioid receptor: implications for understanding opioid analgesia and toleranceRaehal, Kirsten M.; Schmid, Cullen L.; Groer, Chad E.; Bohn, Laura M.Pharmacological Reviews (2011), 63 (4), 1001-1019CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)A review. Opioids are the most effective analgesic drugs for the management of moderate or severe pain, yet their clin. use is often limited because of the onset of adverse side effects. Drugs in this class produce most of their physiol. effects through activation of the μ opioid receptor; however, an increasing no. of studies demonstrate that different opioids, while presumably acting at this single receptor, can activate distinct downstream responses, a phenomenon termed functional selectivity. Functional selectivity of receptor-mediated events can manifest as a function of the drug used, the cellular or neuronal environment examd., or the signaling or behavioral measure recorded. This review summarizes both in vitro and in vivo work demonstrating functional selectivity at the μ opioid receptor in terms of G protein coupling, receptor phosphorylation, interactions with β-arrestins, receptor desensitization, internalization and signaling, and details on how these differences may relate to the progression of analgesic tolerance after their extended use.
- 29Kelly, E. Efficacy and Ligand Bias at the μ-Opioid Receptor. Br. J. Pharmacol. 2013, 169 (7), 1430– 1446, DOI: 10.1111/bph.12222Google Scholar29Efficacy and ligand bias at the μ-opioid receptorKelly, E.British Journal of Pharmacology (2013), 169 (7), 1430-1446CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)A review. In order to describe drug action at a GPCR, a full understanding of the pharmacol. terms affinity, efficacy and potency is necessary. This is true whether comparing the ability of different agonists to produce a measurable response in a cell or tissue, or detg. the relative ability of an agonist to activate a single receptor subtype and produce multiple responses. There is a great deal of interest in the μ-opioid receptor (MOP receptor) and the ligands that act at this GPCR not only because of the clin. important analgesic effects produced by MOP agonists but also because of their liability to induce adverse effects such as respiratory depression and dependence. Our understanding of the mechanisms underlying these effects, as well as the ability to develop new, more effective MOP receptor drugs, depends upon the accurate detn. of the efficacy with which these ligands induce coupling of MOP receptors to downstream signaling events. In this review, which is written with the min. of math. content, the basic meaning of terms including efficacy, intrinsic activity and intrinsic efficacy is discussed, along with their relevance to the field of MOP receptor pharmacol., and in particular in relation to biased agonism at this important GPCR.
- 30Majumdar, S.; Devi, L. A. Strategy for Making Safer Opioids Bolstered. Nature 2018, 553 (7688), 286– 288, DOI: 10.1038/d41586-018-00045-1Google Scholar30Strategy for making safer opioids bolsteredMajumdar, Susruta; Devi, Lakshmi A.Nature (London, United Kingdom) (2018), 553 (7688), 286-288CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Compds. have been made that activate only the G-protein signalling pathway when bound to the μ-opioid receptor - the target of opioid pain relievers. These compds. lack one of the main side effects of currently used opioids.
- 31Sabetghadam, A.; Navaratnam, V.; Mansor, S. M. Dose-Response Relationship, Acute Toxicity, and Therapeutic Index between the Alkaloid Extract of Mitragyna Speciosa and Its Main Active Compound Mitragynine in Mice. Drug Dev. Res. 2013, 74 (1), 23– 30, DOI: 10.1002/ddr.21052Google Scholar31Dose-Response Relationship, Acute Toxicity, and Therapeutic Index between the Alkaloid Extract of Mitragyna speciosa and Its Main Active Compound Mitragynine in MiceSabetghadam, Azadeh; Navaratnam, Visweswaran; Mansor, Sharif MahsufiDrug Development Research (2013), 74 (1), 23-30CODEN: DDREDK; ISSN:0272-4391. (Wiley-Liss, Inc.)Preclin. Research Mitragyna speciosa is a widely used medicinal plant that is commonly used for its morphine-like effect sin folklore medicine in Thailand and Malaysia due to its ability to reduce pain and ameliorate withdrawal signs after cessation of opioid abuse. The aim of the present study was to det. and compare the relative safety and therapeutic indexes of M. speciosa alkaloid ext. and its major component, mitragynine. An alkaloid ext. (20-400 mg/kg) from the leaves of M. speciosa, as well as mitragynine (4.2-84 mg/kg), was orally administered to mice; dose-response relationship, ED50 and LD50 values, as well as the therapeutic index (TI), for the two substances were detd. and compared with that of morphine (2.5-10 mg/kg, s.c.). The results showed a significant dose-dependent response in both ext. (50 mg/kg onward) and mitragynine (10.5 mg/kg) with a higher potency of mitragynine than that of the ext. Although the LD50 for the ext. (591 mg/kg) was higher than that of mitragynine (477 mg/kg), the TI for mitragynine was wider than that of the ext. (21:3). The present study indicated that mitragynine is relatively safer when compared with the alkaloid ext. of M. speciosa in mice.
- 32Philipp, A. A.; Wissenbach, D. K.; Zoerntlein, S. W.; Klein, O. N.; Kanogsunthornrat, J.; Maurer, H. H. Studies on the Metabolism of Mitragynine, the Main Alkaloid of the Herbal Drug Kratom, in Rat and Human Urine Using Liquid Chromatography-Linear Ion Trap Mass Spectrometry. J. Mass Spectrom. 2009, 44 (8), 1249– 1261, DOI: 10.1002/jms.1607Google Scholar32Studies on the metabolism of mitragynine, the main alkaloid of the herbal drug Kratom, in rat and human urine using liquid chromatography-linear ion trap mass spectrometryPhilipp, Anika A.; Wissenbach, Dirk K.; Zoerntlein, Siegfried W.; Klein, Oliver N.; Kanogsunthornrat, Jidapha; Maurer, Hans H.Journal of Mass Spectrometry (2009), 44 (8), 1249-1261CODEN: JMSPFJ; ISSN:1076-5174. (John Wiley & Sons Ltd.)Mitragynine (MG) is an indole alkaloid of the Thai medicinal plant Mitragyna speciosa (Kratom in Thai) and reported to have opioid agonistic properties. Because of its stimulant and euphoric effects, Kratom is used as a herbal drug of abuse. The aim of the presented study is to identify the phase I and II metabolites of MG in rat and human urine after solid-phase extn. (SPE) using liq. chromatog.-linear ion trap mass spectrometry providing detailed structure information in the MSn mode particularly with high resoln. The seven identified phase I metabolites indicated that MG was metabolized by hydrolysis of the methylester in position 16, O-demethylation of the 9-methoxy group and of the 17-methoxy group, followed, via the intermediate aldehydes, by oxidn. to carboxylic acids or redn. to alcs. and combinations of some steps. In rats, four metabolites were addnl. conjugated to glucuronides and one to sulfate, but in humans, three metabolites to glucuronides and three to sulfates. Copyright © 2009 John Wiley & Sons, Ltd.
- 33Finch, N.; Gemenden, C. W.; Hsu, I. H. C.; Kerr, A.; Sim, G. A.; Taylor, W. I. Oxidative Transformations of Indole Alkaloids. III. Pseudoindoxyls from Yohimbinoid Alkaloids and Their Conversion to “Invert” Alkaloids1,2. J. Am. Chem. Soc. 1965, 87 (10), 2229– 2235, DOI: 10.1021/ja01088a024Google Scholar33Oxidative transformations of indole alkaloids. III. Pseudo indoxyls from yohimbinoid alkaloids and their conversion to "invert" alkaloidsFinch, Neville; Gemenden, C. W.; Hsu, Iva Hsiu-Chu; Kerr, Ann; Sim, G. A.; Taylor, W. I.Journal of the American Chemical Society (1965), 87 (10), 2229-35CODEN: JACSAT; ISSN:0002-7863.cf. CA 58, 14011b. Several tetrahydro-β-carboline alkaloids were converted to their pseudoindoxyl analogs by treatment of the derived acyloxy indolenines with base. By use of such a transformation the yellow alkaloid of Rauwolfia vomitoria Afzel. was identified as isoreserpiline pseudoindoxyl. Optical rotatory dispersion measurements were employed to make tentative assignments of stereochemistry for some of the acyloxy indolenines. Borohydride redn. of the pseudoindoxyls and treatment of the product with acid transforms them into their ring AB inverted indole equivs.
- 34Manda, V.; Avula, B.; Ali, Z.; Khan, I.; Walker, L.; Khan, S. Evaluation of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and Mitraphylline. Planta Med. 2014, 80 (07), 568– 576, DOI: 10.1055/s-0034-1368444Google Scholar34Evaluation of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and MitraphyllineManda, Vamshi K.; Avula, Bharathi; Ali, Zulfiqar; Khan, Ikhlas A.; Walker, Larry A.; Khan, Shabana I.Planta Medica (2014), 80 (7), 568-576CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)Mitragyna speciosa (kratom) is a popular herb in Southeast Asia, which is traditionally used to treat withdrawal symptoms assocd. with opiate addiction. Mitragynine, 7-hydroxymitragynine, and mitraphylline are reported to be the central nervous system active alkaloids which bind to the opiate receptors. Mitraphylline is also present in the bark of Uncaria tomentosa (cat's claw). Several therapeutic properties have been reported for these compds. but limited information is available on the absorption and distribution properties. This study focuses on evaluating the absorption, distribution, metab., and excretion (ADME) properties of these compds. and their effect on major efflux transporter P-glycoprotein, using in vitro methods. Quant. anal. was performed by the Q-TOF LC-MS system. Mitragynine was unstable in simulated gastric fluid with 26 % degrdn. but stable in simulated intestinal fluid. 7-Hydroxymitragynine degraded up to 27 % in simulated gastric fluid, which could account for its conversion to mitragynine (23 %), while only 6 % degrdn. was seen in simulated intestinal fluid. Mitraphylline was stable in simulated gastric fluid but unstable in simulated intestinal fluid (13.6 % degrdn.). Mitragynine and 7-hydroxymitragynine showed moderate permeability across Caco-2 and MDR-MDCK monolayers with no significant efflux. However, mitraphylline was subjected to efflux mediated by P-glycoprotein in both Caco-2 and MDR-MDCK monolayers. Mitragynine was found to be metabolically stable in both human liver microsomes and S9 fractions. In contrast, both 7-hydroxymitragynine and mitraphylline were metabolized by human liver microsomes with half-lives of 24 and 50 min, resp. All three compds. exhibited high plasma protein binding (> 90 %) detd. by equil. dialysis. Mitragynine and 7-hydroxymitragynine inhibited P-glycoprotein with EC50 values of 18.2 ± 3.6 μM and 32.4 ± 1.9 μM, resp., detd. by the calcein-AM fluorescent assay, while no inhibition was seen with mitraphylline. These data indicate the possibility of a drug interaction if mitragynine and 7-hydroxymitragynine are coadministered with drugs that are P-glycoprotein substrates.
- 35Semenova, S.; Kuzmin, A.; Zvartau, E. Strain Differences in the Analgesic and Reinforcing Action of Morphine in Mice. Pharmacol., Biochem. Behav. 1995, 50 (1), 17– 21, DOI: 10.1016/0091-3057(94)00221-4Google Scholar35Strain differences in the analgesic and reinforcing action of morphine in miceSemenova, S.; Kuzmin, A.; Zvartau, E.Pharmacology, Biochemistry and Behavior (1995), 50 (1), 17-21CODEN: PBBHAU; ISSN:0091-3057. (Elsevier)The analgesic and reinforcing effects of morphine were compared in four strains of mice (C57BL/6, BALB/c, DBA, CBA). The analgesic action of morphine was measured in tail immersion (49°), hot plate (60°), and tail clip (four-point scale of nociceptive response) tests. The reinforcing action of morphine was studied in IV self-administration and conditioned place preference techniques. The results demonstrate strain differences in the analgesic and reinforcing action of morphine in mice. The relative rank order of the strains varied for the several tests as well as for the morphine effects. The lack of correlation between analgesic and reinforcing action of morphine in inbred strains supports the conclusion that analgesia and reinforcement are sep. processes with different genetic control.
