A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds
Abstract
:1. Introduction
2. Methodology
3. Focus of This Review
4. Nomenclature and Provenance
5. Extraction and Extractive of Kratom
6. Chemistry and Composition-Linked Actions of Kratom
Nature of Alkaloids from Kratom
7. Toxicology and Toxicokinetics of Kratom
8. Neurological Effects of Kratom
8.1. Kratom, an Indole-like Alkaloid for Neurological Effects
8.2. Anti-Inflammatory Effects Leading to Neuroprotective Effects
8.3. Analgesic and Anti-Nociceptive Effects
8.4. Neurological Effects by Gene Regulation
8.5. Antioxidative Effects
9. Other Pharmacological Effects
9.1. Antibacterial Effects
9.2. Gastrointestinal Effects
10. Adverse Effects/Abuse of Kratom
Treatment with Doses | Nature of Kratom Product | Experimental Model | Major Findings (Molecular Changes) | Reference |
---|---|---|---|---|
Anti-bacterial | ||||
Kratom | Methanolic extract (3.12 to 6.25 mg/mL) | Salmonella typhi and Bacillus subtilis | Minimum inhibitory concentrations (MICs) by the broth dilution method | (Parthasarathy, Bin Azizi et al., 2009) [16] |
Mitragynine (40 mg/kg), alkaloid extract (100 mg/kg) | Adult male Wistar rats | Detoxification and elimination of permethrin | (Srichana, Janchawee et al., 2015) [19] | |
Gastrointestinal effects | ||||
Kratom | Methanolic extract (50, 100, 200 and 400 mg/kg) | Adult Wistar rats | Protection against castor oil-induced diarrhea, ↓ intestinal transit | (Chittrakarn, Sawangjaroen et al., 2008) [165] |
mitragynine (3–30 μg) | Male Wistar rats | ↓ 2-deoxy-d-glucose-stimulated gastric acid secretion | (Tsuchiya, Miyashita et al., 2002) [166] | |
7-hydroxymintragynine (ED50 = 1.19 mg/kg) | Male ddY-strain mice | ↓ Gastrointestinal transit and significantly antagonized by β-funaltrexamine hydrochloride (β-FNA) pretreatment, but slightly antagonized by naloxonazine | (Matsumoto, Hatori et al., 2006) [68] | |
Muscle relaxant | ||||
Kratom | Methanolic extract (10–40 mg/mL), mitragynine (2 mg/mL) | Wistar rats | Blockade of nerve conduction, amplitude, and duration | (Chittrakarn, Keawpradub et al., 2010) [172] |
Potential to inhibit enzyme activity | ||||
Kratom | Methanolic extract | Three main CYP450 enzymes: CYP2C9, CYP2D6, and CYP3A4 | Most potent effect on CYP2D6 at IC50 (3.6 ± 0.1 μg/mL) | (Hanapi 2010) [173] |
Alkaloid extract | CYP450 enzymes, Quinidine (CYP2D6), ketoconazole (CYP3A4), tranylcypromine (CYP2C19), and furafylline (CYP1A2) | Most potent inhibitory effect on CYP3A4 and CYP2D6 at IC50 values of 0.78 µg/mL and 0.636 µg/mL | (Kong, Chik et al., 2011) [100] | |
Anti-diabetic | ||||
Kratom | Water extract 0.6 mg mL−1 | L8 muscle cells | ↑ Glucose transporters (GLUT1) | (Purintrapiban, Keawpradub et al., 2011) [174] |
Anti-hypertensive | ||||
Kratom | Methanolic extract (100, 500, and 1000 mg/kg) | Male Albino rats | Blood pressure (diastolic: 102.7 ± 0.72, 98.74 ± 7.95 and 86.85 ± 3.34), and ↑ ALT, AST, albumin, triglycerides, cholesterol, albumin levels | (Harizal, Mansor et al., 2010) [95] |
Weight reduction | ||||
Kratom | Mitragynine (45 and 50 mg/kg) | Male Wistar rats | ↓ Food and water intakes | (Kumarnsit, Keawpradub et al., 2006) [22] |
Mitragynine (100 mg/kg) | Male and female Sprague-Dawley rats | ↓ Food intake, ↓ Body weight of female rats, and ↑ liver weight of both male and female rats | (Sabetghadam, Ramanathan et al., 2013) [164] |
Uses Pattern | Side Effects of Kratom | Condition | History | Reference |
---|---|---|---|---|
For 1 month, kratom leaf tea is brewed with Datura stramonium | 4–5 mm pupils, minimally reactive, roving conjugate gaze, and spasticity of lower extremities with manipulation | Chronic pain after post-colostomy surgery | 64 years male | (Nelsen, Lapoint et al., 2010) [175] |
Powder of leaf 4.6–7 to 8.6–14 g/day for 2 weeks | Loss of appetite, fever and chills, slight abdominal discomfort, concomitant brown discoloration of the urine, jaundice, and pruritus | Intrahepatic cholestasis | 25 years male | (Kapp, Maurer et al., 2011) [176] |
Kratom tea 4 times a day for 3.5 years | A generalized tonic-clonic seizure lasting 5 min, pulse 123 beats per min | Tonic colonic seizure | 43 years male | (Boyer, Babu et al., 2008) [128] |
1 tablespoon of powder daily for 3 months | Jaundice, dark urine, mild confusion, and liver injury | Cholestatic hepatitis | 58 years male | (Dorman, Wong et al., 2015) [177] |
6 g Kratom capsules daily for 2 weeks | Palpation of the right upper quadrant (RUQ) in the presence of vomiting, fatigue, abdominal pain, and brown urine | Hepatomegaly | 21 years male | (Griffiths, Gandhi et al., 2018) [170] |
Sixty tablets over 1 week | A yellowish appearance to the skin, usually associated with nausea, fatigue, joint pains, night sweats, pale stools, and dark urine | Hepatitis | 32 years male | (Tayabali, Bolzon et al., 2018) [171] |
Herbal drug Kratom | Distention, mass, tenderness, rebound, sternal pleuritic chest pain, mild shortness of breath, mild cough, mild coughing, and mild chest pain | Intrahepatic cholestasis | 38 years male | (Riverso, Chang et al., 2018) [178] |
A tablespoon of crushed leaves (−1.5 g/d) | Yellow discoloration of eyes and skin, mild fatigue, jaundice | Intrahepatic cholestasis | 52 years male | (Fernandes, Iqbal et al., 2019) [179] |
Green-colored herbal powder supplement for a few weeks with increasing daily dosage | Pupils were pinpoint and not reactive to light and cool peripheries, the abdomen and pelvis revealed cholestasis without cholecystitis | Intrahepatic cholestasis | 36 years male | (Palasamudram Shekar, Rojas et al., 2019) [180] |
Kratom tea for 2 weeks | Tea-colored urine, malaise, fatigue, and intermittent subjective fever | Acute hepatitis | 31 years male | (Mousa, Sephien et al., 2018) [181] |
Kratom capsules for 3 weeks | Dark urine, pruritus, subjective fevers, fatigue, nonbloody, nonbilious emesis, nonicteric sclera, and sublingual jaundice | Hepatitis | 47 years male | (Osborne, Overstreet et al., 2019) [182] |
11. Critical Remarks and Insights
12. Conclusions and Future Prospective
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AChE | Acetylcholinesterase |
AD | Alzheimer’s disease |
ALT | Alanine aminotransferase |
ASE | Accelerated solvent extraction |
AST | Aspartate aminotransferase |
BBB | Blood–brain barrier |
CAT | Catalase |
COX-2 | Cyclooxygenase-2 |
CUPRAC | Cupric ion reducing antioxidant capacity |
CYPs | Cytochromes P50 |
ED50 | Median effective dose |
ESI | Electrospray ionization |
FRAP | Ferric reducing ability of plasma |
fEPSP | Field excitatory postsynaptic potentials |
HSP | Heat shock proteins |
HSF | Heat shock Factors |
HT2A | Hydroxy-Tryptamine receptor |
IC50 | Half maximal inhibitory concentration |
I. P | Intraperitoneal |
Keap1 | Kelch-like ECH-Associating protein 1 |
Kg | Kilogram |
LD50 | Median lethal dose |
LPS | Lipopolysaccharides |
LTP | Long-term potentiation |
MAO | Monoamine oxidase |
Mg | Milligram |
µg | Microgram |
MIC | Minimum inhibitory concentration |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
Nm | Nanometer |
PD | Parkinson’s disease |
P. O | Per Oral |
QTOF-MS | Quadrupole time-of-flight mass spectrometry |
SOD | Superoxide dismutase |
TPC | Total phenolic content |
TFC | Total flavonoid content |
UDP | Uridine diphosphate |
UGT | UDP-glucuronosyl transferase |
UHPLC | Ultra high-performance liquid chromatography |
