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Doxorubicin is an effective chemotherapeutic agent in the treatment of solid hematological and non-hematological carcinoma. However, its long-term usage could result in side effects, such as cardiomyopathy, chronic heart failure, neurotoxicity and cancer cell resistance. In this study, we reported the sensitivity enhancement of A549 human lung cancer cells on doxorubicin at a low dose (0.1 ppm) in combination with 10–60 ppm of crude and alkaloid extracts derived from the leaves of Kratom (Mitragyna speciosa (Korth.) Havil. Rubiaceae). A549 cancer cell lines were insensitive to the crude extract containing low mitragynine (MG) (4–5%), while these cells were moderately inhibited by the alkaloid extract containing 40–45% MG (IC50 of 48–55 ppm). The alkaloid extract was found to inhibit A549 cancer cells via apoptosis as suggested by the higher relative fluorescence intensity with Annexin compared to that in propidium iodide (PI), i.e., a positive Annexin and a negative PI. The combination of crude extract and doxorubicin sensitized A549 cancer cells to doxorubicin by 1.3 to 2.4 times, while the combination with the alkaloid induced a 2.6- to 3.4-fold increase in sensitivity. The calculated combination index (CI) for doxorubicin with the crude and alkaloid extracts was 0.6 and 0.3, respectively, showing potential synergistic combinations to reduce the level of dosage of doxorubicin used in chemotherapy. In addition, the synergistic enhancement effect of crude extract on the cytotoxic activity of doxorubicin provides insights into the plausibility of non-alkaloids to influence the biological activities of Kratom. [ABSTRACT FROM AUTHOR]

Kratom and cannabidiol products are used to self-treat a variety of conditions, including anxiety and pain, and to elevate mood. Research into the individual pharmacokinetic properties of commercially available kratom and cannabidiol products has been performed, but there are no studies on coadministration of these products. Surveys of individuals with kratom use history indicate that cannabidiol use is one of the strongest predictors of both lifetime and past month kratom use. The purpose of this study was to determine if there are changes in pharmacokinetic properties when commercially available kratom and cannabidiol products are administered concomitantly. It was found that with concomitant administration of cannabidiol, there was a 2.8-fold increase in the exposure of the most abundant kratom alkaloid, mitragynine, and increases in the exposure of other minor alkaloids. The results of this work suggest that with cannabidiol coadministration, the effects of kratom may be both delayed and increased due to a delay in time to reach maximum plasma concentration and higher systemic exposure of the psychoactive alkaloids found in kratom. [ABSTRACT FROM AUTHOR]

Kratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unlike morphine, it does not activate the β-arrestin-2 respiratory depression pathway. Due to few human mitragynine data, the largest randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of 500–4000 mg dried kratom leaf powder (6.65–53.2 mg mitragynine) was conducted. LC-MS/MS mitragynine and 7-hydroxymitragynine plasma concentrations were obtained after single and 15 daily doses. Mitragynine and 7-hydroxymitragynine Cmax increased dose proportionally, and AUC was slightly more than dose proportional. The median mitragynine Tmax was 1.0–1.3 h after single and 1.0–1.7 h after multiple doses; for 7-hydroxymitragynine Tmax, it was 1.2–1.8 h and 1.3–2.0 h. Steady-state mitragynine concentrations were reached in 8–9 days and 7-hydroxymitragynine within 7 days. The highest mean mitragynine T1/2 was 43.4 h after one and 67.9 h after multiple doses, and, for 7-hydroxymitragynine, it was 4.7 and 24.7 h. The mean 7-hydroxy-mitragynine/mitragynine concentration ratios were 0.20–0.31 after a single dose and decreased (0.15–0.21) after multiple doses. These mitragynine and 7-hydroxymitragynine data provide guidance for future clinical kratom dosing studies and an interpretation of clinical and forensic mitragynine and 7-hydroxymitragynine concentrations. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa) is a botanical substance whose leaves produce stimulant- and opioid-like effects. Kratom use has increased precipitously in the United States (U.S.) over the last decade, yet, in our experience, many pharmacists are unfamiliar with this herb. The purpose of this study was to assess pharmacists' awareness and knowledge of kratom. This cross-sectional study used an online questionnaire to preferentially solicit community pharmacists' knowledge of kratom and collect demographic information. The survey was sent via email to approximately 10,000 pharmacists, targeting those in the state of Alabama, U.S. Data were analyzed using descriptive statistics, and the Chi Square test was used to compare nominal data. A total of 257 participants responded to the survey. Almost 50% of participants had heard of kratom, and 50% had not. Compared to females, males were more likely to have heard of kratom (64% vs. 42%; p = 0.0015), as were pharmacists who worked for an independent pharmacy vs. a chain (61% vs. 41%; p = 0.025). Of the participants who had heard of kratom, only 14% considered themselves knowledgeable or very knowledgeable about the herb, and only 44% knew it was illegal in Alabama. These data indicate a need to further kratom education among community pharmacists in Alabama. [ABSTRACT FROM AUTHOR]