- 36Mogil, J. S. Opioid Analgesia, Strain Differences. In Encyclopedia of Pain; Springer Berlin Heidelberg: Berlin, Germany, 2007; pp 1528– 1531.Google ScholarThere is no corresponding record for this reference.
- 37Gomes, I.; Gupta, A.; Filipovska, J.; Szeto, H. H.; Pintar, J. E.; Devi, L. A. A Role for Heterodimerization of Mu and Delta Opiate Receptors in Enhancing Morphine Analgesia. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (14), 5135– 5139, DOI: 10.1073/pnas.0307601101Google Scholar37A role for heterodimerization of μ and δ opiate receptors in enhancing morphine analgesiaGomes, Ivone; Gupta, Achla; Filipovska, Julija; Szeto, Hazel H.; Pintar, John E.; Devi, Lakshmi A.Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (14), 5135-5139CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Opiates such as morphine are the choice analgesic in the treatment of chronic pain. However their long-term use is limited because of the development of tolerance and dependence. Due to its importance in therapy, different strategies have been considered for making opiates such as morphine more effective, while curbing its liability to be abused. One such strategy has been to use a combination of drugs to improve the effectiveness of morphine. In particular, δ opioid receptor ligands have been useful in enhancing morphine's potency. The underlying mol. basis for these observations is not understood. We propose the modulation of receptor function by phys. assocn. between μ and δ opioid receptors as a potential mechanism. In support of this hypothesis, we show that μ-δ interacting complexes exist in live cells and native membranes and that the occupancy of δ receptors (by antagonists) is sufficient to enhance μ opioid receptor binding and signaling activity. Furthermore, δ receptor antagonists enhance morphine-mediated intrathecal analgesia. Thus, heterodimeric assocns. between μ-δ opioid receptors can be used as a model for the development of novel combination therapies for the treatment of chronic pain and other pathologies.
- 38Yusof, S. R.; Mohd Uzid, M.; Teh, E.-H.; Hanapi, N. A.; Mohideen, M.; Mohamad Arshad, A. S.; Mordi, M. N.; Loryan, I.; Hammarlund-Udenaes, M. Rate and Extent of Mitragynine and 7-Hydroxymitragynine Blood-Brain Barrier Transport and Their Intra-Brain Distribution: The Missing Link in Pharmacodynamic Studies. Addict. Biol. 2018, DOI: 10.1111/adb.12661Google ScholarThere is no corresponding record for this reference.
- 39Kamble, S. H.; Sharma, A.; King, T. I.; León, F.; McCurdy, C. R.; Avery, B. A. Metabolite Profiling and Identification of Enzymes Responsible for the Metabolism of Mitragynine, the Major Alkaloid of Mitragyna Speciosa (Kratom). Xenobiotica 2018, 1– 31, DOI: 10.1080/00498254.2018.1552819Google Scholar39Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom)Kamble Shyam H; Sharma Abhisheak; King Tamara I; Avery Bonnie A; Leon Francisco; McCurdy Christopher RXenobiotica; the fate of foreign compounds in biological systems (2018), (), 1-31 ISSN:.1. Mitragynine is the major indole-based alkaloid of Mitragyna speciosa (kratom). Decoctions (teas) of the plant leaves have been used traditionally for cough, diarrhoea, pain, hypertension, and for the treatment of opioid addiction. In the West, kratom has become increasingly utilized for mood elevation, pain treatment, and as a means of self-treating opioid addiction. 2. Metabolic pathways of mitragynine were identified in human liver microsomes (HLM) and S9 fractions. A total of thirteen metabolites were identified, four oxidative metabolites and a metabolite formed by demethylation at the 9-methoxy group were the major metabolites of mitragynine. 3. The cytochrome P450 enzymes involved in the metabolism of mitragynine were identified using selective chemical inhibitors of HLM and recombinant cytochrome P450. The metabolism of mitragynine was predominantly carried out through the CYP3A4 with minor contributions by CYP2D6 and CYP2C9. The formation of five oxidative metabolites (Met2, Met4, Met6 Met8 and Met11) was catalyzed by the CYP3A4. 4. In summary, mitragynine was extensively metabolized in HLM primarily to O-demethylated and monooxidative metabolites. The CYP3A4 enzyme plays a predominant role in the metabolic clearance of mitragynine and also in the formation of 7-hydroxymitragynine (Met2), a known active minor alkaloid identified in the leaf material.
- 40Karinen, R.; Fosen, J. T.; Rogde, S.; Vindenes, V. An Accidental Poisoning with Mitragynine. Forensic Sci. Int. 2014, 245, e29– e32, DOI: 10.1016/j.forsciint.2014.10.025Google Scholar40An accidental poisoning with mitragynineKarinen, Ritva; Fosen, Jan Toralf; Rogde, Sidsel; Vindenes, VigdisForensic Science International (2014), 245 (), e29-e32CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)An increasing no. of drugs of abuse are sold word wide over the internet. Names like "legal highs", "herbal highs" etc. give the impression that these are safe products, although the risk of fatal reactions might be substantial. Leaves from the plant Mitragyna speciosa, contain active compds. like mitragynine and 7-hydroxymitragynine. It has been reported that the potency of 7-hydroxymitragynine at the μ-opioid receptor is 30 times higher than that of mitragynine and 17 times higher than that of morphine. Case reports regarding poisoning with Kratom are reported, but the toxic or lethal ranges for the concns. of the active substances have not been established, and concns. of 7-hydroxymitragynine have not been reported previously.We present a case report where a middle aged man was found dead at home. The deceased had a history of drug abuse and mental illness for several years. At autopsy, there were no significant pathol. findings. Post-mortem anal. of peripheral blood revealed: zopiclone 0.043 mg/L, citalopram 0.36 mg/L and lamotrigine 5.4 mg/L, i.e. concns. regularly seen after therapeutic ingestion of these drugs. Addnl. mitragynine 1.06 mg/L and 7-hydroxymitragynine 0.15 mg/L were detected in blood and both also in urine.The high concns. of mitragynine and 7-hydroxymitragynine indicate that the cause of death is intoxication by these substances; and the circumstances point toward the manner of death being accidental. We recommend that both mitragynine and 7-hydroxymitragynine are analyzed for in cases with suspected Kratom intoxication.
- 41Dean, L. Codeine Therapy and CYP2D6 Genotype. Medical Genetics Summaries; National Center for Biotechnology Information (US), 2012.Google ScholarThere is no corresponding record for this reference.
- 42Heppell, S. P. E.; Isbister, G. K. Lack of Respiratory Depression in Paracetamol-Codeine Combination Overdoses. Br. J. Clin. Pharmacol. 2017, 83 (6), 1273– 1278, DOI: 10.1111/bcp.13224Google Scholar42Lack of respiratory depression in paracetamol-codeine combination overdosesHeppell, Simon P. E.; Isbister, Geoffrey K.British Journal of Clinical Pharmacology (2017), 83 (6), 1273-1278CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)Aims : Codeine contg. analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol-codeine combination overdoses caused respiratory depression more than paracetamol alone. Methods : We reviewed deliberate self-poisoning admissions with paracetamol (>2 g) and paracetamol-codeine combinations presenting to a tertiary toxicol. unit (1987-2013). Demog. information, clin. effects, treatment (naloxone, length of stay [LOS], mech. ventilation) were extd. from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression. Results : From 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol-codeine combinations (346) or paracetamol-codeine-doxylamine combinations (101) without co-ingestants. Median age was 23 years (12-89 years); 1002 (73%) were female. Median dose was 12 g (interquartile range [IQR]: 7.5-20 g). Median LOS was 16 h (IQR: 6.5-27 h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone vs. paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2-1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1-1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol-codeine combinations (0.6%; 95% CI: 0.1-2.3%; abs. difference, 0.26%; 95% CI: -0.7-1.2%; P = 0.62). Two out of 101 patients ingesting paracetamol-codeine-doxylamine combinations (2%; 95% CI: 0.3-8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol-codeine group. Conclusions : Paracetamol-codeine combination overdoses are rarely assocd. with severe respiratory depression, with only two given naloxone and none intubated for respiratory depression.
- 43Smith, L. C.; Lin, L.; Hwang, C. S.; Zhou, B.; Kubitz, D. M.; Wang, H.; Janda, K. D. Lateral Flow Assessment and Unanticipated Toxicity of Kratom. Chem. Res. Toxicol. 2019, 32, 113, DOI: 10.1021/acs.chemrestox.8b00218Google Scholar43Lateral Flow Assessment and Unanticipated Toxicity of KratomSmith, Lauren C.; Lin, Lucy; Hwang, Candy S.; Zhou, Bin; Kubitz, Diane M.; Wang, Huiying; Janda, Kim D.Chemical Research in Toxicology (2019), 32 (1), 113-121CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The leaves of the Mitragynine speciosia tree (also known as Kratom) have long been chewed, smoked, or brewed into a tea by people in Southeastern Asian countries, such as Malaysia and Thailand. Just this past year, the plant Kratom gained popularity in the United States as a 'legal opioid' and scheduling it as a drug of abuse is currently pending. The primary alkaloid found in Kratom is a μ-opioid receptor agonist, mitragynine, whose structure contains a promising scaffold for immunopharmacol. use. Although Kratom is regarded as a safe opioid alternative, here we report the LD50 values detd. for its two main psychoactive alkaloids, mitragynine and 7-hydroxymitragynine, as comparable to heroin in mice when administered i.v. Given Kratom's recent emergence in the U.S., there is currently no diagnostic test available for law enforcement or health professionals, so we sought to design such an assay. Mitragynine was used as a starting point for hapten design, resulting in a hapten with an ether linker extending from the C9 position of the alkaloid. Bacterial flagellin (FliC) was chosen as a carrier protein for active immunization in mice, yielding 32 potential monoclonal antibodies (mAbs) for assay development. Anti-mitragynine mAbs in the range of micro- to nanomolar affinities were uncovered and their utility in producing a convenient lateral flow detection assay of human fluid samples was examd. Antibodies were screened for binding to mitragynine, 7-hydroxymitragynine, and performance in lateral flow assays. Two monoclonal antibodies were subcloned and further purified, with 93 nM and 362 nM affinity to mitragynine. Test strip assays were optimized with a detection cut off of 0.5 μg/mL for mitragynine in buffer and urine (reflecting projected clin. relevant levels of drug in urine), which could be beneficial to law enforcement agencies and health professionals as the opioid epidemic in America continues to evolve.
- 44National Institute on Drug Abuse. Overdose Death Rates. National Institute on Drug Abuse (NIDA) https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates (accessed Dec 26, 2018).Google ScholarThere is no corresponding record for this reference.
- 45Hemby, S. E.; McIntosh, S.; Leon, F.; Cutler, S. J.; McCurdy, C. R. Abuse Liability and Therapeutic Potential of the Mitragyna Speciosa (Kratom) Alkaloids Mitragynine and 7-Hydroxymitragynine. Addict. Biol. 2018, DOI: 10.1111/adb.12639Google ScholarThere is no corresponding record for this reference.