w/w | Weight for weight |
References
- Butler, M.S. The role of natural product chemistry in drug discovery. J. Nat. Prod. 2004, 67, 2141–2153. [Google Scholar] [CrossRef]
- Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 2012, 75, 311–335. [Google Scholar] [CrossRef] [PubMed]
- Koehn, F.E.; Carter, G.T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 2005, 4, 206–220. [Google Scholar] [CrossRef] [PubMed]
- Patwardhan, B.; Mashelkar, R.A. Traditional medicine-inspired approaches to drug discovery: Can Ayurveda show the way forward? Drug Discov. Today 2009, 14, 804–811. [Google Scholar] [CrossRef] [PubMed]
- Arndt, T.; Claussen, U.; Güssregen, B.; Schröfel, S.; Stürzer, B.; Werle, A.; Wolf, G. Kratom alkaloids and O-desmethyltramadol in urine of a “Krypton” herbal mixture consumer. Forensic Sci. Int. 2011, 208, 47–52. [Google Scholar] [CrossRef] [PubMed]
- White, C.M. Pharmacologic and clinical assessment of kratom. Bull. Am. Soc. Hosp. Pharm. 2018, 75, 261–267. [Google Scholar] [CrossRef]
- Gong, F.; Gu, H.P.; Xu, Q.T.; Kang, W.Y. Genus Mitragyna: Ethnomedicinal uses and pharmacological studies. Phytopharmacology 2012, 3, 263–272. [Google Scholar]
- Rech, M.A.; Donahey, E.; Dziedzic, J.M.C.; Oh, L.; Greenhalgh, E. New drugs of abuse. Pharmacotherapy. J. Hum. Pharmacol. Drug Ther. 2015, 35, 189–197. [Google Scholar] [CrossRef]
- Vicknasingam, B.; Narayanan, S.; Beng, G.T.; Mansor, S.M. The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int. J. Drug Policy 2010, 21, 283–288. [Google Scholar] [CrossRef]
- Hassan, Z.; Muzaimi, M.; Navaratnam, V.; Yusoff, N.H.; Suhaimi, F.W.; Vadivelu, R.; Vicknasingam, B.K.; Amato, D.; von Hörsten, S.; Ismail, N.I.; et al. From Kratom to mitragynine and its derivatives: Physiological and behavioural effects related to use, abuse, and addiction. Neurosci. Biobehav. Rev. 2013, 37, 138–151. [Google Scholar] [CrossRef]
- Eisenman, S.W. The botany of Mitragyna speciosa (Korth.) Havil. and related species. In Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium Source; CRC Press: Boca Raton, FL, USA, 2014; Volume 57, pp. 57–76. [Google Scholar]
- Warner, M.L.; Kaufman, N.C.; Grundmann, O. The pharmacology and toxicology of kratom: From traditional herb to drug of abuse. Int. J. Leg. Med. 2016, 130, 127–138. [Google Scholar] [CrossRef] [PubMed]
- Adkins, 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, 1165–1175. [Google Scholar] [CrossRef] [PubMed]
- Jaipaew, J.; Padungchareon, T.; Sukrong, S. PCR-reverse dot blot of the nucleotide signature sequences of matK for the identification of Mitragyna speciosa, a narcotic species. Plant Gene 2018, 14, 46–54. [Google Scholar] [CrossRef]
- Tungphatthong, C.; Urumarudappa, S.K.J.; Awachai, S.; Sooksawate, T.; Sukrong, S. Differentiation of Mitragyna speciosa, a narcotic plant, from allied Mitragyna species using DNA barcoding-high-resolution melting (Bar-HRM) analysis. Sci. Rep. 2021, 11, 6738. [Google Scholar] [CrossRef]
- Parthasarathy, S.; Bin Azizi, J.; Ramanathan, S.; Ismail, S.; Sasidharan, S.; Said, M.I.M.; Mansor, S.M. Evaluation of antioxidant and antibacterial activities of aqueous, methanolic and alkaloid extracts from Mitragyna speciosa (Rubiaceae family) leaves. Molecules 2009, 14, 3964–3974. [Google Scholar] [CrossRef] [PubMed]
- Meireles, V.; Rosado, T.; Barroso, M.; Soares, S.; Gonçalves, J.; Luís, A.; Caramelo, D.; Simão, A.Y.; Fernández, N.; Duarte, A.P.; et al. Mitragyna speciosa: Clinical, toxicological aspects and analysis in biological and non-biological samples. Medicines 2019, 6, 35. [Google Scholar] [CrossRef]
- Yuniarti, R.; Nadia, S.; Alamanda, A.; Zubir, M.; Syahputra, R.A.; Nizam, M. Characterization, phytochemical screenings and antioxidant activity test of kratom leaf ethanol extract (Mitragyna speciosa Korth) using DPPH method. J. Phys. Conf. Ser. IOP Publ. 2020, 1462, 012026. [Google Scholar] [CrossRef]
- Srichana, K.; Janchawee, B.; Prutipanlai, S.; Raungrut, P.; Keawpradub, N. Effects of mitragynine and a crude alkaloid extract derived from Mitragyna speciosa Korth. on permethrin elimination in rats. Pharmaceutics 2015, 7, 10–26. [Google Scholar] [CrossRef]
- Goh, Y.S.; Karunakaran, T.; Murugaiyah, V.; Santhanam, R.; Abu Bakar, M.H.; Ramanathan, S. Accelerated solvent extractions (ASE) of Mitragyna speciosa Korth. (Kratom) leaves: Evaluation of its cytotoxicity and antinociceptive activity. Molecules 2021, 26, 3704. [Google Scholar] [CrossRef]
- Mossadeq, W.S.; Sulaiman, M.; Mohamad, T.T.; Chiong, H.; Zakaria, Z.; Jabit, M.; Baharuldin, M.; Israf, D. Anti-inflammatory and antinociceptive effects of Mitragyna speciosa Korth methanolic extract. Med. Princ. Pract. 2009, 18, 378–384. [Google Scholar] [CrossRef]
- Kumarnsit, E.; Keawpradub, N.; Nuankaew, W. Acute and long-term effects of alkaloid extract of Mitragyna speciosa on food and water intake and body weight in rats. Fitoterapia 2006, 77, 339–345. [Google Scholar] [CrossRef]
- Watanabe, K.; Yano, S.; Horie, S.; Yamamoto, L.T. Inhibitory effect of mitragynine, an alkaloid with analgesic effect from Thai medicinal plant Mitragyna speciosa, on electrically stimulated contraction of isolated guinea-pig ileum through the opioid receptor. Life Sci. 1997, 60, 933–942. [Google Scholar] [CrossRef]
- Pathak, L.; Agrawal, Y.; Dhir, A. Natural polyphenols in the management of major depression. Expert Opin. Investig. Drugs 2013, 22, 863–880. [Google Scholar] [CrossRef] [PubMed]
- Carpenter, J.M.; Criddle, C.A.; Craig, H.K.; Ali, Z.; Zhang, Z.; Khan, I.A.; Sufka, K.J. Comparative effects of Mitragyna speciosa extract, mitragynine, and opioid agonists on thermal nociception in rats. Fitoterapia 2016, 109, 87–90. [Google Scholar] [CrossRef]
- Kruegel, A.C.; Uprety, R.; Grinnell, S.G.; Langreck, C.; Pekarskaya, E.A.; Le Rouzic, V.; Ansonoff, M.; Gassaway, M.M.; Pintar, J.E.; Pasternak, G.W.; et al. 7-Hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects. ACS Cent. Sci. 2019, 5, 992–1001. [Google Scholar] [CrossRef] [PubMed]
- Kumarnsit, E.; Keawpradub, N.; Nuankaew, W. Effect of Mitragyna speciosa aqueous extract on ethanol withdrawal symptoms in mice. Fitoterapia 2007, 78, 182–185. [Google Scholar] [CrossRef]
- Apryani, E.; Hidayat, M.T.; Moklas, M.; Fakurazi, S.; Idayu, N.F. Effects of mitragynine from Mitragyna speciosa Korth leaves on working memory. J. Ethnopharmacol. 2010, 129, 357–360. [Google Scholar] [CrossRef] [PubMed]
- Idayu, N.F.; Hidayat, M.T.; Moklas, M.; Sharida, F.; Raudzah, A.N.; Shamima, A.; Apryani, E. Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of depression. Phytomedicine 2011, 18, 402–407. [Google Scholar] [CrossRef]
- Obeng, S.; Kamble, S.H.; Reeves, M.E.; Restrepo, L.F.; Patel, A.; Behnke, M.; Chear, N.J.Y.; Ramanathan, S.; Sharma, A.; León, F.; et al. Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloids. J. Med. Chem. 2019, 63, 433–439. [Google Scholar] [CrossRef]
- Johnson, L.E.; Balyan, L.; Magdalany, A.; Saeed, F.; Salinas, R.; Wallace, S.; Veltri, C.A.; Swogger, M.T.; Walsh, Z.; Grundmann, O. Focus: Plant-based Medicine and Pharmacology: The Potential for Kratom as an Antidepressant and Antipsychotic. Yale J. Biol. Med. 2020, 93, 283. [Google Scholar]
- Ahmad, I.; Prabowo, W.C.; Arifuddin, M.; Fadraersada, J.; Indriyanti, N.; Herman, H.; Purwoko, R.Y.; Nainu, F.; Rahmadi, A.; Paramita, S.; et al. Mitragyna species as pharmacological agents: From abuse to promising pharmaceutical products. Life 2022, 12, 193. [Google Scholar] [CrossRef]