This work aimed to test the efficacy of an ultrasound (US) and pulsed electric field (PEF) apparatus to extract mitragynine from dried Mitragyna speciosa cv. Karn Dang leaves. Four modes of the device were tested: PEF, US, US + PEF, and PEF + US, and the modes were compared using a conventional technique (maceration, as the control). The liquid chromatography/mass spectrometry (LC-MS/MS) analysis revealed that the mitragynine contents from M. speciosa leaves using the four different modes were significantly different (p < 0.05). The highest extraction (106.63 ± 0.85 mg/L) of mitragynine was obtained by the mode using a combination of PEF + US, followed by US + PEF (97.27 ± 1.33 mg/L), with increased extraction efficiencies of 45.81 ± 0.59% and 33.00 ± 1.85%, respectively. Moreover, the total energy consumption under the combination technique was 25.0% lower than that with PEF assistance. Scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR) were used to analyze the structural and functional features of the alterations in M. speciosa leaves. This study demonstrated that a combination of PEF and US devices may be regarded as a green alternative technique and can assist in streamlining the implementation of agricultural products. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa Korth. Havil) has been considered a narcotic drug for years, barred by the law in many parts of the world, while extensive research over the past few decades proves its several beneficial effects, some of which are still in ambiguity. In many countries, including Thailand, the indiscriminate use and abuse of kratom have led to the loss of life. Nonetheless, researchers have isolated almost fifty pure compounds from kratom, most of which are alkaloids. The most prevalent compounds, mitragynine and 7-hydroxy mitragynine, are reported to display agonist morphine-like effects on human μ-opioid receptors and antagonists at κ- and δ-opioid receptors with multimodal effects at other central receptors. Mitragynine is also credited to be one of the modulatory molecules for the Keap1-Nrf2 pathway and SOD, CAT, GST, and associated genes' upregulatory cascades, leading it to play a pivotal role in neuroprotective actions while evidently causing neuronal disorders at high doses. Additionally, its anti-inflammatory, antioxidative, antibacterial, and gastroprotective effects are well-cited. In this context, this review focuses on the research gap to resolve ambiguities about the neuronal effects of kratom and demonstrate its prospects as a therapeutic target for neurological disorders associated with other pharmacological effects. [ABSTRACT FROM AUTHOR]

The objective of this study was to obtain data on the distribution of alkaloids in kratom plants grown in Thailand. Two collections were performed, covering the southern, central, and northern regions of Thailand and different seasons. The contents of alkaloids, including mitragynine (MG), paynantheine (PAY), and speciogynine (SG), were determined using the validated HPLC method. The 134 samples in the first collection were collected from Nam Phu subdistrict, Ban Na San, Surat Thani, Thailand, during June and October 2019 and January 2020. The maximum mitragynine content was 4.94% w/w in June (late summer), and the minimum content was 0.74% w/w in October (rainy season). To expand the study area after kratom decriminalization, 611 samples were collected in June–August 2021, October–December 2021, and January–April 2022. The accumulation of MG ranged from 0.35 to 3.46% w/w, 0.31 to 2.54% w/w, and 0.48 to 2.81% w/w, respectively. The meteorological data supported the climate's effect on alkaloid production. Soil analysis revealed the importance of Ca and Mg in promoting alkaloid production. Geographical locations played a role in the variation of MG in kratom leaves, but did not affect the color of leaf veins. In conclusion, the present study suggested that the alkaloid content in kratom diverges based on seasonal and geographical origin. [ABSTRACT FROM AUTHOR]