- 46Yue, K.; Kopajtic, T. A.; Katz, J. L. Abuse Liability of Mitragynine Assessed with a Self-Administration Procedure in Rats. Psychopharmacology (Berl). 2018, 235 (10), 2823– 2829, DOI: 10.1007/s00213-018-4974-9Google Scholar46Abuse liability of mitragynine assessed with a self-administration procedure in ratsYue Kai; Kopajtic Theresa A; Katz Jonathan LPsychopharmacology (2018), 235 (10), 2823-2829 ISSN:.RATIONALE: Substantial use of the plant kratom for psychoactive effects has driven interest in its abuse liability. Several place conditioning studies suggest abuse liability of the active ingredient mitragynine, though studies of its self-administration have not been published. METHODS: Binding of mitragynine to rat brain mu, kappa, and delta opioid receptors was compared to that for heroin and morphine. Self-administration of mitragynine, heroin, methamphetamine, or saline was assessed during single-session substitutions in rats trained to self-administer methamphetamine (0.022 mg/kg/injection, i.v.) during 1-h daily sessions. RESULTS: Mitragynine had > 2- or ~ 16-fold greater affinity for the mu opioid receptor than, respectively, for kappa or delta opioid receptors. Its affinity for the mu receptor was ~ 200-fold less than that for morphine. In rats trained to self-administer methamphetamine, saline substitutions significantly decreased the number of responses, whereas different doses of methamphetamine (0.002-0.068 mg/kg/injection) or heroin (0.001-0.03 mg/kg/injection) maintained self-administration with maximal responding at 0.022 or 0.01 mg/kg/injection, respectively. In contrast, no dose of mitragynine maintained response rates greater than those obtained with saline. Presession mitragynine treatment (0.1 to 3.0 mg/kg) decreased response rates maintained by heroin but had little effect on responding maintained by methamphetamine across the same range of doses. CONCLUSIONS: These results suggest a limited abuse liability of mitragynine and potential for mitragynine treatment to specifically reduce opioid abuse. With the current prevalence of opioid abuse and misuse, it appears currently that mitragynine is deserving of more extensive exploration for its development or that of an analog as a medical treatment for opioid abuse.
- 47Kathiramalainathan, K.; Kaplan, H. L.; Romach, M. K.; Busto, U. E.; Li, N. Y.; Säwe, J.; Tyndale, R. F.; Sellers, E. M. Inhibition of Cytochrome P450 2D6Modifies Codeine Abuse Liability. J. Clin. Psychopharmacol. 2000, 20 (4), 435– 444, DOI: 10.1097/00004714-200008000-00008Google Scholar47Inhibition of cytochrome P450 2D6 modifies codeine abuse liabilityKathiramalainathan, Kalyani; Kaplan, Howard L.; Romach, Myroslava K.; Busto, Usoa E.; Li, Ning-Yuan; Sawe, Juliette; Tyndale, Rachel F.; Sellers, Edward M.Journal of Clinical Psychopharmacology (2000), 20 (4), 435-444CODEN: JCPYDR; ISSN:0271-0749. (Lippincott Williams & Wilkins)Oral codeine prepns., widely used for analgesia and cough suppression, are abused by some individuals for their mood-altering properties. The enzymic O-demethylation of codeine is catalyzed by cytochrome P 450 2D6 (CYP2D6), leading to the prodn. of metabolites (morphine, morphine-6-glucuronide) that are pharmacol. more potent than codeine. A placebo-controlled, single-blind study was conducted to characterize the subjective effects of codeine assocd. with abuse liability and to det. the importance of metabolic O-demethylation to codeine abuse liability. Twelve non-drug-dependent subjects received oral administration of placebo and codeine 60, 120, and 180 mg, and a favorite dose (FD) was detd. for each subject. The FD was readministered after pretreatment with placebo, 50 mg of quinidine (a specific, selective CYP2D6 inhibitor) once, or 50 mg of quinidine given four times a day for 4 days. Single-dose quinidine pretreatment significantly decreased the recovery of O-demethylated metabolites in plasma (p < 0.01) and resulted in a decrease in the pos. (e.g., "high," p < 0.05) and neg. (e.g., nausea, p < 0.05) subjective effects of codeine in both the FD120 and FD180 groups. Short-term quinidine pretreatment inhibited codeine O-demethylation more than did single-dose quinidine pretreatment (p < 0.01), and it decreased pos. codeine effects in the FD120 group (N = 7), but unexpectedly not in the FD180 group (N = 5). These results suggest that the O-demethylated metabolites contribute substantially to the subjective effects and abuse liability of codeine.
- 48Kong, W. M.; Chik, Z.; Ramachandra, M.; Subramaniam, U.; Aziddin, R. E. R.; Mohamed, Z. Evaluation of the Effects of Mitragyna Speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay. Molecules 2011, 16 (12), 7344– 7356, DOI: 10.3390/molecules16097344Google Scholar48Evaluation of the effects of Mitragyna speciosa alkaloid extract on cytochrome P450 enzymes using a high throughput assayKong, Wai Mun; Chik, Zamri; Ramachandra, Murali; Subramaniam, Umarani; Aziddin, Raja Elina Raja; Mohamed, ZahurinMolecules (2011), 16 (), 7344-7356CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)The ext. from Mitragyna speciosa has been widely used as an opium substitute, mainly due to its morphine-like pharmacol. effects. This study investigated the effects of M. speciosa alkaloid ext. (MSE) on human recombinant cytochrome P 450 (CYP) enzyme activities using a modified Crespi method. As compared with the liq. chromatog.-mass spectrometry method, this method has shown to be a fast and cost-effective way to perform CYP inhibition studies. The results indicated that MSE has the most potent inhibitory effect on CYP3A4 and CYP2D6, with apparent half-maximal inhibitory concn. (IC50) values of 0.78 μg/mL and 0.636 μg/mL, resp. In addn., moderate inhibition was obsd. for CYP1A2, with an IC50 of 39 μg/mL, and weak inhibition was detected for CYP2C19. The IC50 of CYP2C19 could not be detd., however, because inhibition was <50%. Competitive inhibition was found for the MSE-treated CYP2D6 inhibition assay, whereas non-competitive inhibition was shown in inhibition assays using CYP3A4, CYP1A2 and CYP2C19. Quinidine (CYP2D6), ketoconazole (CYP3A4), tranylcypromine (CYP2C19) and furafylline (CYP1A2) were used as pos. controls throughout the expts. This study shows that MSE may contribute to an herb-drug interaction if administered concomitantly with drugs that are substrates for CYP3A4, CYP2D6 and CYP1A2.
- 49Manda, V. K.; Avula, B.; Dale, O. R.; Ali, Z.; Khan, I. A.; Walker, L. A.; Khan, S. I. PXR Mediated Induction of CYP3A4, CYP1A2, and P-Gp by Mitragyna Speciosa and Its Alkaloids. Phytother. Res. 2017, 31 (12), 1935– 1945, DOI: 10.1002/ptr.5942Google Scholar49PXR mediated induction of CYP3A4, CYP1A2, and P-gp by Mitragyna speciosa and its alkaloidsManda, Vamshi K.; Avula, Bharathi; Dale, Olivia R.; Ali, Zulfiqar; Khan, Ikhlas A.; Walker, Larry A.; Khan, Shabana I.Phytotherapy Research (2017), 31 (12), 1935-1945CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)Kratom (Mitragyna speciosa), a native herb of Southeast Asia, is widely known for its psychoactive properties. Recent increase in the use of kratom as a recreational drug has increased the risk of its interaction with conventional drugs if taken concomitantly. A few reports are available related to the effects of kratom on the activity of cytochrome P 450 enzymes (CYPs), but there are no reports of its effects on pregnane X receptor (PXR), a transcription factor that regulates the expression of CYPs and P-glycoprotein (P-gp). This study was carried out to evaluate the effects of a methanolic ext. of kratom leaves, an alkaloid rich fraction and its 5 indole and 4 oxindole alkaloids on PXR activation and the resulting changes in the mRNA expression of PXR target genes (CYP3A4, CYP1A2, and P-gp). A significant activation of PXR was obsd. by the ext. (3-fold), alkaloidal fraction (4-fold) and all 9 alkaloids (4- to 6-fold) that was assocd. with an increased mRNA expression which resulted into an increase in the activity of CYP3A4, CYP1A2, and P-gp. These results indicate that high consumption of Mitragyna speciosa ext. along with the conventional drugs may lead to potential herb-drug interactions due to its effects on PXR.
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Abstract
Figure 1
Figure 1. Known (Pathway A) and proposed (Pathway B) metabolic transformations of mitragynine.
Figure 2
Figure 2. Decomposition of mitragynine and formation of 7-OH in liver microsomes was quantified by LC-MS/MS. (A) Mitragynine was unstable in both MLM and HLM, while deuteration of all three methyl groups, as in mitragynine-d9, had little effect on microsomal stability. (B) Loss of mitragynine in microsomal preparations was accompanied by formation of 7-OH as a metabolite, and this conversion was more efficient in HLM. There was a strong main effect of species on 7-OH concentration. Two-way ANOVA: F1,30 = 51.66, p < 0.0001. ****p < 0.0001 relative to MLM, **p < 0.01 relative to MLM, *p < 0.05 relative to MLM, ns = p > 0.05 relative to MLM. All data points represent the means of two independent experiments with two incubations per experiment, with error bars representing ± SEM.
Scheme 1
Scheme 1. Conversion of Mitragynine to 7-OH by Chemical OxidantsFigure 3
Figure 3. CYP3A4 mediates conversion of mitragynine to 7-OH. (A) Mitragynine was incubated in vitro with recombinant preparations of the five major human CYP isoforms alongside a reference substrate of each isoform as positive control. The relative percent remaining of mitragyine or reference substrate in each incubation was quantified by LC-MS/MS. Disappearance of mitragynine was most rapid in the presence of CYP3A4, whereas incubations with the other isoforms resulted in little or no decomposition. The activity of each preparation was confirmed by the nearly complete disappearance of the corresponding reference substrates. (B) Formation of 7-OH was monitored by LC-MS/MS during incubation of mitragynine with each of the recombinant CYP preparations. CYP3A4 resulted in the most robust conversion to 7-OH. All data points represent the means of two independent experiments with two incubations per experiment, with error bars representing ± SEM.
Figure 4
Figure 4. CYP3A-dependence of 7-OH formation was confirmed in HLM. Disappearance of mitragynine and formation of 7-OH was monitored by LC-MS/MS. (A) In HLM, the CYP3A isoform inhibitor ketoconazole (Ket) dose-dependently attenuated metabolic decomposition of mitragynine. In contrast, the CYP2C19 inhibitor ticlopidine (Tic) had little effect. (B) During incubation of mitragynine with HLM, ketoconazole (and to a small degree, ticlopidine) also inhibited formation of 7-OH. All data points represent the means of two independent experiments with two incubations per experiment, with error bars representing ± SEM.
Figure 5
Figure 5. Analgesic activity of mitragynine in 129 mice. (A) Dose–responses of mitragynine and 7-OH in the tail-flick assay at time of maximal analgesic effect (15 min). Mice (n = 5–17 per dose, per treatment; 129S1 strain) were treated with ascending doses of mitragynine or 7-OH by the indicated route of administration in a cumulative dosing procedure, and tail-flick latency was recorded for each animal at 15 min post drug administration (peak analgesic effect). ED50s (95% CI) were as follows: mitragynine, s.c. = 106 (57.4–195) mg/kg; mitragynine, p.o. = 2.05 (1.24–3.38); 7-OH, s.c. = 0.57 (0.19–1.7). The means of each point were calculated as percentage maximal possible effect (%MPE) [(observed latency – baseline latency)/(maximal latency – baseline latency)] × 100. Error bars represent ± SEM. (B) The analgesic effect of mitragynine (10 mg/kg, p.o.) in the tail-flick assay was evaluated 15 min post drug administration in WT, MOR-1 KO, KOR-1 KO, and DOR-1 KO mice, and WT mice following pretreatment with naloxone (1 mg/kg, s.c.), in two independent experiments (n = 5 per group per experiment, n = 10 total per group; 129S6 strain). The analgesic effect of mitragynine was attenuated by naloxone pretreatment and in MOR-1 KO, while the effect was found intact in KOR-1 KO and DOR-1 KO mice. One-way ANOVA: F4,45 = 19.90, p < 0.0001. ****p < 0.0001 relative to WT, ns = p > 0.05 relative to WT. All values are expressed as the mean ± SEM. (C) The analgesic effect of 7-OH (1 mg/kg, s.c.) in the tail-flick assay was evaluated 15 min post drug administration in WT, MOR-1 KO, KOR-1 KO, and DOR-1 KO mice, and WT mice following pretreatment with naloxone (1 mg/kg, s.c.), in two independent experiments (n = 5 per group per experiment, n = 10 total per group; 129S6 strain). The analgesic effect of 7-OH was attenuated by naloxone pretreatment and in MOR-1 KO, while the effect was found intact in KOR-1 KO and DOR-1 KO mice. One-way ANOVA: F4,45 = 101.7, p < 0.0001. ****p < 0.0001 relative to WT, *p < 0.05 relative to WT. All values are expressed as the mean ± SEM.