- Vijeepallam, K.; Pandy, V.; Murugan, D.D.; Naidu, M. Methanolic extract of Mitragyna speciosa Korth leaf inhibits ethanol seeking behaviour in mice: Involvement of antidopaminergic mechanism. Metab. Brain Dis. 2019, 34, 1713–1722. [Google Scholar] [CrossRef] [PubMed]
- Salleh, N.A.S.M.; Halim, S.; Ridzuan, P.M.; Uzid, M.M.; Ramli, M.D. The Potential Role of Neuroprotective Effects of Kratom (Mitragyna speciosa) On Brain Aging. J. Cell. Mol. Anesth. 2021, 6, 352–353. [Google Scholar]
- Aznal, A.N.Z.; Hazalin, N.A.M.N.; Hassan, Z.; Mat, N.H.; Chear, N.J.-Y.; Teh, L.K.; Salleh, M.Z.; Suhaimi, F.W. Adolescent kratom exposure affects cognitive behaviours and brain metabolite profiles in Sprague-Dawley rats. Front. Pharmacol. 2022, 28, 1057423. [Google Scholar] [CrossRef]
- Singh, D.; Narayanan, S.; Müller, C.P.; Vicknasingam, B.; Yücel, M.; Ho, E.T.W.; Hassan, Z.; Mansor, S.M. Long-Term Cognitive Effects of Kratom (Mitragyna speciosa Korth.) Use. J. Psychoact. Drugs 2019, 51, 19–27. [Google Scholar] [CrossRef]
- Flores-Bocanegra, L.; Raja, H.A.; Graf, T.N.; Augustinović, M.; Wallace, E.D.; Hematian, S.; Kellogg, J.J.; Todd, D.A.; Cech, N.B.; Oberlies, N.H. The Chemistry of Kratom [Mitragyna speciosa]: Updated Characterization Data and Methods to Elucidate Indole and Oxindole Alkaloids. J. Nat. Prod. 2020, 83, 2165–2177. [Google Scholar] [CrossRef]
- Suwanlert, S. A study of kratom eaters in Thailand. Bull. Narc. 1975, 27, 21–27. [Google Scholar]
- Ahmad, K.; Aziz, Z. Mitragyna speciosa use in the northern states of Malaysia: A cross-sectional study. J. Ethnopharmacol. 2012, 141, 446–450. [Google Scholar] [CrossRef] [PubMed]
- Cinosi, E.; Martinotti, G.; Simonato, P.; Singh, D.; Demetrovics, Z.; Roman-Urrestarazu, A.; Bersani, F.S.; Vicknasingam, B.; Piazzon, G.; Li, J.-H.; et al. Following “the roots” of Kratom (Mitragyna speciosa): The evolution of an enhancer from a traditional use to increase work and productivity in Southeast Asia to a recreational psychoactive drug in western countries. BioMed Res. Int. 2015, 2015, 968786. [Google Scholar] [CrossRef] [PubMed]
- Ruck, C. Mushrooms, Myth and Mithras: The Drug Cult that Civilized Europe; City Lights Books: San Francisco, CA, USA, 2021. [Google Scholar]
- Tanguay, P. Kratom in Thailand: Decriminalisation and Community Control? Series on legislative reform of drug policies; Transnational Institute (TNI): Amsterdam, The Netherlands; International Drug Policy Consortium (IDPC): London, UK, 2011; Volume 13. [Google Scholar]
- Saingam, D.; Assanangkornchai, S.; Geater, A.F.; Balthip, Q. Pattern and consequences of krathom (Mitragyna speciosa Korth.) use among male villagers in southern Thailand: A qualitative study. Int. J. Drug Policy 2013, 24, 351–358. [Google Scholar] [CrossRef]
- Singh, 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. [Google Scholar] [CrossRef] [PubMed]
- Khalil, S.; Abdullah, S.A.J.; Ahmad, R. Enforcement status of the poison act 1952 against offences related to kratom (Mitragyna speciosa korth) misuse in Malaysia. UUM J. Leg. Stud. 2020, 11, 75–93. [Google Scholar] [CrossRef]
- Swogger, 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, 360–367. [Google Scholar] [CrossRef]
- Assanangkornchai, S.; Muekthong, A.; Sam-Angsri, N.; Pattanasattayawong, U. The use of Mitragynine speciosa (“Krathom”), an addictive plant, in Thailand. Subst. Use Misuse 2007, 42, 2145–2157. [Google Scholar] [CrossRef]
- Grundmann, O. Patterns of Kratom use and health impact in the US-Results from an online survey. Drug Alcohol Depend. 2017, 176, 63–70. [Google Scholar] [CrossRef]
- Hillebrand, J.; Olszewski, D.; Sedefov, R. Legal highs on the Internet. Subst. Use Misuse 2010, 45, 330–340. [Google Scholar] [CrossRef]
- Schmidt, M.M.; Sharma, A.; Schifano, F.; Feinmann, C. “Legal highs” on the net-Evaluation of UK-based Websites, products and product information. Forensic Sci. Int. 2011, 206, 92–97. [Google Scholar] [CrossRef]
- Feng, L.-Y.; Battulga, A.; Han, E.; Chung, H.; Li, J.-H. New psychoactive substances of natural origin: A brief review. J. Food Drug Anal. 2017, 25, 461–471. [Google Scholar] [CrossRef] [PubMed]
- Mustafa, A.; Trevino, L.M.; Turner, C. Pressurized hot ethanol extraction of carotenoids from carrot by-products. Molecules 2012, 17, 1809–1818. [Google Scholar] [CrossRef]
- Mohamed, H.M. Green, environment-friendly, analytical tools give insights in pharmaceuticals and cosmetics analysis. TrAC Trends Anal. Chem. 2015, 66, 176–192. [Google Scholar] [CrossRef]
- Techasakul, S.; Chimnoi, N.; Khunnawutm, N.; Feungfuloy, P.; Chatrewong, K. Facile isolation and purification of thailandine, a biologically active oxoaporphine alkaloid, from Stephania venosa leaves using ion-pair liquid-liquid extraction. Res. J. Med. Plant 2013, 7, 68–76. [Google Scholar] [CrossRef]
- Fatima, N.; Tapondjou, L.A.; Lontsi, D.; Sondengam, B.; Rahman, A.U.; Choudhary, M.I. Quinovic acid glycosides from Mitragyna stipulosa-first examples of natural inhibitors of snake venom phosphodiesterase I. Nat. Prod. Lett. 2002, 16, 389–393. [Google Scholar] [CrossRef] [PubMed]
- Asase, A.; Kokubun, T.; Grayer, R.J.; Kite, G.; Simmonds, M.S.J.; Oteng-Yeboah, A.A.; Odamtten, G.T. Chemical constituents and antimicrobial activity of medicinal plants from Ghana: Cassia sieberiana, Haematostaphis barteri, Mitragyna inermis and Pseudocedrela kotschyi. Phytother. Res. 2008, 22, 1013–1016. [Google Scholar] [CrossRef] [PubMed]
- Phongprueksapattana, S.; Putalun, W.; Keawpradub, N.; Wungsintaweekul, J. Mitragyna speciosa: Hairy root culture for triterpenoid production and high yield of mitragynine by regenerated plants. Z. Naturforsch. C J. Biosci. 2008, 63, 691–698. [Google Scholar] [CrossRef] [PubMed]
- Ponglux, D.; Wongseripipatana, S.; Takayama, H.; Kikuchi, M.; Kurihara, M.; Kitajima, M.; Aimi, N.; Sakai, S.-I. A New Indole Alkaloid, 7 alpha-Hydroxy-7H-mitragynine, from Mitragyna speciosa in Thailand. Planta Med. 1994, 60, 580–581. [Google Scholar] [CrossRef]
- León, F.; Habib, E.; Adkins, J.E.; Furr, E.B.; McCurdy, C.R.; Cutler, S.J. Phytochemical characterization of the leaves of Mitragyna speciosa grown in U.S.A. Nat. Prod. Commun. 2009, 4, 907–910. [Google Scholar] [CrossRef] [PubMed]
- Jaleel, C.A.; Gopi, R.; Kishorekumar, A.; Manivannan, P.; Sankar, B.; Panneerselvam, R. Interactive effects of triadimefon and salt stress on antioxidative status and ajmalicine accumulation in Catharanthus roseus. Acta Physiol. Plant. 2008, 30, 287–292. [Google Scholar] [CrossRef]
- Gajalakshmi, S.; Vijayalakshmi, S.; Devi, R.V. Pharmacological activities of Catharanthus roseus: A perspective review. Int. J. Pharma Bio Sci. 2013, 4, 431–439. [Google Scholar]
- Duwiejua, M.; Woode, E.; Obiri, D. Pseudo-akuammigine, an alkaloid from Picralima nitida seeds, has anti-inflammatory and analgesic actions in rats. J. Ethnopharmacol. 2002, 81, 73–79. [Google Scholar] [CrossRef]
- Trager, W.; Lee, C.M.; Phillipson, J.; Haddock, R.; Dwuma-Badu, D.; Beckett, A. Configurational analysis of rhynchophylline-type oxindole alkaloids. The absolute configuration of ciliaphylline, rhynchociline, specionoxeine, isospecionoxeine, rotundifoline and isorotundifoline. Tetrahedron 1968, 24, 523–543. [Google Scholar] [CrossRef]
