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      Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant


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          Kratom or Mitragyna speciosa (Korth.) is an evergreen tree of the coffee family native to South-East Asia and Australasia. It is used by locals recreationally to induce stimulant and sedative effects and medically to soothe pain and opiate withdrawal. Its leaves are smoked, chewed, or infused, or ground to yield powders or extracts for use as liquids. It contains more than 40 alkaloids; among these, mitragynine and 7-hydroxymitragynine are endowed with variable mu, delta, and kappa opioid stimulating properties (with 7-hydroxymitragynine having a more balanced affinity), rhynchophylline, which is a non-competitive NMDA glutamate receptor antagonist, but is present in negligible quantities, and raubasine, which inhibits α 1-adrenceptors preferentially over α 2-adrenceptors, while the latter are bound by 7-hydroxymitragynine, while mitragynine counters 5-HT 2A receptors. This complexity of neurochemical mechanisms may account for kratom's sedative-analgesic and stimulant effects. It is commonly held that kratom at low doses is stimulant and at higher doses sedative, but no cut-off has been possible to define. Long-term use of kratom may produce physical and psychological effects that are very similar to its withdrawal syndrome, that is, anxiety, irritability, mood, eating, and sleep disorders, other than physical symptoms resembling opiate withdrawal. Kratom's regulatory status varies across countries; in Italy, both mitragynine and the entire tree and its parts are included among regulated substances. We describe the case of a patient who developed anxiety and dysphoric mood and insomnia while using kratom, with these symptoms persisting after withdrawal. He did not respond to a variety of antidepressant combinations and tramadol for various months, and responded after 1 month of clomipramine. Well-being persisted after discontinuing tramadol.

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          Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2.

          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 pharmacology. Herein, we report the pharmacology 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 [(35)S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical 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.
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            Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth).

            Kratom (Mitragynia speciosa korth) is recognized increasingly as a remedy for opioid withdrawal by individuals who self-treat chronic pain. A patient who had abruptly ceased injection hydromorphone abuse self-managed opioid withdrawal and chronic pain using kratom. After co-administering the herb with modafinil he experienced a tonic-clonic seizure, but he reported only modest abstinence once kratom administration stopped. We confirmed the identity of the plant matter he ingested as kratom and identified no contaminants or adulterants. We also conducted high-throughput molecular screening and the binding affinity at mu, delta and kappa receptors of mitragynine. We report the self-treatment of chronic pain and opioid withdrawal with kratom. The predominant alkaloid of kratom, mitragynine, binds mu- and kappa-opioid receptors, but has additional receptor affinities that might augment its effectiveness at mitigating opioid withdrawal. The natural history of kratom use, including its clinical pharmacology and toxicology, are poorly understood.
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              Opiate Receptor: Demonstration in Nervous Tissue


                Author and article information

                Front Psychiatry
                Front Psychiatry
                Front. Psychiatry
                Frontiers in Psychiatry
                Frontiers Media S.A.
                31 March 2021
                : 12
                : 640218
                [1] 1ASL (Azienda Sanitaria Locale) Roma 2 , Rome, Italy
                [2] 2Addictions' Observatory (ODDPSS) , Rome, Italy
                [3] 3ASL , Rieti, Italy
                [4] 4Villa von Siebenthal Neuropsychiatric Clinic and Hospital , Genzano di Roma, Italy
                [5] 5Psychopharmacology, Drug Misuse & Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire , Hatfield, United Kingdom
                [6] 6NESMOS Department (Neurosciences, Mental Health, and Sensory Organs), School of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University , Rome, Italy
                Author notes

                Edited by: Liana Fattore, National Research Council (CNR), Italy

                Reviewed by: Oliver Grundmann, University of Florida, United States; Walter Prozialeck, Midwestern University, United States; Susruta Majumdar, St. Louis College of Pharmacy, United States

                *Correspondence: Georgios D. Kotzalidis giorgio.kotzalidis@ 123456uniroma1.it

                This article was submitted to Addictive Disorders, a section of the journal Frontiers in Psychiatry

                Copyright © 2021 Vento, de Persis, De Filippis, Schifano, Napoletano, Corkery and Kotzalidis.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 10 December 2020
                : 05 March 2021
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 129, Pages: 9, Words: 8046
                Case Report

                Clinical Psychology & Psychiatry
                kratom,mitragynine,substance use disorder,clomipramine,withdrawal syndrome


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