Figure 6
Figure 6. Conversion of mitragynine to 7-OH was confirmed in vivo in 129S1 mice using LC-MS/MS. (A) Mitragynine was detected in both the plasma and brains of mice treated with mitragynine (10 mg/kg, s.c.). n = 4 per time point for plasma; n = 8–9 per time point for brain. (B) At the same time, 7-OH was also detected in the plasma and brains of the same animals, but at lower concentrations.
Figure 7
Figure 7. 7-OH formed as a metabolite is sufficient to explain mitragynine’s analgesic effect in 129S1 mice. (A) Selected doses of mitragynine (140 mg/kg, s.c.) and 7-OH (0.7 mg/kg, s.c.) were equianalgesic at 15 min in the tail-flick assay and induced ∼50% MPE. n = 10 per treatment. Two-tailed t test, t(18) = 0.66, p = 0.52. ns = p > 0.05. (B) 7-OH was detected in the brains of the same animals at 15 min (sacrifice and sample collection immediately after tail-flick), and there was no difference in mean brain concentration between the two treatments. n = 9 for mitragynine, n = 10 for 7-OH. Two-tailed t test, t(17) = 1.19, p = 0.25. ns = p > 0.05. (C) Mitragynine was detected in the brains of the same animals at 15 min, and there was a significant difference between the two treatments, with a 170-fold higher brain concentration of mitragynine in the animals directly treated with this drug compared to those treated with 7-OH. n = 10 for mitragynine, n = 6 for 7-OH (four values below the lower limit of quantitation, 5 ng/g, were excluded from analysis). Two-tailed t test, t(13) = 4.88, p = 0.0003. ***p < 0.001. All bars represent mean ± SEM.
References
This article references 49 other publications.
- 1Kruegel, A. C.; Grundmann, O. The Medicinal Chemistry and Neuropharmacology of Kratom: A Preliminary Discussion of a Promising Medicinal Plant and Analysis of Its Potential for Abuse. Neuropharmacology 2018, 134, 108– 120, DOI: 10.1016/j.neuropharm.2017.08.0261The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuseKruegel, Andrew C.; Grundmann, OliverNeuropharmacology (2018), 134 (Part_A), 108-120CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu-opioid receptors and competitive antagonists at kappa- and delta-opioid receptors. Furthermore, both alkaloids are G protein-biased agonists of the mu-opioid receptor and therefore, may induce less respiratory depression than classical opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex pharmacol. profile of raw kratom exts., although characterization of effects at these other targets remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-hydroxymitragynine used in animal studies can be related to single doses of raw kratom plant commonly consumed by humans, permitting preliminary interpretation of expected behavioral and physiol. effects in man based on this preclin. data and comparison to both anecdotal human experience and multiple epidemiol. surveys. Kratom exposure alone has not been causally assocd. with human fatalities to date. However, further research is needed to clarify the complex mechanism of action of the Mitragyna alkaloids and unlock their full therapeutic potential.
- 2Adkins, J. E.; Boyer, E. W.; McCurdy, C. R. Mitragyna Speciosa, a Psychoactive Tree from Southeast Asia with Opioid Activity. Curr. Top. Med. Chem. 2011, 11 (9), 1165– 1175, DOI: 10.2174/1568026117953713052Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activityAdkins, Jessica E.; Boyer, Edward W.; McCurdy, Christopher R.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2011), 11 (9), 1165-1175CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. Mitragyna speciosa Korth. (Rubiaceae) is a tree that is commonly found in Southeast Asia. Leaves from this tree have been traditionally been used for both their stimulant properties as well as an opium substitute. The tree/leaves are currently illegal in four countries, but is currently legal and widely available in the United States. To date over 40 compds. have been isolated from the leaves. The major alkaloid found within the crude ext., mitragynine, has been the subject of many pharmacol. studies. In addn. to the pharmacol. studies, two total syntheses of mitragynine have been published as well as general structure-activity relationships with respect to opioid activity.
- 3Prozialeck, W. C.; Jivan, J. K.; Andurkar, S. V. Pharmacology of Kratom: An Emerging Botanical Agent with Stimulant, Analgesic and Opioid-like Effects. J. Am. Osteopath. Assoc. 2012, 112 (12), 792– 7993Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effectsProzialeck Walter C; Jivan Jateen K; Andurkar Shridhar VThe Journal of the American Osteopathic Association (2012), 112 (12), 792-9 ISSN:.Kratom (Mitragyna speciosa) is a plant indigenous to Thailand and Southeast Asia. Kratom leaves produce complex stimulant and opioid-like analgesic effects. In Asia, kratom has been used to stave off fatigue and to manage pain, diarrhea, cough, and opioid withdrawal. Recently, kratom has become widely available in the United States and Europe by means of smoke shops and the Internet. Analyses of the medical literature and select Internet sites indicate that individuals in the United States are increasingly using kratom for the self-management of pain and opioid withdrawal. Kratom contains pharmacologically active constituents, most notably mitragynine and 7-hydroxymitragynine. Kratom is illegal in many countries. Although it is still legal in the United States, the US Drug Enforcement Administration has placed kratom on its "Drugs and Chemicals of Concern" list. Physicians should be aware of the availability, user habits, and health effects of kratom. Further research on the therapeutic uses, toxic effects, and abuse potential of kratom and its constituent compounds are needed.
- 4Singh, D.; Narayanan, S.; Vicknasingam, B. Traditional and Non-Traditional Uses of Mitragynine (Kratom): A Survey of the Literature. Brain Res. Bull. 2016, 126, 41– 46, DOI: 10.1016/j.brainresbull.2016.05.0044Traditional and non-traditional uses of Mitragynine (Kratom): A survey of the literatureSingh, Darshan; Narayanan, Suresh; Vicknasingam, BalasingamBrain Research Bulletin (2016), 126 (Part_1), 41-46CODEN: BRBUDU; ISSN:0361-9230. (Elsevier)The objective of the paper was to highlight the differences in the traditional and non-traditional users of kratom in the South East Asian and Western contexts. A literature survey of published kratom studies among humans was conducted. Forty published studies relevant to the objective were reviewed. Apart from the differences in the sources of supply, patterns of use and social acceptability of kratom within these two regions, the most interesting finding is its evolution to a recreational drug in both settings and the severity of the adverse effects of kratom use reported in the West. While several cases of toxicity and death have emerged in the West, such reports have been non-existent in South East Asia where kratom has had a longer history of use. We highlight the possible reasons for this as discussed in the literature. More importantly, it should be borne in mind that the individual clin. case-reports emerging from the West that link kratom use to adverse reactions or fatalities frequently pertained to kratom used together with other substances. Therefore, there is a danger of these reports being used to strengthen the case for legal sanction against kratom. This would be unfortunate since the experiences from South East Asia suggest considerable potential for therapeutic use among people who use drugs. Despite its addictive properties, reported side-effects and its tendency to be used a recreational drug, more scientific clin. human studies are necessary to det. its potential therapeutic value.
- 5Takayama, H. Chemistry and Pharmacology of Analgesic Indole Alkaloids from the Rubiaceous Plant, Mitragyna Speciosa. Chem. Pharm. Bull. 2004, 52 (8), 916– 928, DOI: 10.1248/cpb.52.9165Chemistry and pharmacology of analgesic indole alkaloids from the Rubiaceous plant, Mitragyna speciosaTakayama, HiromitsuChemical & Pharmaceutical Bulletin (2004), 52 (8), 916-928CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)A review. The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochem. studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compds. were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of mitragynine, the major constituent of this plant, and its analogs were found in in vitro and in vivo expts. and the mechanisms underlying the analgesic activity were clarified. The essential structural features of mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacol. evaluation of the natural and synthetic derivs. Among the mitragynine derivs., 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.
- 6Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi, N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto, L. T.; Watanabe, K.; Murayama, T.; Horie, S. Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands. J. Med. Chem. 2002, 45 (9), 1949– 1956, DOI: 10.1021/jm010576e6Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid LigandsTakayama, Hiromitsu; Ishikawa, Hayato; Kurihara, Mika; Kitajima, Mariko; Aimi, Norio; Ponglux, Dhavadee; Koyama, Fumi; Matsumoto, Kenjiro; Moriyama, Tomoyuki; Yamamoto, Leonard T.; Watanabe, Kazuo; Murayama, Toshihiko; Horie, SyunjiJournal of Medicinal Chemistry (2002), 45 (9), 1949-1956CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mitragynine is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa, and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compd., synthesis of some derivs., evaluations of the structure-activity relationship, and surveys of the intrinsic activities and potencies on opioid receptors were performed with guinea pig ileum. The affinities of some compds. for μ-, δ-, and κ-receptors were detd. in a receptor binding assay. The essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were also clarified. The oxidative derivs. of mitragynine, i.e., mitragynine pseudoindoxyl (I) and 7-hydroxymitragynine, were found as opioid agonists with higher potency than morphine in the expt. with guinea pig ileum. In addn., I induced an analgesic activity in the tail flick test in mice.
- 7Raffa, R. B.; Beckett, J. R.; Brahmbhatt, V. N.; Ebinger, T. M.; Fabian, C. A.; Nixon, J. R.; Orlando, S. T.; Rana, C. A.; Tejani, A. H.; Tomazic, R. J. Orally Active Opioid Compounds from a Non-Poppy Source. J. Med. Chem. 2013, 56 (12), 4840– 4848, DOI: 10.1021/jm400143z7Orally Active Opioid Compounds from a Non-Poppy SourceRaffa, Robert B.; Beckett, Jaclyn R.; Brahmbhatt, Vivek N.; Ebinger, Theresa M.; Fabian, Chrisjon A.; Nixon, Justin R.; Orlando, Steven T.; Rana, Chintan A.; Tejani, Ali H.; Tomazic, Robert J.Journal of Medicinal Chemistry (2013), 56 (12), 4840-4848CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The basic science and clin. use of morphine and other opioid drugs are based almost exclusively on the exts. or analogs of compds. isolated from a single source, the opium poppy (Papaver somniferum). However, it now appears that biol. diversity has evolved an alternative source. Specifically, at least two alkaloids isolated from the plant Mitragyna speciosa, mitragynine ((E)-2-[(2S,3S)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[3,2-h]quinolizin-2-yl]-3-methoxyprop-2-enoic acid Me ester; 9-methoxy coryantheidine; MG) and 7-hydroxymitragynine (7-OH-MG), and several synthetic analogs of these natural products display centrally mediated (supraspinal and spinal) antinociceptive (analgesic) activity in various pain models. Several characteristics of these compds. suggest a classic opioid mechanism of action: nanomolar affinity for opioid receptors, competitive interaction with the opioid receptor antagonist naloxone, and two-way analgesic cross-tolerance with morphine. However, other characteristics of the compds. suggest novelty, particularly chem. structure and possible greater sepn. from side effects. We review the chem. and pharmacol. properties of these compds.
- 8Suhaimi, F. W.; Yusoff, N. H. M.; Hassan, R.; Mansor, S. M.; Navaratnam, V.; Müller, C. P.; Hassan, Z. Neurobiology of Kratom and Its Main Alkaloid Mitragynine. Brain Res. Bull. 2016, 126, 29– 40, DOI: 10.1016/j.brainresbull.2016.03.0158Neurobiology of Kratom and its main alkaloid mitragynineSuhaimi, Farah W.; Yusoff, Nurul H. M.; Hassan, Rahimah; Mansor, Sharif M.; Navaratnam, Visweswaran; Muller, Christian P.; Hassan, ZurinaBrain Research Bulletin (2016), 126 (Part_1), 29-40CODEN: BRBUDU; ISSN:0361-9230. (Elsevier)Kratom or its main alkaloid, mitragynine is derived from the plant Mitragyna speciosa Korth which is indigenous to Southeast Asian countries. This substance has become widely available in other countries like Europe and United States due to its opium- and coca-like effects. In this article, we have reviewed available reports on mitragynine and other M. speciosa exts. M. speciosa has been proven to have a rewarding effect and is effective in alleviating the morphine and ethanol withdrawal effects. However, studies in human revealed that prolonged consumption of this plant led to dependence and tolerance while cessation caused a series of aversive withdrawal symptoms. Findings also showed that M. speciosa exts. possess antinociceptive, anti-inflammatory, anti-depressant, and muscle relaxant properties. Available evidence further supports the adverse effects of M. speciosa prepns., mitragynine on cognition. Pharmacol. activities are mainly mediated via opioid receptors as well as neuronal Ca2+ channels, expression of cAMP and CREB protein and via descending monoaminergic system. Physicochem. properties of mitragynine have been documented which may further explain the variation in pharmacol. responses. In summary, current researchs on its main indole alkaloid, mitragynine suggest both therapeutic and addictive potential but further research on its mol. effects is needed.