- Roquebert, J.; Demichel, P. Inhibition of the alpha 1 and alpha 2-adrenoceptor-mediated pressor response in pithed rats by raubasine, tetrahydroalstonine and akuammigine. Eur. J. Pharmacol. 1984, 106, 203–205. [Google Scholar] [CrossRef]
- Chen, L.-L.; Song, J.-X.; Lu, J.-H.; Yuan, Z.-W.; Liu, L.-F.; Durairajan, S.S.K.; Li, M. Corynoxine, a Natural Autophagy Enhancer, Promotes the Clearance of Alpha-Synuclein via Akt/mTOR Pathway. J. Neuroimmune Pharmacol. 2014, 9, 380–387. [Google Scholar] [CrossRef]
- Gutierrez-Salmean, G.; Ciaraldi, T.P.; Nogueira, L.; Barboza, J.; Taub, P.R.; Hogan, M.C.; Henry, R.R.; Meaney, E.; Villarreal, F.; Ceballos, G.; et al. Effects of (−)-epicatechin on molecular modulators of skeletal muscle growth and differentiation. J. Nutr. Biochem. 2014, 25, 91–94. [Google Scholar] [CrossRef]
- Escandón, R.A.; del Campo, M.; López-Solis, R.; Obreque-Slier, E.; Toledo, H. Antibacterial effect of kaempferol and (−)-epicatechin on Helicobacter pylori. Eur. Food Res. Technol. 2016, 242, 1495–1502. [Google Scholar] [CrossRef]
- Matsumoto, K.; Hatori, Y.; Murayama, T.; Tashima, K.; Wongseripipatana, S.; Misawa, K.; Kitajima, M.; Takayama, H.; Horie, S. Involvement of μ-opioid receptors in antinociception and inhibition of gastrointestinal transit induced by 7-hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa. Eur. J. Pharmacol. 2006, 549, 63–70. [Google Scholar] [CrossRef] [PubMed]
- Shukla, A.; Srinivasan, B.P. 16,17-Dihydro-17b-hydroxy isomitraphylline alkaloid as an inhibitor of DPP-IV, and its effect on incretin hormone and β-cell proliferation in diabetic rat. Eur. J. Pharm Sci. 2012, 47, 512–519. [Google Scholar] [CrossRef] [PubMed]
- García, R.; Cayunao, C.; Bocic, R.; Backhouse, N.; Delporte, C.; Zaldivar, M.; Erazo, S. Antimicrobial activity of isopteropodine. Z. Naturforsch. C J. Biosci. 2005, 60, 385–388. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.L.; Zhang, L.M.; Hua, Z. Blocking effect of rhynchophylline on calcium channels in isolated rat ventricular myocytes. Zhongguo Yao Li Xue Bao 1994, 15, 115–118. [Google Scholar] [PubMed]
- Kocialski, A.B.; Marozzi, F.J.; Malone, M.H. Effects of certain nonsteroid anti-inflammatory drugs, tolbutamide, and tetrahydroalstonine on blood glucose and carrageen in-induced pedal edema in rats. J. Pharm. Sci. 1972, 61, 1202–1205. [Google Scholar] [CrossRef]
- Kang, T.-H.; Murakami, Y.; Matsumoto, K.; Takayama, H.; Kitajima, M.; Aimi, N.; Watanabe, H. Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytes. Eur. J. Pharmacol. 2002, 455, 27–34. [Google Scholar] [CrossRef]
- Philipp, A.A.; Wissenbach, D.K.; Weber, A.A.; Zapp, J.; Maurer, H.H. Metabolism studies of the Kratom alkaloids mitraciliatine and isopaynantheine, diastereomers of the main alkaloids mitragynine and paynantheine, in rat and human urine using liquid chromatography-linear ion trap-mass spectrometry. J Chromatogr. B Analyt. Technol. Biomed Life Sci. 2011, 879, 1049–1055. [Google Scholar] [CrossRef] [PubMed]
- Kruegel, 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, 6754–6764. [Google Scholar] [CrossRef]
- Joshi, B.; Taylor, W. Structure of mitragynine (9-methoxycorynantheidine). Chem. Ind. 1963, 54, 573. [Google Scholar]
- Zacharias, D.E.; Rosenstein, R.D.; Jeffrey, G.A. The structure of mitragynine hydroiodide. Acta Crystallogr. 1965, 18, 1039–1043. [Google Scholar] [CrossRef]
- Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi, N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto, L.T.; et al. 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, 1949–1956. [Google Scholar] [CrossRef]
- Sharma, A.; Kamble, S.H.; Leon, F.; Chear, N.J.Y.; King, T.I.; Berthold, E.C.; Ramanathan, S.; McCurdy, C.R.; Avery, B.A. Simultaneous quantification of ten key Kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometry. Drug Test. Anal. 2019, 11, 1162–1171. [Google Scholar] [CrossRef]
- Ellis, C.R.; Racz, R.; Kruhlak, N.L.; Kim, M.T.; Zakharov, A.V.; Southall, N.; Hawkins, E.G.; Burkhart, K.; Strauss, D.G.; Stavitskaya, L. Evaluating kratom alkaloids using PHASE. PLoS ONE 2020, 15, e0229646. [Google Scholar] [CrossRef]
- Gutridge, A.M.; Robins, M.T.; Cassell, R.J.; Uprety, R.; Mores, K.L.; Ko, M.J.; Pasternak, G.W.; Majumdar, S.; van Rijn, R.M. G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder. Br. J. Pharmacol. 2020, 177, 1497–1513. [Google Scholar] [CrossRef]
- Chear, N.J.-Y.; León, F.; Sharma, A.; Kanumuri, S.R.R.; Zwolinski, G.; Abboud, K.A.; Singh, D.; Restrepo, L.F.; Patel, A.; Hiranita, T.; et al. Exploring the Chemistry of Alkaloids from Malaysian Mitragyna speciosa (Kratom) and the Role of Oxindoles on Human Opioid Receptors. J. Nat. Prod. 2021, 84, 1034–1043. [Google Scholar] [CrossRef]
- Houghton, P.J.; Said, I.M. 3-dehydromitragynine: An alkaloid from Mitragyna speciosa. Phytochemistry 1986, 25, 2910–2912. [Google Scholar] [CrossRef]
- Houghton, P.J.; Latiff, A.; Said, I.M. Alkaloids from Mitragyna speciosa. Phytochemistry 1991, 30, 347–350. [Google Scholar] [CrossRef]
- Limsuwanchote, S.; Wungsintaweekul, J.; Keawpradub, N.; Putalun, W.; Morimoto, S.; Tanaka, H. Development of indirect competitive ELISA for quantification of mitragynine in Kratom (Mitragyna speciosa (Roxb.) Korth.). Forensic Sci. Int. 2014, 244, 70–77. [Google Scholar] [CrossRef] [PubMed]
- Ramanathan, S.; León, F.; Chear, N.J.; Yusof, S.R.; Murugaiyah, V.; McMahon, L.R.; McCurdy, C.R. Kratom (Mitragyna speciosa Korth.): A description on the ethnobotany, alkaloid chemistry, and neuropharmacology. Stud. Nat. Prod. Chem. 2021, 69, 195–225. [Google Scholar] [CrossRef]
- Manwill, P.K.; Flores-Bocanegra, L.; Khin, M.; Raja, H.A.; Cech, N.B.; Oberlies, N.H.; Todd, D.A. Kratom (Mitragyna speciosa) Validation: Quantitative Analysis of Indole and Oxindole Alkaloids Reveals Chemotypes of Plants and Products. Planta Medica 2022, 88, 838–857. [Google Scholar] [CrossRef] [PubMed]
- Wang, M.; Carrell, E.J.; Ali, Z.; Avula, B.; Avonto, C.; Parcher, J.F.; Khan, I.A. Comparison of three chromatographic techniques for the detection of mitragynine and other indole and oxindole alkaloids in Mitragyna speciosa (kratom) plants. J. Sep. Sci. 2014, 37, 1411–1418. [Google Scholar] [CrossRef]
- Azizi, J.; Ismail, S.; Mordi, M.N.; Ramanathan, S.; Said, M.I.M.; Mansor, S.M. In vitro and in vivo effects of three different Mitragyna speciosa Korth leaf extracts on phase II drug metabolizing enzymes—Glutathione transferases (GSTs). Molecules 2010, 15, 432–441. [Google Scholar] [CrossRef]
- Raffa, R.B. Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium Source; CRC Press: Boca Raton, FL, USA, 2014. [Google Scholar]
- Veeramohan, R.; Azizan, K.A.; Aizat, W.M.; Goh, H.-H.; Mansor, S.M.; Yusof, N.S.M.; Baharum, S.N.; Ng, C.L. Metabolomics data of Mitragyna speciosa leaf using LC-ESI-TOF-MS. Data Brief 2018, 18, 1212–1216. [Google Scholar] [CrossRef]
- Trakulsrichai, S.; Sathirakul, K.; Auparakkitanon, S.; Krongvorakul, J.; Sueajai, J.; Noumjad, N.; Sukasem, C.; Wananukul, W. Pharmacokinetics of mitragynine in man. Drug Des. Dev. Ther. 2015, 9, 2421. [Google Scholar] [CrossRef]
- Smith, K.E.; Rogers, J.M.; Dunn, K.E.; Grundmann, O.; McCurdy, C.R.; Schriefer, D.; Epstein, D.H. Searching for a Signal: Self-Reported Kratom Dose-Effect Relationships Among a sample of US adults with regular Kratom use histories. Front. Pharmacol. 2022, 1, 765917. [Google Scholar] [CrossRef]