Mitragynine and its congeners are one of the major phytoconstituents present in Mitragyna speciosa Korth. (ketum) leaves and a well-known factor that contributes to ketum's pharmacological activities. This study describes the usage of a green extraction method to yield botanical leaf extracts of ketum. The leaf extracts were assessed for mitragynine content, total phenolic and flavonoid content, and cytotoxicities. The Ultrasound Assisted Extraction (UAE) method showed a varying dry yield of the extracts (0.22–1.92 g) that were obtained with solvents of variable polarities. However, the mitragynine content was consistent among the organic solvent extracts (7.22–9.40%). This method calls for a minimal extraction solvent volume (solid to solvent ratio, 1:30) and a shorter extraction period (20 min). Of the solvents tested, the methanolic extract showed the highest content of total phenolic (419.50 ± 2.50 GAE mg/g) and flavonoids (177.33 ± 3.00 QE mg/g). The extract was nontoxic towards kidney (HEK-293) and Chang liver (HeLa) cell lines. Analysis via UHPLC-ESI-QTOF-MS/MS made it possible to identify mitragynine congeners, such as mitragynine, paynantheine, and speciociliatine, in the leaves extract. In conclusion, the UAE method using methanol as the extraction solvent provides a noncytotoxic ketum botanical extract for future preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

Mitragynine (MTR), the main indole alkaloid of the well-known plant kratom (Mitragyna speciosa), is one of the most studied natural products nowadays, due to its remarkable biological effects. It is a partial agonist on the opioid receptors, and as such relieves pain without the well-known side-effects of the opioids applied in the clinical practice. MTR and its derivatives therefore became novel candidates for drug development. The poor aqueous solubility and low bioavailability of drugs are often improved by cyclodextrins (CyDs) as excipients through host-guest type complex formation. Among the wide variety of CyDs, sulfobutylether-beta-cyclodextrin (SBEβCyD) is frequently used and official in the European and U.S. Pharmacopoeia. Herein, the host-guest complexation of MTR with βCyD and SBEβCyD was studied using chiroptical and NMR spectroscopy. It was found by NMR measurements that MTR forms a rather weak (logβ11 = 0.8) 1:1 host-guest complex with βCyD, while the co-existence of the 2MTR∙SBEβCyD and MTR∙SBEβCyD species was deducted from 1H NMR titrations in the millimolar MTR concentration range. Sulfobutylation of βCyD significantly enhanced the affinity towards MTR. The structure of the formed inclusion complex was extensively studied by circular dichroism spectroscopy and 2D ROESY NMR. The insertion of the indole moiety was confirmed by both techniques. [ABSTRACT FROM AUTHOR]

Increasing use of the botanical kratom to self-manage opioid withdrawal and pain has led to increased kratom-linked overdose deaths. Despite these serious safety concerns, rigorous fundamental pharmacokinetic knowledge of kratom in humans remains lacking. We assessed the pharmacokinetics of a single low dose (2 g) of a well-characterized kratom product administered orally to six healthy participants. Median concentration-time profiles for the kratom alkaloids examined were best described by a two-compartment model with central elimination. Pronounced pharmacokinetic differences between alkaloids with the 3S configuration (mitragynine, speciogynine, paynantheine) and alkaloids with the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) were attributed to differences in apparent intercompartmental distribution clearance, volumes of distribution, and clearance. Based on noncompartmental analysis of individual concentration-time profiles, the 3S alkaloids exhibited a shorter median time to maximum concentration (1–2 vs. 2.5–4.5 h), lower area under the plasma concentration-time curve (430–490 vs. 794–5120 nM × h), longer terminal half-life (24–45 vs. ~12–18 h), and higher apparent volume of distribution during the terminal phase (960–12,700 vs. ~46–130 L) compared to the 3R alkaloids. Follow-up mechanistic in vitro studies suggested differential hepatic/intestinal metabolism, plasma protein binding, blood-to-plasma partitioning, and/or distribution coefficients may explain the pharmacokinetic differences between the two alkaloid types. This first comprehensive pharmacokinetic characterization of kratom alkaloids in humans provides the foundation for further research to establish safety and effectiveness of this emerging botanical product. [ABSTRACT FROM AUTHOR]