- 9Grundmann, O. Patterns of Kratom Use and Health Impact in the US—Results from an Online Survey. Drug Alcohol Depend. 2017, 176, 63– 70, DOI: 10.1016/j.drugalcdep.2017.03.0079Patterns of Kratom use and health impact in the US-Results from an online surveyGrundmann OliverDrug and alcohol dependence (2017), 176 (), 63-70 ISSN:.BACKGROUND: Kratom preparations have raised concerns of public health and safety in the US. Investigation into the demographics, perceived beneficial and detrimental effects of Kratom as well as common doses and purposes of its use are important to properly evaluate its potential health impact. METHODS: An anonymous cross-sectional online survey was conducted in October 2016 of 10,000 current Kratom users through available social media and online resources from the American Kratom Association. A total of 8049 respondents completed the survey. RESULTS: Kratom is primarily used by a middle-aged (31-50 years), middle-income ($35,000 and above) population for purposes of self-treating pain (68%) and emotional or mental conditions (66%). Kratom preparations present with a dose-dependent effect with negative effects, which were primarily gastrointestinal related including nausea and constipation, mainly presenting at high (5g or more/dose) and more frequent (22 or more doses/week) dosing. CONCLUSIONS: Kratom shows a dose-dependent opioid-like effect providing self-reported perceived beneficial effects in alleviating pain and relieving mood disorders. Kratom was primarily used for self-treatment of pain, mood disorders, and withdrawal symptoms associated with prescription opioid use.
- 10Swogger, M. T.; Hart, E.; Erowid, F.; Erowid, E.; Trabold, N.; Yee, K.; Parkhurst, K. A.; Priddy, B. M.; Walsh, Z. Experiences of Kratom Users: A Qualitative Analysis. J. Psychoact. Drugs 2015, 47 (5), 360– 367, DOI: 10.1080/02791072.2015.109643410Experiences of Kratom Users: A Qualitative AnalysisSwogger Marc T; Hart Elaine; Yee Kaila; Parkhurst Kimberly A; Priddy Brittany M; Erowid Fire; Erowid Earth; Trabold Nicole; Walsh ZachJournal of psychoactive drugs (2015), 47 (5), 360-7 ISSN:0279-1072.Kratom (Mitragyna speciosa) is a psychoactive plant that has been used since at least 1836 in folk medicine in Southeast Asian countries. More recently, kratom has become widely available in the West and is used for both recreational and medicinal purposes. There has, however, been little scientific research into the short- and long-term effects of kratom in humans, and much of the information available is anecdotal. To supplement the increasing scientific understanding of kratom's pharmacology and research into its effects in animals, we report the results of a qualitative analysis of first-hand descriptions of human kratom use that were submitted to, and published by, a psychoactive substance information website (Erowid.org). Themes that emerged from these experience reports indicate that kratom may be useful for analgesia, mood elevation, anxiety reduction, and may aid opioid withdrawal management. Negative response themes also emerged, indicating potential problems and unfavorable "side" effects, especially stomach upset and vomiting. Based on our analyses, we present preliminary hypotheses for future examination in controlled, quantitative studies of kratom.
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- 12Smith, K. E.; Lawson, T. Prevalence and Motivations for Kratom Use in a Sample of Substance Users Enrolled in a Residential Treatment Program. Drug Alcohol Depend. 2017, 180, 340– 348, DOI: 10.1016/j.drugalcdep.2017.08.03412Prevalence and motivations for kratom use in a sample of substance users enrolled in a residential treatment programSmith Kirsten Elin; Lawson ThomasDrug and alcohol dependence (2017), 180 (), 340-348 ISSN:.BACKGROUND: Kratom use in the West has increased recently, yet the prevalence and motives for use among individuals with a history of substance use disorder (SUD) have not been fully examined. Kratom has been documented as a means of treating chronic pain, mitigating drug dependence, and easing withdrawal symptoms, yet it is unclear if substance users are utilizing kratom as a self-medication. Abuse liability, side effects, and overall appeal of kratom remain uncertain. METHODS: In April 2017, an anonymous survey regarding kratom use and motivations was completed by clients enrolled in a 12-Step-oriented residential program. 500 respondents with a self-reported history of SUD completed the survey. RESULTS: 20.8% of respondents endorsed lifetime kratom use and 10.2% reported past-12-month use. Kratom-users were younger (=32.1 vs. 35.9, p<0.001) and were more versatile substance users. A majority (68.9%) of kratom-users reported having used the drug as a means of reducing or abstaining from non-prescription opioids (NPO) and/or heroin, and 64.1% reported using kratom as a substitute for NPO/heroin. 18.4% of kratom-users reported using the drug due to a disability or chronic pain. One-third of kratom-users stated that kratom was a helpful substance and that they would try it again. However, kratom was not preferred and was indicated as having less appeal than NPO, heroin, amphetamines, and Suboxone. CONCLUSIONS: Among substance users, kratom use may be initiated for a variety of reasons, including as a novel form of harm-reduction or drug substitution, particularly in the context of dependence and withdrawal from other substances.
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- 20Ponglux, D.; Wongseripipatana, S.; Takayama, H.; Kikuchi, M.; Kurihara, M.; Kitajima, M.; Aimi, N.; Sakai, S. A New Indole Alkaloid, 7α-Hydroxy-7H-Mitragynine, from Mitragyna Speciosa in Thailand. Planta Med. 1994, 60 (6), 580– 581, DOI: 10.1055/s-2006-95957820A new indole alkaloid, 7α-hydroxy-7H-mitragynine, from Mitragyna speciosa in Thailand.Ponglux, Dhavadee; Wongseripipatana, Sumphan; Takayama, Hiromitsu; Kikuchi, Masae; Kurihara, Mika; Kitajima, Mariko; Aimi, Norio; Sakai, Shin-ichiroPlanta Medica (1994), 60 (6), 580-1CODEN: PLMEAA; ISSN:0032-0943. (Thieme)7α-Hydroxy-7H-mitragynine (I) was isolated from M. speciosa. I was synthesized from mitragynine by treatment with iodosobenzene diacetate in MeCN.
- 21Kruegel, A. C.; Gassaway, M. M.; Kapoor, A.; Váradi, A.; Majumdar, S.; Filizola, M.; Javitch, J. A.; Sames, D. Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. J. Am. Chem. Soc. 2016, 138 (21), 6754– 6764, DOI: 10.1021/jacs.6b0036021Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor ModulatorsKruegel, Andrew C.; Gassaway, Madalee M.; Kapoor, Abhijeet; Varadi, Andras; Majumdar, Susruta; Filizola, Marta; Javitch, Jonathan A.; Sames, DaliborJournal of the American Chemical Society (2016), 138 (21), 6754-6764CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is assocd. with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacol. properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analog 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (-)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich-Michael reaction sequence as the key transformation. Pharmacol. evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chem. transformations developed in the total synthesis allowed the elucidation of previously unexplored structure-activity relationships (SAR) within the Mitragyna scaffold. Mol. docking studies, in combination with the obsd. chem. SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids.
- 22Matsumoto, K.; Horie, S.; Ishikawa, H.; Takayama, H.; Aimi, N.; Ponglux, D.; Watanabe, K. Antinociceptive Effect of 7-Hydroxymitragynine in Mice: Discovery of an Orally Active Opioid Analgesic from the Thai Medicinal Herb Mitragyna Speciosa. Life Sci. 2004, 74 (17), 2143– 2155, DOI: 10.1016/j.lfs.2003.09.05422Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosaMatsumoto, Kenjiro; Horie, Syunji; Ishikawa, Hayato; Takayama, Hiromitsu; Aimi, Norio; Ponglux, Dhavadee; Watanabe, KazuoLife Sciences (2004), 74 (17), 2143-2155CODEN: LIFSAK; ISSN:0024-3205. (Elsevier Science Inc.)Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa. The authors previously reported the morphine-like action of mitragynine and its related compds. in the in vitro assays. In the present study, the authors investigated the opioid effects of 7-hydroxymitragynine, which is isolated as its novel constituent, on contraction of isolated ileum, binding of the specific ligands to opioid receptors and nociceptive stimuli in mice. In guinea-pig ileum, 7-hydroxymitragynine inhibited elec. induced contraction through the opioid receptors. Receptor-binding assays revealed that 7-hydroxymitragynine has a higher affinity for μ-opioid receptors relative to the other opioid receptors. Administration of 7-hydroxymitragynine (2.5-10 mg/kg, s.c.) induced dose-dependent antinociceptive effects in tail-flick and hot-plate tests in mice. Its effect was more potent than that of morphine in both tests. When orally administered, 7-hydroxymitragynine (5-10 mg/kg) showed potent antinociceptive activities in tail-flick and hot-plate tests. In contrast, only weak antinociception was obsd. in the case of oral administration of morphine at a dose of 20 mg/kg. It was found that 7-hydroxymitragynine is a novel opioid agonist that is structurally different from the other opioid agonists, and has potent analgesic activity when orally administered.
- 23Matsumoto, K.; Mizowaki, M.; Suchitra, T.; Takayama, H.; Sakai, S.; Aimi, N.; Watanabe, H. Antinociceptive Action of Mitragynine in Mice: Evidence for the Involvement of Supraspinal Opioid Receptors. Life Sci. 1996, 59 (14), 1149– 1155, DOI: 10.1016/0024-3205(96)00432-823Antinociceptive action of mitragynine in mice: evidence for the involvement of supraspinal opioid receptorsMatsumoto, Kinzo; Mizowaki, Maho; Suchitra, Thongpradichote; Takayama, Hiromitsu; Sakai, Shin-ichiro; Aimi, Norio; Watanabe, HiroshiLife Sciences (1996), 59 (14), 1149-1155CODEN: LIFSAK; ISSN:0024-3205. (Elsevier)Mitragynine is a major alkaloidal constituent extd. from the young leaves of Mitragyna speciosa Korth. (Rubiaceae). The authors investigated an antinociceptive activity of i.p. and intracerebroventricular (i.c.v.) injection of this alkaloid by the tail-pinch and hot-plate tests in mice, and evaluated the mechanisms of the action using naloxone, an opioid receptor antagonist. Mitragynine (5.0-30 mg/kg, i.p. and 1.0-10 μg/mouse, i.c.v.) exerted a dose-dependent antinociceptive activity which was maximal at 15-45 min after injection in the tail-pinch and hot-plate tests, but it did not induce a morphine-like behavioral change. The antinociceptive actions of i.p. mitragynine were completely abolished by both s.c. (2 mg/kg) and i.c.v (10 μg/mouse) naloxone. The action of i.c.v. mitragynine (10 μg/mouse) was also antagonized by i.c.v. naloxone (10 μg/mouse). These results indicate that mitragynine itself can induce antinociception by acting in the brain, and that the supraspinal opioid systems are at least partly involved in the antinociceptive action of mitragynine in mice.
- 24Macko, E.; Weisbach, J. A.; Douglas, B. Some Observations on the Pharmacology of Mitragynine. Arch. Int. Pharmacodyn. thérapie 1972, 198 (1), 145– 16124Pharmacology of mitragynineMacko, E.; Weisbach, J. A.; Douglas, B.Archives Internationales de Pharmacodynamie et de Therapie (1972), 198 (1), 145-61CODEN: AIPTAK; ISSN:0003-9780.Mitragynine-HCl (SKF 12711A) (I-HCl) [36455-45-5] or mitragynine ethanedisulfonate (SKF 12711J) [36455-46-6] exhibited analgesic and antitussive properties in animals. Unlike the narcotic analgesics, I had little effect on gastric mobility, failed to produce excitement in cats, was not antagonized by nalorphine, and had only weak respiratory depressant activity in anesthetized animals.