- Manda, V.K.; Avula, B.; Ali, Z.; Khan, I.A.; Walker, L.A.; Khan, S.I. Evaluation of in vitro absorption, distribution, metabolism, and excretion (ADME) properties of mitragynine, 7-hydroxymitragynine, and mitraphylline. Planta Med. 2014, 80, 568–576. [Google Scholar] [CrossRef]
- Harizal, S.; Mansor, S.; Hasnan, J.; Tharakan, J.; Abdullah, J. Acute toxicity study of the standardized methanolic extract of Mitragyna speciosa Korth in rodents. J. Ethnopharmacol. 2010, 131, 404–409. [Google Scholar] [CrossRef]
- Ilmie, M.U.; Jaafar, H.; Mansor, S.M.; Abdullah, J.M. Subchronic toxicity study of standardized methanolic extract of Mitragyna speciosa Korth in Sprague-Dawley Rats. Front. Neurosci. 2015, 9, 189. [Google Scholar] [CrossRef] [PubMed]
- Saidin, N.A.; Randall, T.; Takayama, H.; Holmes, E.; Gooderham, N.J. Malaysian Kratom, a phyto-pharmaceutical of abuse: Studies on the mechanism of its cytotoxicity. Toxicology 2008, 1, 19–20. [Google Scholar] [CrossRef]
- Rusli, N.; Amanah, A.; Kaur, G.; Adenan, M.I.; Sulaiman, S.F.; Wahab, H.A.; Tan, M.L. The inhibitory effects of mitragynine on P-glycoprotein in vitro. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2019, 392, 481–496. [Google Scholar] [CrossRef] [PubMed]
- Azizi, J.; Ismail, S.; Mansor, S.M. Mitragyna speciosa Korth leaves extracts induced the CYP450 catalyzed aminopyrine-N-demethylase (APND) and UDP-glucuronosyl transferase (UGT) activities in male Sprague-Dawley rat livers. Drug Metab. Drug Interact. 2013, 28, 95–105. [Google Scholar] [CrossRef]
- Kong, 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, 7344–7356. [Google Scholar] [CrossRef]
- Kamble, 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 2019, 49, 1279–1288. [Google Scholar] [CrossRef]
- Uno, Y.; Uehara, S.; Murayama, N.; Yamazaki, H. Cytochrome P450 1A1, 2C9, 2C19, and 3A4 polymorphisms account for interindividual variability of toxicological drug metabolism in cynomolgus macaques. Chem. Res. Toxicol. 2018, 31, 1373–1381. [Google Scholar] [CrossRef]
- Ismail, S.; Mansor, S.; Hanapi, N. Inhibitory effect of mitragynine on human cytochrome P450 enzyme activities. Pharmacogn. Res. 2013, 5, 241. [Google Scholar] [CrossRef]
- Showande, S.J.; Fakeye, T.O.; Kajula, M.; Hokkanen, J.; Tolonen, A. Potential inhibition of major human cytochrome P450 isoenzymes by selected tropical medicinal herbs—Implication for herb–drug interactions. Food Sci. Nutr. 2019, 7, 44–55. [Google Scholar] [CrossRef]
- Ulbricht, C.; Costa, D.; Dao, J.; Isaac, R.; LeBlanc, Y.C.; Rhoades, J.; Windsor, R.C. An evidence-based systematic review of kratom (Mitragyna speciosa) by the Natural Standard Research Collaboration. J. Diet. Suppl. 2013, 10, 152–170. [Google Scholar] [CrossRef]
- Hughes, R.L. Fatal combination of mitragynine and quetiapine–a case report with discussion of a potential herb-drug interaction. Forensic Sci. Med. Pathol. 2019, 15, 110–113. [Google Scholar] [CrossRef]
- Fluyau, D.; Revadigar, N. Biochemical benefits, diagnosis, and clinical risks evaluation of kratom. Front. Psychiatry 2017, 8, 62. [Google Scholar] [CrossRef]
- Grewal, K.S. Observations OX the Pharmacology of Mitragynine. J. Pharmacol. 1932, 46, 251–271. [Google Scholar]
- Mohammad Yusoff, N.H.; Mansor, S.M.; Visweswaran, N.; Muller, C.P.; Hassan, Z. GABAB receptor system modulates mitragynine-induced conditioned place preference in rats. In Proceedings of the 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27–30 August 2016. [Google Scholar] [CrossRef]
- Effendy, M.A.; Yunusa, S.; Mat, N.H.; Has, A.T.C.; Müller, C.P.; Hassan, Z. The role of AMPA and NMDA receptors in mitragynine effects on hippocampal synaptic plasticity. Behav. Brain Res. 2023, 13, 114169. [Google Scholar] [CrossRef] [PubMed]
- Kruegel, 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 Pt A, 108–120. [Google Scholar] [CrossRef]
- Ammar, I.H.; Muzaimi, M.; Sharif, M.M. The effects on motor behaviour and short-term memory tasks in mice following an acute administration of Mitragyna speciosa alkaloid extract and mitragynine. J. Med. Plants Res. 2011, 5, 5810–5817. [Google Scholar]
- Ismail, N.I.W.; Jayabalan, N.; Mansor, S.M.; Müller, C.P.; Muzaimi, M. Chronic mitragynine (kratom) enhances punishment resistance in natural reward seeking and impairs place learning in mice. Addict. Biol. 2017, 22, 967–976. [Google Scholar] [CrossRef] [PubMed]
- Senik, M.; Mansor, S.; Rammes, G.; Tharakan, J.; Abdullah, J. Mitragyna speciosa Korth standardized methanol extract induced short-term potentiation of CA1 subfield in rat hippocampal slices. J. Med. Plants Res. 2012, 6, 1234–1243. [Google Scholar] [CrossRef]
- Raymond-Hamet, A. Les alcaloïdes du Mitragyna speciosa Korthals [The alkaloids of Mitragyna speciosa Korthals–French]. Ann. Pharm. Françaises 1950, 8, 482–490. [Google Scholar]
- Federico, A.; Morgillo, F.; Tuccillo, C.; Ciardiello, F.; Loguercio, C. Chronic inflammation and oxidative stress in human carcinogenesis. Int. J. Cancer 2007, 121, 2381–2386. [Google Scholar] [CrossRef] [PubMed]
- Hussain, S.P.; Harris, C.C. Inflammation and cancer: An ancient link with novel potentials. Int. J. Cancer 2007, 121, 2373–2380. [Google Scholar] [CrossRef]
- Utar, Z.; Majid, M.I.A.; Adenan, M.I.; Jamil, M.F.A.; Lan, T.M. Mitragynine inhibits the COX-2 mRNA expression and prostaglandin E2 production induced by lipopolysaccharide in RAW264.7 macrophage cells. J. Ethnopharmacol. 2011, 136, 75–82. [Google Scholar] [CrossRef] [PubMed]
- Otero-Losada, M.; Capani, F.; Perez Lloret, S. Neuroprotection—New Approaches and Prospects; IntechOpen: London, UK, 2020; p. 77918. [Google Scholar]
- Vermaire, D.J.; Skaer, D.; Tippets, W. Kratom and general anesthesia: A case report and review of the literature. AA Pract. 2019, 12, 103–105. [Google Scholar] [CrossRef]
- Horie, S.; Koyama, F.; Takayama, H.; Ishikawa, H.; Aimi, N.; Ponglux, D.; Matsumoto, K.; Murayama, T. Indole alkaloids of a Thai medicinal herb, Mitragyna speciosa, that has opioid agonistic effect in guinea-pig ileum. Planta Medica 2005, 71, 231–236. [Google Scholar] [CrossRef] [PubMed]
- Matsumoto, K.; Takayama, H.; Ishikawa, H.; Aimi, N.; Ponglux, D.; Watanabe, K.; Horie, S. Partial agonistic effect of 9-hydroxycorynantheidine on mu-opioid receptor in the guinea-pig ileum. Life Sci. 2005, 78, 2265–2271. [Google Scholar] [CrossRef]
- Reanmongkol, W.; Keawpradub, N.; Sawangjaroen, K. Effects of the extracts from Mitragyna speciosa Korth. leaves on analgesic and behavioral activities in experimental animals. Songklanakarin J. Sci. Technol. 2007, 29 (Suppl. S1), 39–48. [Google Scholar]
- Sabetghadam, A.; Ramanathan, S.; Mansor, S.M. The evaluation of antinociceptive activity of alkaloid, methanolic, and aqueous extracts of Malaysian Mitragyna speciosa Korth leaves in rats. Pharmacogn. Res. 2010, 2, 181. [Google Scholar] [CrossRef]
- Idid, S.; Saad, L.; Yaacob, H.; Shahimi, M. Evaluation of analgesia induced by mitragynine, morphine and paracetamol on mice. ASEAN Rev. Biodivers. Environ. Conserv. 1998, 4, 1–7. [Google Scholar]
- Botpiboon, O. Effects of Caffeine and Codeine on Pharmacokinetics and Antinociceptive Activity of Alkaloid Extract from Leaves of Kratom (Mitragyna speciosa Korth.). Ph.D. Thesis, Prince of Songkla University, Hat Yai, Thailand, 2010. [Google Scholar]