Kratom ( Mitragyna speciosa ) is a Southeast Asian plant containing various alkaloids that induce pharmacological effects in humans. In Western countries, online vendors sell a variety of different kratom strains which are marketed to have distinct effect profiles. However, as of yet such marketing claims are unsubstantiated, and therefore the current study investigated whether differently colored kratom products can induce distinct effects, as self-reported by users. Six hundred forty-four current kratom users were anonymously surveyed to compare the self-reported effects of and motivations for using kratom products sold as red, green, and white strains. Most of the survey respondents were customers of the same kratom vendor, the products of which had been analyzed for their alkaloid content by an independent laboratory. The survey respondents reported distinct subjective experiences for different kratom strains, in a manner congruent with common marketing descriptions. However, the product analyses revealed no significant cross-strain differences in alkaloid content, suggesting that the reported effect differences might be disproportionally influenced by marketing narratives and anecdotal reports. Future studies should engage a more diverse population and include kratom strains from various vendors. Controlled, blinded experiments could assess whether the reported effect differences stem from a placebo effect or from alternative factors, e.g., minor alkaloids and terpenes.

Varied pharmacological responses have been reported for mitragynine in the literature, but no supportive scientific explanations have been given for this. These studies have been undertaken without a sufficient understanding of the physicochemical properties of mitragynine. In this work a UV spectrophotometer approach and HPLC-UV method were employed to ascertain the physicochemical properties of mitragynine. The pKa of mitragynine measured by conventional UV (8.11 ± 0.11) was in agreement with the microplate reader determination (8.08 ± 0.04). Mitragynine is a lipophilic alkaloid, as indicated by a logP value of 1.73. Mitragynine had poor solubility in water and basic media, and conversely in acidic environments, but it is acid labile. In an in vitro dissolution the total drug release was higher for the simulated gastric fluid but was prolonged and incomplete for the simulated intestinal fluid. The hydrophobicity, poor water solubility, high variability of drug release in simulated biological fluids and acid degradable characteristics of mitragynine probably explain the large variability of its pharmacological responses reported in the literature. The determined physicochemical properties of mitragynine will provide a basis for developing a suitable formulation to further improve its solubility, stability and oral absorption for better assessment of this compound in preclinical studies. [ABSTRACT FROM AUTHOR]

Cannabinoids and opioids systems share numerous pharmacological properties and antinociception is one of them. Previous findings have shown that mitragynine (MG), a major indole alkaloid found in Mitragyna speciosa (MS) can exert its antinociceptive effects through the opioids system. In the present study, the action of MG was investigated as the antinociceptive agent acting on Cannabinoid receptor type 1 (CB1) and effects on the opioids receptor. The latency time was recorded until the mice showed pain responses such as shaking, licking or jumping and the duration of latency was measured for 2 h at every 15 min interval by hot plate analysis. To investigate the beneficial effects of MG as antinociceptive agent, it was administered intraperitoneally 15 min prior to pain induction with a single dosage (3, 10, 15, 30, and 35 mg/kg b.wt). In this investigation, 35 mg/kg of MG showed significant increase in the latency time and this dosage was used in the antagonist receptor study. The treated groups were administered with AM251 (cannabinoid receptor-1 antagonist), naloxone (non-selective opioid antagonist), naltrindole (δ-opioid antagonist) naloxonazine (µ1-receptor antagonist) and norbinaltorpimine (κ-opioid antagonist) respectively, prior to administration of MG (35 mg/kg). The results showed that the antinociceptive effect of MG was not antagonized by AM251; naloxone and naltrindole were effectively blocked; and norbinaltorpimine partially blocked the antinociceptive effect of MG. Naloxonazine did inhibit the effect of MG, but it was not statistically significant. These results demonstrate that CB1 does not directly have a role in the antinociceptive action of MG where the effect was observed with the activation of opioid receptor. [ABSTRACT FROM AUTHOR]