- 25Váradi, A.; Marrone, G. F.; Palmer, T. C.; Narayan, A.; Szabó, M. R.; Le Rouzic, V.; Grinnell, S. G.; Subrath, J. J.; Warner, E.; Kalra, S.; Hunkele, A.; Pagirsky, J.; Eans, S. O.; Medina, J. M.; Xu, J.; Pan, Y.-X.; Borics, A.; Pasternak, G. W.; McLaughlin, J. P.; Majumdar, S. Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2. J. Med. Chem. 2016, 59 (18), 8381– 8397, DOI: 10.1021/acs.jmedchem.6b0074825Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2Varadi, Andras; Marrone, Gina F.; Palmer, Travis C.; Narayan, Ankita; Szabo, Marton R.; Le Rouzic, Valerie; Grinnell, Steven G.; Subrath, Joan J.; Warner, Evelyn; Kalra, Sanjay; Hunkele, Amanda; Pagirsky, Jeremy; Eans, Shainnel O.; Medina, Jessica M.; Xu, Jin; Pan, Ying-Xian; Borics, Attila; Pasternak, Gavril W.; McLaughlin, Jay P.; Majumdar, SusrutaJournal of Medicinal Chemistry (2016), 59 (18), 8381-8397CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacol. Herein, we report the pharmacol. and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [35S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is assocd. with opioid side effects. Addnl., 3 developed analgesic tolerance more slowly than morphine, showed limited phys. dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.
- 26Schmid, C. L.; Kennedy, N. M.; Ross, N. C.; Lovell, K. M.; Yue, Z.; Morgenweck, J.; Cameron, M. D.; Bannister, T. D.; Bohn, L. M. Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics. Cell 2017, 171 (5), 1165– 1175e13, DOI: 10.1016/j.cell.2017.10.03526Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid AnalgesicsSchmid, Cullen L.; Kennedy, Nicole M.; Ross, Nicolette C.; Lovell, Kimberly M.; Yue, Zhizhou; Morgenweck, Jenny; Cameron, Michael D.; Bannister, Thomas D.; Bohn, Laura M.Cell (Cambridge, MA, United States) (2017), 171 (5), 1165-1175.e13CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Biased agonism has been proposed as a means to sep. desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compds. spanning a wide range of signaling bias. We find that β-arrestin-biased compds., such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression.
- 27Soergel, D. G.; Subach, R. A.; Burnham, N.; Lark, M. W.; James, I. E.; Sadler, B. M.; Skobieranda, F.; Violin, J. D.; Webster, L. R. Biased Agonism of the μ-Opioid Receptor by TRV130 Increases Analgesia and Reduces on-Target Adverse Effects versus Morphine: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Volunteers. Pain 2014, 155 (9), 1829– 1835, DOI: 10.1016/j.pain.2014.06.01127Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteersSoergel, David G.; Subach, Ruth Ann; Burnham, Nancy; Lark, Michael W.; James, Ian E.; Sadler, Brian M.; Skobieranda, Franck; Violin, Jonathan D.; Webster, Lynn R.Pain (2014), 155 (9), 1829-1835CODEN: PAINDB; ISSN:0304-3959. (Elsevier B.V.)Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclin. models suggest that differential activation of signaling pathways downstream of these receptors dissocs. analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single i.v. injections of the biased ligand TRV130 (1.5, 3, or 4.5 mg), placebo, or morphine (10 mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiog., clin. lab. values), and analgesia (cold pain test) vs. placebo. Other measures included respiratory drive (minute vol. after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5 mg) elicited higher peak analgesia (105, 116 s latency vs 75 s for morphine, P < .02), with faster onset and similar duration of action. More subjects doubled latency or achieved max. latency (180 s) with TRV130 (3, 4.5 mg). Respiratory drive redn. was greater after morphine than any TRV130 dose (-15.9 for morphine vs. -7.3, -7.6, and -9.4 h * L/min, P < .05). More subjects experienced severe nausea after morphine (n = 7) than TRV130 1.5 or 3 mg (n = 0, 1), but not 4.5 mg (n = 9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less redn. in respiratory drive and less severe nausea. This demonstrates early clin. translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.
- 28Raehal, K. M.; Schmid, C. L.; Groer, C. E.; Bohn, L. M. Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance. Pharmacol. Rev. 2011, 63 (4), 1001– 1019, DOI: 10.1124/pr.111.00459828Functional selectivity at the μ-opioid receptor: implications for understanding opioid analgesia and toleranceRaehal, Kirsten M.; Schmid, Cullen L.; Groer, Chad E.; Bohn, Laura M.Pharmacological Reviews (2011), 63 (4), 1001-1019CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)A review. Opioids are the most effective analgesic drugs for the management of moderate or severe pain, yet their clin. use is often limited because of the onset of adverse side effects. Drugs in this class produce most of their physiol. effects through activation of the μ opioid receptor; however, an increasing no. of studies demonstrate that different opioids, while presumably acting at this single receptor, can activate distinct downstream responses, a phenomenon termed functional selectivity. Functional selectivity of receptor-mediated events can manifest as a function of the drug used, the cellular or neuronal environment examd., or the signaling or behavioral measure recorded. This review summarizes both in vitro and in vivo work demonstrating functional selectivity at the μ opioid receptor in terms of G protein coupling, receptor phosphorylation, interactions with β-arrestins, receptor desensitization, internalization and signaling, and details on how these differences may relate to the progression of analgesic tolerance after their extended use.
- 29Kelly, E. Efficacy and Ligand Bias at the μ-Opioid Receptor. Br. J. Pharmacol. 2013, 169 (7), 1430– 1446, DOI: 10.1111/bph.1222229Efficacy and ligand bias at the μ-opioid receptorKelly, E.British Journal of Pharmacology (2013), 169 (7), 1430-1446CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)A review. In order to describe drug action at a GPCR, a full understanding of the pharmacol. terms affinity, efficacy and potency is necessary. This is true whether comparing the ability of different agonists to produce a measurable response in a cell or tissue, or detg. the relative ability of an agonist to activate a single receptor subtype and produce multiple responses. There is a great deal of interest in the μ-opioid receptor (MOP receptor) and the ligands that act at this GPCR not only because of the clin. important analgesic effects produced by MOP agonists but also because of their liability to induce adverse effects such as respiratory depression and dependence. Our understanding of the mechanisms underlying these effects, as well as the ability to develop new, more effective MOP receptor drugs, depends upon the accurate detn. of the efficacy with which these ligands induce coupling of MOP receptors to downstream signaling events. In this review, which is written with the min. of math. content, the basic meaning of terms including efficacy, intrinsic activity and intrinsic efficacy is discussed, along with their relevance to the field of MOP receptor pharmacol., and in particular in relation to biased agonism at this important GPCR.
- 30Majumdar, S.; Devi, L. A. Strategy for Making Safer Opioids Bolstered. Nature 2018, 553 (7688), 286– 288, DOI: 10.1038/d41586-018-00045-130Strategy for making safer opioids bolsteredMajumdar, Susruta; Devi, Lakshmi A.Nature (London, United Kingdom) (2018), 553 (7688), 286-288CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Compds. have been made that activate only the G-protein signalling pathway when bound to the μ-opioid receptor - the target of opioid pain relievers. These compds. lack one of the main side effects of currently used opioids.
- 31Sabetghadam, A.; Navaratnam, V.; Mansor, S. M. Dose-Response Relationship, Acute Toxicity, and Therapeutic Index between the Alkaloid Extract of Mitragyna Speciosa and Its Main Active Compound Mitragynine in Mice. Drug Dev. Res. 2013, 74 (1), 23– 30, DOI: 10.1002/ddr.2105231Dose-Response Relationship, Acute Toxicity, and Therapeutic Index between the Alkaloid Extract of Mitragyna speciosa and Its Main Active Compound Mitragynine in MiceSabetghadam, Azadeh; Navaratnam, Visweswaran; Mansor, Sharif MahsufiDrug Development Research (2013), 74 (1), 23-30CODEN: DDREDK; ISSN:0272-4391. (Wiley-Liss, Inc.)Preclin. Research Mitragyna speciosa is a widely used medicinal plant that is commonly used for its morphine-like effect sin folklore medicine in Thailand and Malaysia due to its ability to reduce pain and ameliorate withdrawal signs after cessation of opioid abuse. The aim of the present study was to det. and compare the relative safety and therapeutic indexes of M. speciosa alkaloid ext. and its major component, mitragynine. An alkaloid ext. (20-400 mg/kg) from the leaves of M. speciosa, as well as mitragynine (4.2-84 mg/kg), was orally administered to mice; dose-response relationship, ED50 and LD50 values, as well as the therapeutic index (TI), for the two substances were detd. and compared with that of morphine (2.5-10 mg/kg, s.c.). The results showed a significant dose-dependent response in both ext. (50 mg/kg onward) and mitragynine (10.5 mg/kg) with a higher potency of mitragynine than that of the ext. Although the LD50 for the ext. (591 mg/kg) was higher than that of mitragynine (477 mg/kg), the TI for mitragynine was wider than that of the ext. (21:3). The present study indicated that mitragynine is relatively safer when compared with the alkaloid ext. of M. speciosa in mice.
- 32Philipp, A. A.; Wissenbach, D. K.; Zoerntlein, S. W.; Klein, O. N.; Kanogsunthornrat, J.; Maurer, H. H. Studies on the Metabolism of Mitragynine, the Main Alkaloid of the Herbal Drug Kratom, in Rat and Human Urine Using Liquid Chromatography-Linear Ion Trap Mass Spectrometry. J. Mass Spectrom. 2009, 44 (8), 1249– 1261, DOI: 10.1002/jms.160732Studies on the metabolism of mitragynine, the main alkaloid of the herbal drug Kratom, in rat and human urine using liquid chromatography-linear ion trap mass spectrometryPhilipp, Anika A.; Wissenbach, Dirk K.; Zoerntlein, Siegfried W.; Klein, Oliver N.; Kanogsunthornrat, Jidapha; Maurer, Hans H.Journal of Mass Spectrometry (2009), 44 (8), 1249-1261CODEN: JMSPFJ; ISSN:1076-5174. (John Wiley & Sons Ltd.)Mitragynine (MG) is an indole alkaloid of the Thai medicinal plant Mitragyna speciosa (Kratom in Thai) and reported to have opioid agonistic properties. Because of its stimulant and euphoric effects, Kratom is used as a herbal drug of abuse. The aim of the presented study is to identify the phase I and II metabolites of MG in rat and human urine after solid-phase extn. (SPE) using liq. chromatog.-linear ion trap mass spectrometry providing detailed structure information in the MSn mode particularly with high resoln. The seven identified phase I metabolites indicated that MG was metabolized by hydrolysis of the methylester in position 16, O-demethylation of the 9-methoxy group and of the 17-methoxy group, followed, via the intermediate aldehydes, by oxidn. to carboxylic acids or redn. to alcs. and combinations of some steps. In rats, four metabolites were addnl. conjugated to glucuronides and one to sulfate, but in humans, three metabolites to glucuronides and three to sulfates. Copyright © 2009 John Wiley & Sons, Ltd.