- Matsumoto, K.; Mizowaki, M.; Suchitra, T.; Takayama, H.; Sakai, S.-I.; Aimi, N.; Watanabe, H. Antinociceptive action of mitragynine in mice: Evidence for the involvement of supraspinal opioid receptors. Life Sci. 1996, 59, 1149–1155. [Google Scholar] [CrossRef] [PubMed]
- Boyer, E.W.; Babu, K.M.; Adkins, J.E.; McCurdy, C.R.; Halpern, J.H. Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth). Addiction 2008, 103, 1048–1050. [Google Scholar] [CrossRef] [PubMed]
- Takayama, H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem. Pharm. Bull. 2004, 52, 916–928. [Google Scholar] [CrossRef] [PubMed]
- Thongpradichote, S.; Matsumoto, K.; Tohda, M.; Takayama, H.; Aimi, N.; Sakai, S.-I.; Watanabe, H. Identification of opioid receptor subtypes in antinociceptive actions of supraspinally-admintstered mitragynine in mice. Life Sci. 1998, 62, 1371–1378. [Google Scholar] [CrossRef]
- Yamamoto, L.T.; Horie, S.; Takayama, H.; Aimi, N.; Sakai, S.-I.; Yano, S.; Shan, J.; Pang, P.K.; Ponglux, D.; Watanabe, K. Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa. Gen. Pharmacol. Vasc. Syst. 1999, 33, 73–81. [Google Scholar] [CrossRef]
- Stolt, A.-C.; Schröder, H.; Neurath, H.; Grecksch, G.; Höllt, V.; Meyer, M.R.; Maurer, H.H.; Ziebolz, N.; Havemann-Reinecke, U.; Becker, A. Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract. Psychopharmacology 2014, 231, 13–25. [Google Scholar] [CrossRef]
- Hemby, 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. 2019, 24, 874–885. [Google Scholar] [CrossRef]
- Havemann-Reinecke, U. P01-50-Kratom and alcohol dependence: Clinical symptoms, withdrawal treatment and pharmacological mechanisms-A case report. Eur. Psychiatry 2011, 26 (Suppl. S2), 50. [Google Scholar] [CrossRef]
- Obeng, S.; Leon, F.; Patel, A.; Gonzalez, J.D.Z.; Da Silva, L.C.; Restrepo, L.F.; Gamez-Jimenez, L.R.; Ho, N.P.; Calvache, M.P.G.; Pallares, V.L.; et al. Interactive Effects of µ-Opioid and Adrenergic-α (2) Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine. J. Pharmacol. Exp. Ther. 2022, 383, 182–198. [Google Scholar] [CrossRef]
- Vijeepallam, K.; Pandy, V.; Kunasegaran, T.; Murugan, D.D.; Naidu, M. Mitragyna speciosa leaf extract exhibits antipsychotic-like effect with the potential to alleviate positive and negative symptoms of psychosis in mice. Front. Pharmacol. 2016, 7, 464. [Google Scholar] [CrossRef]
- Lu, J.; Wei, H.; Wu, J.; Jamil, M.F.A.; Tan, M.L.; Adenan, M.I.; Wong, P.; Shim, W. Evaluation of the cardiotoxicity of mitragynine and its analogues using human induced pluripotent stem cell-derived cardiomyocytes. PLoS ONE 2014, 9, e115648. [Google Scholar] [CrossRef]
- Sandager, M.; Nielsen, N.D.; Stafford, G.I.; van Staden, J.; Jäger, A.K. Alkaloids from Boophane disticha with affinity to the serotonin transporter in rat brain. J. Ethnopharmacol. 2005, 98, 367–370. [Google Scholar] [CrossRef]
- Elgorashi, E.E.; Stafford, G.I.; Jäger, A.K.; Van Staden, J. Inhibition of [3H] citalopram binding to the rat brain serotonin transporter by Amaryllidaceae alkaloids. Planta Medica 2006, 72, 470–473. [Google Scholar] [CrossRef]
- Neergaard, J.S.; Andersen, J.; Pedersen, M.E.; Stafford, G.I.; Van Staden, J.; Jäger, A.K. Alkaloids from Boophone disticha with affinity to the serotonin transporter. S. Afr. J. Bot. 2009, 75, 371–374. [Google Scholar] [CrossRef]
- Kong, L.; Cheng, C.H.; Tan, R. Inhibition of MAO A and B by some plant-derived alkaloids, phenols and anthraquinones. J. Ethnopharmacol. 2004, 91, 351–355. [Google Scholar] [CrossRef] [PubMed]
- Oboh, G.; Oyeleye, S.; Ademiluyi, A. The food and medicinal values of indigenous leafy vegetables. Afr. Veg. Forum 2017, 1238, 137–156. [Google Scholar] [CrossRef]
- Nwanna, E.; Oyeleye, S.; Ogunsuyi, O.; Oboh, G.; Boligon, A.; Athayde, M. In vitro neuroprotective properties of some commonly consumed green leafy vegetables in Southern Nigeria. NFS J. 2016, 2, 19–24. [Google Scholar] [CrossRef]
- Oboh, G.; Akinyemi, A.J.; Adeleye, B.; Oyeleye, S.I.; Ogunsuyi, O.B.; Ademosun, A.O.; Ademiluyi, A.O.; Boligon, A.A. Polyphenolic compositions and in vitro angiotensin-I-converting enzyme inhibitory properties of common green leafy vegetables: A comparative study. Food Sci. Biotechnol. 2016, 25, 1243–1249. [Google Scholar] [CrossRef] [PubMed]
- Oboh, G.; Ogunruku, O.O.; Oyeleye, S.I.; Olasehinde, T.A.; Ademosun, A.O.; Boligon, A.A. Phenolic extracts from Clerodendrum volubile leaves inhibit cholinergic and monoaminergic enzymes relevant to the management of some neurodegenerative diseases. J. Diet. Suppl. 2017, 14, 358–371. [Google Scholar] [CrossRef]
- Lühr, S.; Vilches-Herrera, M.; Fierro, A.; Ramsay, R.R.; Edmondson, D.E.; Reyes-Parada, M.; Cassels, B.K.; Iturriaga-Vásquez, P. 2-Arylthiomorpholine derivatives as potent and selective monoamine oxidase B inhibitors. Bioorganic Med. Chem. 2010, 18, 1388–1395. [Google Scholar] [CrossRef]
- Chen, L.; Fei, S.; Olatunji, O.J. LC/ESI/TOF-MS Characterization, Anxiolytic and Antidepressant-like Effects of Mitragyna speciosa Korth Extract in Diabetic Rats. Molecules 2022, 27, 2208. [Google Scholar] [CrossRef]
- Innok, W.; Hiranrat, A.; Chana, N.; Rungrotmongkol, T.; Kongsune, P. In silico and in vitro anti-AChE activity investigations of constituents from Mytragyna speciosa for Alzheimer’s disease treatment. J. Comput.-Aided Mol. Des. 2021, 35, 325–336. [Google Scholar] [CrossRef]
- Tsuji, M.; Takeuchi, T.; Miyagawa, K.; Ishii, D.; Imai, T.; Takeda, K.; Kitajima, M.; Takeda, H. Yokukansan, a traditional Japanese herbal medicine, alleviates the emotional abnormality induced by maladaptation to stress in mice. Phytomedicine 2014, 21, 363–371. [Google Scholar] [CrossRef] [PubMed]
- Neef, D.W.; Jaeger, A.M.; Thiele, D.J. Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat. Rev. Drug Discov. 2011, 10, 930–944. [Google Scholar] [CrossRef] [PubMed]
- Gomez-Pastor, R.; Burchfiel, E.T.; Thiele, D.J. Regulation of heat shock transcription factors and their roles in physiology and disease. Nat. Rev. Mol. Cell Biol. 2018, 19, 4–19. [Google Scholar] [CrossRef] [PubMed]
- Steinkraus, K.A.; Smith, E.D.; Davis, C.; Carr, D.; Pendergrass, W.R.; Sutphin, G.L.; Kennedy, B.K.; Kaeberlein, M. Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 2008, 7, 394–404. [Google Scholar] [CrossRef]
- Gülçin, I.; Elmastaş, M.; Aboul-Enein, H.Y. Antioxidant activity of clove oil–A powerful antioxidant source. Arab. J. Chem. 2012, 5, 489–499. [Google Scholar] [CrossRef]
- Sadeli, R.A. Uji Aktivitas Antioksidan Dengan Metode DPPH (1, 1-Diphenyl-2-Picrylhydrazyl) Ekstrak Bromelain Buah Nanas (Ananas comosus (L.) Merr.). Ph.D. Thesis, Fakultas Farmasi, Universitas Sanata Dharma, Yogyakarta, Indonesia, 2016. [Google Scholar]
- Rusmarilin, H.; Lubis, Z.; Lubis, L.M.; Barutu, Y.A.P. Potential of natural antioxidants of black cumin seed (Nigella sativa) and sesame seed (Sesamum indicum) extract by microencapsulation methods. IOP Conf. Ser. Earth Environ. Sci. IOP Publ. 2019, 260, 012097. [Google Scholar] [CrossRef]
- Suhaling, S. Uji Aktivitas Antioksidan Ekstrak Metanol Kacang Merah (Phaseolus vulgaris L.) Dengan Metode DPPH. Master’s Thesis, Universitas Islam Negeri Alauddin Makassar, Sulawesi Selatan, Indonesia, 2010. [Google Scholar]
- Ikhlas, N. Uji Aktivitas Antioksidan Ekstrak Herba Kemangi (Ocimum americanum Linn) dengan Metode DPPH (2, 2-Difenil-1-Pikrilhidrazil). Master’s Thesis. 2013. Available online: http://repository.uinjkt.ac.id/dspace/handle/123456789/25905 (accessed on 7 September 2023).