Mitragyna is a genus belonging to the Rubiaceae family and is a plant endemic to Asia and Africa. Traditionally, the plants of this genus were used by local people to treat some diseases from generation to generation. Mitragyna speciosa (Korth.) Havil. is a controversial plant from this genus, known under the trading name "kratom", and contains more than 40 different types of alkaloids. Mitragynine and 7-hydroxymitragynine have agonist morphine-like effects on opioid receptors. Globally, Mitragyna plants have high economic value. However, regulations regarding the circulation and use of these commodities vary in several countries around the world. This review article aims to comprehensively examine Mitragyna plants (mainly M. speciosa) as potential pharmacological agents by looking at various aspects of the plants. A literature search was performed and information collected using electronic databases including Scopus, ScienceDirect, PubMed, directory open access journal (DOAJ), and Google Scholar in early 2020 to mid-2021. This narrative review highlights some aspects of this genus, including historical background and botanical origins, habitat, cultivation, its use in traditional medicine, phytochemistry, pharmacology and toxicity, abuse and addiction, legal issues, and the potential of Mitragyna species as pharmaceutical products. [ABSTRACT FROM AUTHOR]

Mitragyna speciosa Korth (kratom) is known for its psychoactive and analgesic properties. Mitragynine is the primary constituent present in kratom leaves. This study highlights the utilisation of the green accelerated solvent extraction technique to produce a better, non-toxic and antinociceptive active botanical extract of kratom. ASE M. speciosa extract had a dry yield (0.53–2.91 g) and showed a constant mitragynine content (6.53–7.19%) when extracted with organic solvents of different polarities. It only requires a shorter extraction time (5 min) and a reduced amount of solvents (less than 100 mL). A substantial amount of total phenolic (407.83 ± 2.50 GAE mg/g and flavonoids (194.00 ± 5.00 QE mg/g) were found in ASE kratom ethanol extract. The MTT test indicated that the ASE kratom ethanolic leaf extract is non-cytotoxic towards HEK-293 and HeLa Chang liver cells. In mice, ASE kratom ethanolic extract (200 mg/kg) demonstrated a better antinociceptive effect compared to methanol and ethyl acetate leaf extracts. The presence of bioactive indole alkaloids and flavonols such as mitragynine, paynantheine, quercetin, and rutin in ASE kratom ethanolic leaf extract was detected using UHPLC-ESI-QTOF-MS/MS analysis supports its antinociceptive properties. ASE ethanolic leaf extract offers a better, safe, and cost-effective choice of test botanical extract for further preclinical studies. [ABSTRACT FROM AUTHOR]

Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity. [ABSTRACT FROM AUTHOR]

The co-use of conventional drug and herbal medicines may lead to herb-drug interaction via modulation of drug-metabolizing enzymes (DMEs) by herbal constituents. UDP-glucuronosyltransferases (UGTs) catalyzing glucuronidation are the major metabolic enzymes of Phase II DMEs. The in vitro inhibitory effect of several herbal constituents on one of the most important UGT isoforms, UGT2B7, in human liver microsomes (HLM) and rat liver microsomes (RLM) was investigated. Zidovudine (ZDV) was used as the probe substrate to determine UGT2B7 activity. The intrinsic clearance (Vmax/Km) of ZDV in HLM is 1.65 µL/mg/min which is ten times greater than in RLM, which is 0.16 µL/mg/min. Andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone inhibited ZDV glucuronidation in HLM with IC50 values of 6.18 ± 1.27, 18.56 ± 8.62, 8.11 ± 4.48 and 4.57 ± 0.23 µM, respectively, hence, herb-drug interactions are possible if andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone are taken together with drugs that are highly metabolized by UGT2B7. Meanwhile, only mitragynine and zerumbone inhibited ZDV glucuronidation in RLM with IC50 values of 51.20 ± 5.95 μM and 8.14 ± 2.12 µM, respectively, indicating a difference between the human and rat microsomal model so caution must be exercised when extrapolating inhibitory metabolic data from rats to humans. [ABSTRACT FROM AUTHOR]