- 33Finch, N.; Gemenden, C. W.; Hsu, I. H. C.; Kerr, A.; Sim, G. A.; Taylor, W. I. Oxidative Transformations of Indole Alkaloids. III. Pseudoindoxyls from Yohimbinoid Alkaloids and Their Conversion to “Invert” Alkaloids1,2. J. Am. Chem. Soc. 1965, 87 (10), 2229– 2235, DOI: 10.1021/ja01088a02433Oxidative transformations of indole alkaloids. III. Pseudo indoxyls from yohimbinoid alkaloids and their conversion to "invert" alkaloidsFinch, Neville; Gemenden, C. W.; Hsu, Iva Hsiu-Chu; Kerr, Ann; Sim, G. A.; Taylor, W. I.Journal of the American Chemical Society (1965), 87 (10), 2229-35CODEN: JACSAT; ISSN:0002-7863.cf. CA 58, 14011b. Several tetrahydro-β-carboline alkaloids were converted to their pseudoindoxyl analogs by treatment of the derived acyloxy indolenines with base. By use of such a transformation the yellow alkaloid of Rauwolfia vomitoria Afzel. was identified as isoreserpiline pseudoindoxyl. Optical rotatory dispersion measurements were employed to make tentative assignments of stereochemistry for some of the acyloxy indolenines. Borohydride redn. of the pseudoindoxyls and treatment of the product with acid transforms them into their ring AB inverted indole equivs.
- 34Manda, V.; Avula, B.; Ali, Z.; Khan, I.; Walker, L.; Khan, S. Evaluation of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and Mitraphylline. Planta Med. 2014, 80 (07), 568– 576, DOI: 10.1055/s-0034-136844434Evaluation of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and MitraphyllineManda, Vamshi K.; Avula, Bharathi; Ali, Zulfiqar; Khan, Ikhlas A.; Walker, Larry A.; Khan, Shabana I.Planta Medica (2014), 80 (7), 568-576CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)Mitragyna speciosa (kratom) is a popular herb in Southeast Asia, which is traditionally used to treat withdrawal symptoms assocd. with opiate addiction. Mitragynine, 7-hydroxymitragynine, and mitraphylline are reported to be the central nervous system active alkaloids which bind to the opiate receptors. Mitraphylline is also present in the bark of Uncaria tomentosa (cat's claw). Several therapeutic properties have been reported for these compds. but limited information is available on the absorption and distribution properties. This study focuses on evaluating the absorption, distribution, metab., and excretion (ADME) properties of these compds. and their effect on major efflux transporter P-glycoprotein, using in vitro methods. Quant. anal. was performed by the Q-TOF LC-MS system. Mitragynine was unstable in simulated gastric fluid with 26 % degrdn. but stable in simulated intestinal fluid. 7-Hydroxymitragynine degraded up to 27 % in simulated gastric fluid, which could account for its conversion to mitragynine (23 %), while only 6 % degrdn. was seen in simulated intestinal fluid. Mitraphylline was stable in simulated gastric fluid but unstable in simulated intestinal fluid (13.6 % degrdn.). Mitragynine and 7-hydroxymitragynine showed moderate permeability across Caco-2 and MDR-MDCK monolayers with no significant efflux. However, mitraphylline was subjected to efflux mediated by P-glycoprotein in both Caco-2 and MDR-MDCK monolayers. Mitragynine was found to be metabolically stable in both human liver microsomes and S9 fractions. In contrast, both 7-hydroxymitragynine and mitraphylline were metabolized by human liver microsomes with half-lives of 24 and 50 min, resp. All three compds. exhibited high plasma protein binding (> 90 %) detd. by equil. dialysis. Mitragynine and 7-hydroxymitragynine inhibited P-glycoprotein with EC50 values of 18.2 ± 3.6 μM and 32.4 ± 1.9 μM, resp., detd. by the calcein-AM fluorescent assay, while no inhibition was seen with mitraphylline. These data indicate the possibility of a drug interaction if mitragynine and 7-hydroxymitragynine are coadministered with drugs that are P-glycoprotein substrates.
- 35Semenova, S.; Kuzmin, A.; Zvartau, E. Strain Differences in the Analgesic and Reinforcing Action of Morphine in Mice. Pharmacol., Biochem. Behav. 1995, 50 (1), 17– 21, DOI: 10.1016/0091-3057(94)00221-435Strain differences in the analgesic and reinforcing action of morphine in miceSemenova, S.; Kuzmin, A.; Zvartau, E.Pharmacology, Biochemistry and Behavior (1995), 50 (1), 17-21CODEN: PBBHAU; ISSN:0091-3057. (Elsevier)The analgesic and reinforcing effects of morphine were compared in four strains of mice (C57BL/6, BALB/c, DBA, CBA). The analgesic action of morphine was measured in tail immersion (49°), hot plate (60°), and tail clip (four-point scale of nociceptive response) tests. The reinforcing action of morphine was studied in IV self-administration and conditioned place preference techniques. The results demonstrate strain differences in the analgesic and reinforcing action of morphine in mice. The relative rank order of the strains varied for the several tests as well as for the morphine effects. The lack of correlation between analgesic and reinforcing action of morphine in inbred strains supports the conclusion that analgesia and reinforcement are sep. processes with different genetic control.
- 36Mogil, J. S. Opioid Analgesia, Strain Differences. In Encyclopedia of Pain; Springer Berlin Heidelberg: Berlin, Germany, 2007; pp 1528– 1531.There is no corresponding record for this reference.
- 37Gomes, I.; Gupta, A.; Filipovska, J.; Szeto, H. H.; Pintar, J. E.; Devi, L. A. A Role for Heterodimerization of Mu and Delta Opiate Receptors in Enhancing Morphine Analgesia. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (14), 5135– 5139, DOI: 10.1073/pnas.030760110137A role for heterodimerization of μ and δ opiate receptors in enhancing morphine analgesiaGomes, Ivone; Gupta, Achla; Filipovska, Julija; Szeto, Hazel H.; Pintar, John E.; Devi, Lakshmi A.Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (14), 5135-5139CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Opiates such as morphine are the choice analgesic in the treatment of chronic pain. However their long-term use is limited because of the development of tolerance and dependence. Due to its importance in therapy, different strategies have been considered for making opiates such as morphine more effective, while curbing its liability to be abused. One such strategy has been to use a combination of drugs to improve the effectiveness of morphine. In particular, δ opioid receptor ligands have been useful in enhancing morphine's potency. The underlying mol. basis for these observations is not understood. We propose the modulation of receptor function by phys. assocn. between μ and δ opioid receptors as a potential mechanism. In support of this hypothesis, we show that μ-δ interacting complexes exist in live cells and native membranes and that the occupancy of δ receptors (by antagonists) is sufficient to enhance μ opioid receptor binding and signaling activity. Furthermore, δ receptor antagonists enhance morphine-mediated intrathecal analgesia. Thus, heterodimeric assocns. between μ-δ opioid receptors can be used as a model for the development of novel combination therapies for the treatment of chronic pain and other pathologies.
- 38Yusof, S. R.; Mohd Uzid, M.; Teh, E.-H.; Hanapi, N. A.; Mohideen, M.; Mohamad Arshad, A. S.; Mordi, M. N.; Loryan, I.; Hammarlund-Udenaes, M. Rate and Extent of Mitragynine and 7-Hydroxymitragynine Blood-Brain Barrier Transport and Their Intra-Brain Distribution: The Missing Link in Pharmacodynamic Studies. Addict. Biol. 2018, DOI: 10.1111/adb.12661There is no corresponding record for this reference.
- 39Kamble, S. H.; Sharma, A.; King, T. I.; León, F.; McCurdy, C. R.; Avery, B. A. Metabolite Profiling and Identification of Enzymes Responsible for the Metabolism of Mitragynine, the Major Alkaloid of Mitragyna Speciosa (Kratom). Xenobiotica 2018, 1– 31, DOI: 10.1080/00498254.2018.155281939Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom)Kamble Shyam H; Sharma Abhisheak; King Tamara I; Avery Bonnie A; Leon Francisco; McCurdy Christopher RXenobiotica; the fate of foreign compounds in biological systems (2018), (), 1-31 ISSN:.1. Mitragynine is the major indole-based alkaloid of Mitragyna speciosa (kratom). Decoctions (teas) of the plant leaves have been used traditionally for cough, diarrhoea, pain, hypertension, and for the treatment of opioid addiction. In the West, kratom has become increasingly utilized for mood elevation, pain treatment, and as a means of self-treating opioid addiction. 2. Metabolic pathways of mitragynine were identified in human liver microsomes (HLM) and S9 fractions. A total of thirteen metabolites were identified, four oxidative metabolites and a metabolite formed by demethylation at the 9-methoxy group were the major metabolites of mitragynine. 3. The cytochrome P450 enzymes involved in the metabolism of mitragynine were identified using selective chemical inhibitors of HLM and recombinant cytochrome P450. The metabolism of mitragynine was predominantly carried out through the CYP3A4 with minor contributions by CYP2D6 and CYP2C9. The formation of five oxidative metabolites (Met2, Met4, Met6 Met8 and Met11) was catalyzed by the CYP3A4. 4. In summary, mitragynine was extensively metabolized in HLM primarily to O-demethylated and monooxidative metabolites. The CYP3A4 enzyme plays a predominant role in the metabolic clearance of mitragynine and also in the formation of 7-hydroxymitragynine (Met2), a known active minor alkaloid identified in the leaf material.
- 40Karinen, R.; Fosen, J. T.; Rogde, S.; Vindenes, V. An Accidental Poisoning with Mitragynine. Forensic Sci. Int. 2014, 245, e29– e32, DOI: 10.1016/j.forsciint.2014.10.02540An accidental poisoning with mitragynineKarinen, Ritva; Fosen, Jan Toralf; Rogde, Sidsel; Vindenes, VigdisForensic Science International (2014), 245 (), e29-e32CODEN: FSINDR; ISSN:0379-0738. (Elsevier Ltd.)An increasing no. of drugs of abuse are sold word wide over the internet. Names like "legal highs", "herbal highs" etc. give the impression that these are safe products, although the risk of fatal reactions might be substantial. Leaves from the plant Mitragyna speciosa, contain active compds. like mitragynine and 7-hydroxymitragynine. It has been reported that the potency of 7-hydroxymitragynine at the μ-opioid receptor is 30 times higher than that of mitragynine and 17 times higher than that of morphine. Case reports regarding poisoning with Kratom are reported, but the toxic or lethal ranges for the concns. of the active substances have not been established, and concns. of 7-hydroxymitragynine have not been reported previously.We present a case report where a middle aged man was found dead at home. The deceased had a history of drug abuse and mental illness for several years. At autopsy, there were no significant pathol. findings. Post-mortem anal. of peripheral blood revealed: zopiclone 0.043 mg/L, citalopram 0.36 mg/L and lamotrigine 5.4 mg/L, i.e. concns. regularly seen after therapeutic ingestion of these drugs. Addnl. mitragynine 1.06 mg/L and 7-hydroxymitragynine 0.15 mg/L were detected in blood and both also in urine.The high concns. of mitragynine and 7-hydroxymitragynine indicate that the cause of death is intoxication by these substances; and the circumstances point toward the manner of death being accidental. We recommend that both mitragynine and 7-hydroxymitragynine are analyzed for in cases with suspected Kratom intoxication.
- 41Dean, L. Codeine Therapy and CYP2D6 Genotype. Medical Genetics Summaries; National Center for Biotechnology Information (US), 2012.There is no corresponding record for this reference.
- 42Heppell, S. P. E.; Isbister, G. K. Lack of Respiratory Depression in Paracetamol-Codeine Combination Overdoses. Br. J. Clin. Pharmacol. 2017, 83 (6), 1273– 1278, DOI: 10.1111/bcp.1322442Lack of respiratory depression in paracetamol-codeine combination overdosesHeppell, Simon P. E.; Isbister, Geoffrey K.British Journal of Clinical Pharmacology (2017), 83 (6), 1273-1278CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)Aims : Codeine contg. analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol-codeine combination overdoses caused respiratory depression more than paracetamol alone. Methods : We reviewed deliberate self-poisoning admissions with paracetamol (>2 g) and paracetamol-codeine combinations presenting to a tertiary toxicol. unit (1987-2013). Demog. information, clin. effects, treatment (naloxone, length of stay [LOS], mech. ventilation) were extd. from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression. Results : From 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol-codeine combinations (346) or paracetamol-codeine-doxylamine combinations (101) without co-ingestants. Median age was 23 years (12-89 years); 1002 (73%) were female. Median dose was 12 g (interquartile range [IQR]: 7.5-20 g). Median LOS was 16 h (IQR: 6.5-27 h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone vs. paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2-1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1-1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol-codeine combinations (0.6%; 95% CI: 0.1-2.3%; abs. difference, 0.26%; 95% CI: -0.7-1.2%; P = 0.62). Two out of 101 patients ingesting paracetamol-codeine-doxylamine combinations (2%; 95% CI: 0.3-8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol-codeine group. Conclusions : Paracetamol-codeine combination overdoses are rarely assocd. with severe respiratory depression, with only two given naloxone and none intubated for respiratory depression.