- Chae, H.S.; Park, H.J.; Hwang, H.R.; Kwon, A.; Lim, W.H.; Yi, W.J.; Han, D.H.; Kim, Y.H.; Baek, J.H. The effect of antioxidants on the production of pro-inflammatory cytokines and orthodontic tooth movement. Mol. Cells 2011, 32, 189–196. [Google Scholar] [CrossRef]
- Nau, R.; Eiffert, H. Modulation of release of proinflammatory bacterial compounds by antibacterials: Potential impact on course of inflammation and outcome in sepsis and meningitis. Clin. Microbiol. Rev. 2002, 15, 95–110. [Google Scholar] [CrossRef]
- Luderitz, O.; Tanamoto, K.; Galanos, C.; McKenzie, G.R.; Brade, H.; Zahringer, U.; Rietschel, E.T.; Kusumoto, S.; Shiba, T. Lipopolysaccharides: Structural principles and biologic activities. Clin. Infect. Dis. 1984, 6, 428–431. [Google Scholar] [CrossRef] [PubMed]
- Sejvar, J.; Lutterloh, E.; Naiene, J.; Likaka, A.; Manda, R.; Nygren, B.; Monroe, S.; Khaila, T.; Lowther, S.A.; Capewell, L.; et al. Neurologic manifestations associated with an outbreak of typhoid fever, Malawi—Mozambique, 2009: An epidemiologic investigation. PLoS ONE 2012, 7, e46099. [Google Scholar] [CrossRef] [PubMed]
- Alvarez-Arellano, L.; Maldonado-Bernal, C. Helicobacter pylori and neurological diseases: Married by the laws of inflammation. World J. Gastrointest Pathophysiol. 2014, 15, 400–404. [Google Scholar] [CrossRef]
- Arneth, B.M. Gut–brain axis biochemical signalling from the gastrointestinal tract to the central nervous system: Gut dysbiosis and altered brain function. Postgrad. Med. J. 2018, 94, 446–452. [Google Scholar] [CrossRef]
- Sabetghadam, A.; Ramanathan, S.; Sasidharan, S.; Mansor, S.M. Subchronic exposure to mitragynine, the principal alkaloid of Mitragyna speciosa, in rats. J. Ethnopharmacol. 2013, 146, 815–823. [Google Scholar] [CrossRef] [PubMed]
- Chittrakarn, S.; Sawangjaroen, K.; Prasettho, S.; Janchawee, B.; Keawpradub, N. Inhibitory effects of kratom leaf extract (Mitragyna speciosa Korth.) on the rat gastrointestinal tract. J. Ethnopharmacol. 2008, 116, 173–178. [Google Scholar] [CrossRef] [PubMed]
- Tsuchiya, S.; Miyashita, S.; Yamamoto, M.; Horie, S.; Sakai, S.-I.; Aimi, N.; Takayama, H.; Watanabe, K. Effect of mitragynine, derived from Thai folk medicine, on gastric acid secretion through opioid receptor in anesthetized rats. Eur. J. Pharmacol. 2002, 443, 185–188. [Google Scholar] [CrossRef]
- Anwar, M.; Law, R.; Schier, J. Notes from the field: Kratom (Mitragyna speciosa) exposures reported to poison centers—United States, 2010–2015. Morb. Mortal. Wkly. Rep. 2016, 65, 748–749. [Google Scholar] [CrossRef]
- Scott Gottlieb, M.D. Agency’s Scientific Evidence on the Presence of Opioid Compounds in Kratom, Underscoring Its Potential for Abuse, Food and Drug Administration Statement from FDA Commissioner. Statement from FDA Commissioner, [Press Release] 6 February 2018. Available online: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm595622.htm (accessed on 25 June 2018).
- Sethi, R.; Hoang, N.; Ravishankar, D.A.; McCracken, M.; Manzardo, A.M. Kratom (Mitragyna speciosa): Friend or foe? Prim. Care Companion CNS Disord. 2020, 22, 27410. [Google Scholar] [CrossRef]
- Griffiths, C.L.; Gandhi, N.; Olin, J.L. Possible kratom-induced hepatomegaly: A case report. J. Am. Pharm. Assoc. 2018, 58, 561–563. [Google Scholar] [CrossRef]
- Tayabali, K.; Bolzon, C.; Foster, P.; Patel, J.; Kalim, M.O. Kratom: A dangerous player in the opioid crisis. J. Community Hosp. Intern. Med. Perspect 2018, 8, 107–110. [Google Scholar] [CrossRef] [PubMed]
- Chittrakarn, S.; Keawpradub, N.; Sawangjaroen, K.; Kansenalak, S.; Janchawee, B. The neuromuscular blockade produced by pure alkaloid, mitragynine and methanol extract of kratom leaves (Mitragyna speciosa Korth. ). J. Ethnopharmacol. 2010, 129, 344–349. [Google Scholar] [CrossRef]
- Hanapi, N.; Azizi, J.; Ismail, S.; Mansor, S. Evaluation of Selected Malaysian Medicinal Plants on Phase I Drug Metabolizing Enzymes, CYP 2 C 9, CYP 2 D 6 and CYP 3 A 4 Activities in vitro. Int. J. Pharmacol. 2010, 6, 494–499. [Google Scholar] [CrossRef]
- Purintrapiban, J.; Keawpradub, N.; Kansenalak, S.; Chittrakarn, S.; Janchawee, B.; Sawangjaroen, K. Study on glucose transport in muscle cells by extracts from Mitragyna speciosa (Korth) and mitragynine. Nat. Prod. Res. 2011, 25, 1379–1387. [Google Scholar] [CrossRef]
- Nelsen, J.L.; Lapoint, J.; Hodgman, M.J.; Aldous, K.M. Seizure and coma following Kratom (Mitragynina speciosa Korth) exposure. J. Med. Toxicol. 2010, 6, 424–426. [Google Scholar] [CrossRef]
- Kapp, F.G.; Maurer, H.H.; Auwärter, V.; Winkelmann, M.; Hermanns-Clausen, M. Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J. Med. Toxicol. 2011, 7, 227–231. [Google Scholar] [CrossRef]
- Dorman, C.; Wong, M.; Khan, A. Cholestatic hepatitis from prolonged kratom use: A case report. Hepatology 2015, 61, 1086–1087. [Google Scholar] [CrossRef] [PubMed]
- Riverso, M.; Chang, M.; Soldevila-Pico, C.; Lai, J.; Liu, X. Histologic Characterization of Kratom Use-Associated Liver Injury. Gastroenterol. Res. 2018, 11, 79–82. [Google Scholar] [CrossRef]
- Fernandes, C.T.; Iqbal, U.; Tighe, S.P.; Ahmed, A. Kratom-Induced Cholestatic Liver Injury and Its Conservative Management. J. Investig. Med. High Impact Case Rep. 2019, 7. [Google Scholar] [CrossRef]
- Palasamudram Shekar, S.; Rojas, E.E.; D’Angelo, C.C.; Gillenwater, S.R.; Galvis, N.P.M. Legally Lethal Kratom: A Herbal Supplement with Overdose Potential. J. Psychoact. Drugs 2019, 51, 28–30. [Google Scholar] [CrossRef] [PubMed]
- Mousa, M.S.; Sephien, A.; Gutierrez, J.; O’Leary, C. N-Acetylcysteine for Acute Hepatitis Induced by Kratom Herbal Tea. Am. J. Ther. 2018, 25, e550–e551. [Google Scholar] [CrossRef] [PubMed]
- Osborne, C.S.; Overstreet, A.N.; Rockey, D.C.; Schreiner, A.D. Drug-Induced Liver Injury Caused by Kratom Use as an Alternative Pain Treatment Amid an Ongoing Opioid Epidemic. J. Investig. Med. High Impact Case Rep. 2019, 7. [Google Scholar] [CrossRef] [PubMed]
Antioxidative Effect | ||||
---|---|---|---|---|
Treatment with Doses | Nature of Kratom Product | Experimental Model | Major Findings (Molecular Changes) | Reference |
Kratom | Methanolic, water, alkaloids | In vitro | The high content of phenolic, flavonoid compounds and the result of DPPH, high antioxidant activity in methanolic extract | (Parthasarathy, Bin Azizi et al., 2009) [16] |
Ethanolic extract | In vitro (DPPH) | The IC50 value of 38.56 μg/mL | (Yuniarti, Nadia et al., 2020) [18] | |
Aqueous extract (100 mg/kg) | Male Sprague Dawley rats | ↑ Glutathione transferase (GSTs) activity | (Azizi, Ismail et al., 2010) [89] | |
Neurophysiological | ||||
Kratom | Mitragynine (5, 10 and 15 mg/kg) | Male ICR mice | Mitragynine neither altered locomotor activity nor its high or low dose | (Apryani, Hidayat et al., 2010) [28] |
Methanolic extract (0.008%) | Male Sprague Dawley rats | ↓ Field excitatory post-synaptic potentials (fEPSP) in the CA1 region concentration-dependently, and blocked long-term potentiation (LTP) | (Senik, Mansor et al., 2012) [114] | |
Anti-inflammatory | ||||
Kratom | Methanolic extract (100–200 mg/kg) | Male Sprague Dawley rats | Dose-dependently suppressed the development of carrageenan-induced rat paw edema, and ↓ granulomatous tissue formation at 200 mg/kg | (Mossadeq, Sulaiman et al., 2009) [21] |
Methanolic extract (10 and 20 g/mL) | RAW264.7 macrophage cells | ↓ mRNA expression of COX-2, ↓ PGE2 production, and ↓ COX-1 expression | (Utar, Majid et al., 2011) [118] | |
Analgesic/Anti-nociceptive | ||||
Kratom | 7-hydroxymitragynine (ED50 = 0.80 mg/kg, and ED50 = 0.93 mg/kg) | Male ddY-strain mice and male albino guinea pigs | 4.4–5.7 times more potent as μ-opioid agonist than morphine in tail-flick and hot-plate test | (Matsumoto, Hatori et al., 2006) [68] |
7-hydroxymitragynine (100 nM), speciociliatine (30 μM) | Male Albino Dunkin–Hartley guinea pigs | ↓ Twitch contraction and 7-hydroxymitragynine showed most potent opioid effect on the electrically stimulated contraction (pD2 = 8.38 ± 0.12) | (Horie, Koyama et al., 2005) [121] | |
Methanolic and alkaloid extract (100 mg/kg) | Male Swiss mice and Wistar rats | Prolong the latency of nociceptive response in the hot plate test | (Reanmongkol, Keawpradub et al., 2007) [123] | |
Mitragynine alkaloid (10 nM–1 μM) | Male Albino guinea pigs | Block the reversible Ca2+ channel that activates neurotransmitters | (Matsumoto, Takayama et al., 2005) [122] | |
Alkaloid (20 mg/kg), methanolic (200 mg/kg), and aqueous extract (400 mg/kg) | Male Spraque Dawley rats | Both hot plate and tail-flick tests showed prolonged nociceptive responses | (Sabetghadam, Ramanathan et al., 2010) [124] | |
Mitragynine alkaloid (100 mg/kg), co-administration of caffeine (25 mg/kg, p.o.) and codeine (3 mg/kg, p.o.) | Male Wistar rats | ↑ Latency period in a hot plate test after 30 min | (Botpiboon 2010) [126] | |
Mitragynine (2.0 mg/kg) and paynantheine (0.1 mg/kg) | Male wild-type mice (+/+) and μ opioid receptor (MOR) knockout mice (−/−) | Exert analgesic effects predominantly via κ opioid receptors | (Stolt, Schröder et al., 2014) [132] | |
Anti-depressant | ||||
Kratom | Mitragynine (10 mg/kg and 30 mg/kg) | Male mice from the ICR strain | ↓ Corticosterone in forced swim test (FST) and tail suspension test (TST) | (Idayu, Hidayat et al., 2011) [29] |
Aqueous extract (100, 300, and 500 mg/kg) | Male Swiss albino mice | Effects on serotonin or noradrenaline neurotransmissions | (Kumarnsit, Keawpradub et al., 2006) [22] | |
Mitragynine or alkaloid extract (20, 40, and 80 mg/kg) | Male Swiss albino mice | ↑ Total number of arm entries, rearing frequency and ↓ grooming, and immobility time in the Y-maze test, Alkaloid extract exhibits more potent opioid agonistic effects than mitragynine | (Ammar, Muzaimi et al., 2011) [112] | |
Mitragynine (5, 15, 20, and 25 mg/kg) | Male Swiss albino mice | Chronic mitragynine treatment impaired spatial learning and memory | (Ismail, Jayabalan et al., 2017) [113] | |
Mitragynine (72.5 mg and 74.9 mg) of Kratom tea or >3 glasses daily | Human | Executive function, memory, and attention were not impaired | (Singh, Narayanan et al., 2019) [36] | |
Anti-psychotic/ Anti-dopaminergic | ||||
Kratom | Methanolic extract (75 and 100 mg/kg) | Male Swiss albino mice | Apomorphine-induced cage climbing behavior ↓, ↓ dopamine-induced contractile response | (Vijeepallam, Pandy et al., 2016) [136] |
Kratom and Its Compounds | Receptors/Modulators | Resulting Effects | References |
---|---|---|---|
Kratom alkaloid | Inhibition of CYP3A4, CYP2D6, and CYP2C9 | Alter drug metabolism | [91] |
Mitragynine | Activate GABAB receptor | Anti-depressant activity | [27] |
Mitragynine | Antagonize NMDA receptor | Dissociative anesthesia | [110] |
Mitragynine | Regulation of the Keap-1/Nrf-2 pathway | Ensure neuroprotection | [115] |
Mitragynine | Activation of Nrf2, HO-1, and NQO1 | Decrease level of ROS | [115] |
Kratom | Binds with nuclear factor kappa B (NF-κB) | Inhibit the release of proinflammatory mediators | [107] |
Mitragynine and 7-hydroxymitragynine | Binds with adrenergic-α2 (Aα2R) | Antinociceptive effect | [135] |
Mitragynine | Inhibit the enzyme acetylcholinesterase (AChE) receptor | Attenuate Alzheimer’s disease | [148] |
Mitragynine | Binds with the HSF-1 | Inhibition of the mRNA expression of COX-2 | [118] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Hossain, R.; Sultana, A.; Nuinoon, M.; Noonong, K.; Tangpong, J.; Hossain, K.H.; Rahman, M.A. A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds. Molecules 2023, 28, 7372. https://doi.org/10.3390/molecules28217372
Hossain R, Sultana A, Nuinoon M, Noonong K, Tangpong J, Hossain KH, Rahman MA. A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds. Molecules. 2023; 28(21):7372. https://doi.org/10.3390/molecules28217372
Chicago/Turabian StyleHossain, Rahni, Abida Sultana, Manit Nuinoon, Kunwadee Noonong, Jitbanjong Tangpong, Kazi Helal Hossain, and Md Atiar Rahman. 2023. "A Critical Review of the Neuropharmacological Effects of Kratom: An Insight from the Functional Array of Identified Natural Compounds" Molecules 28, no. 21: 7372. https://doi.org/10.3390/molecules28217372