- 43Smith, L. C.; Lin, L.; Hwang, C. S.; Zhou, B.; Kubitz, D. M.; Wang, H.; Janda, K. D. Lateral Flow Assessment and Unanticipated Toxicity of Kratom. Chem. Res. Toxicol. 2019, 32, 113, DOI: 10.1021/acs.chemrestox.8b0021843Lateral Flow Assessment and Unanticipated Toxicity of KratomSmith, Lauren C.; Lin, Lucy; Hwang, Candy S.; Zhou, Bin; Kubitz, Diane M.; Wang, Huiying; Janda, Kim D.Chemical Research in Toxicology (2019), 32 (1), 113-121CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The leaves of the Mitragynine speciosia tree (also known as Kratom) have long been chewed, smoked, or brewed into a tea by people in Southeastern Asian countries, such as Malaysia and Thailand. Just this past year, the plant Kratom gained popularity in the United States as a 'legal opioid' and scheduling it as a drug of abuse is currently pending. The primary alkaloid found in Kratom is a μ-opioid receptor agonist, mitragynine, whose structure contains a promising scaffold for immunopharmacol. use. Although Kratom is regarded as a safe opioid alternative, here we report the LD50 values detd. for its two main psychoactive alkaloids, mitragynine and 7-hydroxymitragynine, as comparable to heroin in mice when administered i.v. Given Kratom's recent emergence in the U.S., there is currently no diagnostic test available for law enforcement or health professionals, so we sought to design such an assay. Mitragynine was used as a starting point for hapten design, resulting in a hapten with an ether linker extending from the C9 position of the alkaloid. Bacterial flagellin (FliC) was chosen as a carrier protein for active immunization in mice, yielding 32 potential monoclonal antibodies (mAbs) for assay development. Anti-mitragynine mAbs in the range of micro- to nanomolar affinities were uncovered and their utility in producing a convenient lateral flow detection assay of human fluid samples was examd. Antibodies were screened for binding to mitragynine, 7-hydroxymitragynine, and performance in lateral flow assays. Two monoclonal antibodies were subcloned and further purified, with 93 nM and 362 nM affinity to mitragynine. Test strip assays were optimized with a detection cut off of 0.5 μg/mL for mitragynine in buffer and urine (reflecting projected clin. relevant levels of drug in urine), which could be beneficial to law enforcement agencies and health professionals as the opioid epidemic in America continues to evolve.
- 44National Institute on Drug Abuse. Overdose Death Rates. National Institute on Drug Abuse (NIDA) https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates (accessed Dec 26, 2018).There is no corresponding record for this reference.
- 45Hemby, S. E.; McIntosh, S.; Leon, F.; Cutler, S. J.; McCurdy, C. R. Abuse Liability and Therapeutic Potential of the Mitragyna Speciosa (Kratom) Alkaloids Mitragynine and 7-Hydroxymitragynine. Addict. Biol. 2018, DOI: 10.1111/adb.12639There is no corresponding record for this reference.
- 46Yue, K.; Kopajtic, T. A.; Katz, J. L. Abuse Liability of Mitragynine Assessed with a Self-Administration Procedure in Rats. Psychopharmacology (Berl). 2018, 235 (10), 2823– 2829, DOI: 10.1007/s00213-018-4974-946Abuse liability of mitragynine assessed with a self-administration procedure in ratsYue Kai; Kopajtic Theresa A; Katz Jonathan LPsychopharmacology (2018), 235 (10), 2823-2829 ISSN:.RATIONALE: Substantial use of the plant kratom for psychoactive effects has driven interest in its abuse liability. Several place conditioning studies suggest abuse liability of the active ingredient mitragynine, though studies of its self-administration have not been published. METHODS: Binding of mitragynine to rat brain mu, kappa, and delta opioid receptors was compared to that for heroin and morphine. Self-administration of mitragynine, heroin, methamphetamine, or saline was assessed during single-session substitutions in rats trained to self-administer methamphetamine (0.022 mg/kg/injection, i.v.) during 1-h daily sessions. RESULTS: Mitragynine had > 2- or ~ 16-fold greater affinity for the mu opioid receptor than, respectively, for kappa or delta opioid receptors. Its affinity for the mu receptor was ~ 200-fold less than that for morphine. In rats trained to self-administer methamphetamine, saline substitutions significantly decreased the number of responses, whereas different doses of methamphetamine (0.002-0.068 mg/kg/injection) or heroin (0.001-0.03 mg/kg/injection) maintained self-administration with maximal responding at 0.022 or 0.01 mg/kg/injection, respectively. In contrast, no dose of mitragynine maintained response rates greater than those obtained with saline. Presession mitragynine treatment (0.1 to 3.0 mg/kg) decreased response rates maintained by heroin but had little effect on responding maintained by methamphetamine across the same range of doses. CONCLUSIONS: These results suggest a limited abuse liability of mitragynine and potential for mitragynine treatment to specifically reduce opioid abuse. With the current prevalence of opioid abuse and misuse, it appears currently that mitragynine is deserving of more extensive exploration for its development or that of an analog as a medical treatment for opioid abuse.
- 47Kathiramalainathan, K.; Kaplan, H. L.; Romach, M. K.; Busto, U. E.; Li, N. Y.; Säwe, J.; Tyndale, R. F.; Sellers, E. M. Inhibition of Cytochrome P450 2D6Modifies Codeine Abuse Liability. J. Clin. Psychopharmacol. 2000, 20 (4), 435– 444, DOI: 10.1097/00004714-200008000-0000847Inhibition of cytochrome P450 2D6 modifies codeine abuse liabilityKathiramalainathan, Kalyani; Kaplan, Howard L.; Romach, Myroslava K.; Busto, Usoa E.; Li, Ning-Yuan; Sawe, Juliette; Tyndale, Rachel F.; Sellers, Edward M.Journal of Clinical Psychopharmacology (2000), 20 (4), 435-444CODEN: JCPYDR; ISSN:0271-0749. (Lippincott Williams & Wilkins)Oral codeine prepns., widely used for analgesia and cough suppression, are abused by some individuals for their mood-altering properties. The enzymic O-demethylation of codeine is catalyzed by cytochrome P 450 2D6 (CYP2D6), leading to the prodn. of metabolites (morphine, morphine-6-glucuronide) that are pharmacol. more potent than codeine. A placebo-controlled, single-blind study was conducted to characterize the subjective effects of codeine assocd. with abuse liability and to det. the importance of metabolic O-demethylation to codeine abuse liability. Twelve non-drug-dependent subjects received oral administration of placebo and codeine 60, 120, and 180 mg, and a favorite dose (FD) was detd. for each subject. The FD was readministered after pretreatment with placebo, 50 mg of quinidine (a specific, selective CYP2D6 inhibitor) once, or 50 mg of quinidine given four times a day for 4 days. Single-dose quinidine pretreatment significantly decreased the recovery of O-demethylated metabolites in plasma (p < 0.01) and resulted in a decrease in the pos. (e.g., "high," p < 0.05) and neg. (e.g., nausea, p < 0.05) subjective effects of codeine in both the FD120 and FD180 groups. Short-term quinidine pretreatment inhibited codeine O-demethylation more than did single-dose quinidine pretreatment (p < 0.01), and it decreased pos. codeine effects in the FD120 group (N = 7), but unexpectedly not in the FD180 group (N = 5). These results suggest that the O-demethylated metabolites contribute substantially to the subjective effects and abuse liability of codeine.
- 48Kong, W. M.; Chik, Z.; Ramachandra, M.; Subramaniam, U.; Aziddin, R. E. R.; Mohamed, Z. Evaluation of the Effects of Mitragyna Speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay. Molecules 2011, 16 (12), 7344– 7356, DOI: 10.3390/molecules1609734448Evaluation of the effects of Mitragyna speciosa alkaloid extract on cytochrome P450 enzymes using a high throughput assayKong, Wai Mun; Chik, Zamri; Ramachandra, Murali; Subramaniam, Umarani; Aziddin, Raja Elina Raja; Mohamed, ZahurinMolecules (2011), 16 (), 7344-7356CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)The ext. from Mitragyna speciosa has been widely used as an opium substitute, mainly due to its morphine-like pharmacol. effects. This study investigated the effects of M. speciosa alkaloid ext. (MSE) on human recombinant cytochrome P 450 (CYP) enzyme activities using a modified Crespi method. As compared with the liq. chromatog.-mass spectrometry method, this method has shown to be a fast and cost-effective way to perform CYP inhibition studies. The results indicated that MSE has the most potent inhibitory effect on CYP3A4 and CYP2D6, with apparent half-maximal inhibitory concn. (IC50) values of 0.78 μg/mL and 0.636 μg/mL, resp. In addn., moderate inhibition was obsd. for CYP1A2, with an IC50 of 39 μg/mL, and weak inhibition was detected for CYP2C19. The IC50 of CYP2C19 could not be detd., however, because inhibition was <50%. Competitive inhibition was found for the MSE-treated CYP2D6 inhibition assay, whereas non-competitive inhibition was shown in inhibition assays using CYP3A4, CYP1A2 and CYP2C19. Quinidine (CYP2D6), ketoconazole (CYP3A4), tranylcypromine (CYP2C19) and furafylline (CYP1A2) were used as pos. controls throughout the expts. This study shows that MSE may contribute to an herb-drug interaction if administered concomitantly with drugs that are substrates for CYP3A4, CYP2D6 and CYP1A2.
- 49Manda, V. K.; Avula, B.; Dale, O. R.; Ali, Z.; Khan, I. A.; Walker, L. A.; Khan, S. I. PXR Mediated Induction of CYP3A4, CYP1A2, and P-Gp by Mitragyna Speciosa and Its Alkaloids. Phytother. Res. 2017, 31 (12), 1935– 1945, DOI: 10.1002/ptr.594249PXR mediated induction of CYP3A4, CYP1A2, and P-gp by Mitragyna speciosa and its alkaloidsManda, Vamshi K.; Avula, Bharathi; Dale, Olivia R.; Ali, Zulfiqar; Khan, Ikhlas A.; Walker, Larry A.; Khan, Shabana I.Phytotherapy Research (2017), 31 (12), 1935-1945CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)Kratom (Mitragyna speciosa), a native herb of Southeast Asia, is widely known for its psychoactive properties. Recent increase in the use of kratom as a recreational drug has increased the risk of its interaction with conventional drugs if taken concomitantly. A few reports are available related to the effects of kratom on the activity of cytochrome P 450 enzymes (CYPs), but there are no reports of its effects on pregnane X receptor (PXR), a transcription factor that regulates the expression of CYPs and P-glycoprotein (P-gp). This study was carried out to evaluate the effects of a methanolic ext. of kratom leaves, an alkaloid rich fraction and its 5 indole and 4 oxindole alkaloids on PXR activation and the resulting changes in the mRNA expression of PXR target genes (CYP3A4, CYP1A2, and P-gp). A significant activation of PXR was obsd. by the ext. (3-fold), alkaloidal fraction (4-fold) and all 9 alkaloids (4- to 6-fold) that was assocd. with an increased mRNA expression which resulted into an increase in the activity of CYP3A4, CYP1A2, and P-gp. These results indicate that high consumption of Mitragyna speciosa ext. along with the conventional drugs may lead to potential herb-drug interactions due to its effects on PXR.
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Opioid functional activity of desmethyl metabolites, additional microsome and plasma stability experiments, formation of 7-OH in mouse microsomes, synthetic scheme and procedures for preparation of deuterated analogues, biological procedures (PDF)
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