Assessing physiological dependence and withdrawal potential of mitragynine using schedule-controlled behaviour in rats

Harun, Norsyifa; Johari, Illa Syafiqah; Mansor, Sharif Mahsufi; Shoaib, Mohammed

doi:10.1007/s00213-019-05418-6

Cited by 28 publications

(24 citation statements)

References 56 publications

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“…Conversely, other studies have shown that mitragynine does not substitute for morphine (Hemby et al, 2019) or methamphetamine (Yue et al, 2018) in intravenous self-administration, a finding that is consistent with the known affinity of mitragynine for the MOR being approximately 200 times less than that of morphine (Yue et al, 2018). Further, in a recent schedule-controlled behaviour study, unlike morphine, acute mitragynine did not produce a dose-related decrease in fixed-ratio responding, as well as any suppression of response rates following cessation (Harun et al, 2019). However, 7-HMG is self-administered and readily substituted for morphine in a self-administration paradigm (Hemby et al, 2019).…”

Section: Discussionmentioning

confidence: 96%

“…However, the addictive potential of mitragynine has been less clear. In self-administration studies, mitragynine did not induce physiological dependence (Harun et al, 2019), and did not substitute for morphine (Hemby et al, 2019), or methamphetamine (Yue et al, 2018), suggesting a lack of addictive properties. Conversely, mitragynine has been found to induce a conditioned place preference in rats, indicating that systemic administration of the alkaloid is rewarding (Yusoff et al, 2016, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Acute mitragynine administration suppresses cortical oscillatory power and systems theta coherence in rats

et al. 2020

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Background: Mitragynine is the major alkaloid of Mitragyna speciosa (kratom) with potential as a therapeutic in pain management and in depression. There has been debate over the potential side effects of the drug including addiction risk and cognitive decline. Aims: To evaluate the effects of mitragynine on neurophysiological systems function in the prefrontal cortex (PFC), cingulate cortex (Cg), orbitofrontal cortex, nucleus accumbens (NAc), hippocampus (HIP), thalamus (THAL), basolateral amygdala (BLA) and ventral tegmental area of rats. Methods: Local field potential recordings were taken from animals at baseline and for 45 min following mitragynine administration (10 mg/kg, intraperitoneally). Drug-induced changes in spectral power and coherence between regions at specific frequencies were evaluated. Mitragynine-induced changes in c-fos expression were also analyzed. Results: Mitragynine increased delta power and reduced theta power in all three cortical regions that were accompanied by increased c-fos expression. A transient suppression of gamma power in PFC and Cg was also evident. There were no effects of mitragynine on spectral power in any of the other regions. Mitragynine induced a widespread reduction in theta coherence (7–9 Hz) that involved disruptions in cortical and NAc connectivity with the BLA, HIP and THAL. Conclusions: These findings show that mitragynine induces frequency-specific changes in cortical neural oscillatory activity that could potentially impact cognitive functioning. However, the absence of drug effects within regions of the mesolimbic pathway may suggest either a lack of addiction potential, or an underlying mechanism of addiction that is distinct from other opioid analgesic agents.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Acute mitragynine administration suppresses cortical oscillatory power and systems theta coherence in rats

et al. 2020

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“…Mitragynine is a psychoactive substance which also can produce dependence for which no pharmacotreatment is available yet. Mitragynine has been reported to cause physical dependence after spontaneously mitragynine withdrawal ( Hassan et al, 2021 ) and after naloxone-precipitated withdrawal ( Harun et al, 2020 ) in animal studies. In addition, Yusoff et al (2016) also reported that chronic mitragynine withdrawal triggers anxiety-like behaviour in rats.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, Yusoff et al (2017) revealed that mitragynine-induced CPP establishment, but not expression, is mediated by an opioid receptor mechanism. Moreover, recently, the effect of naloxone on precipitated of mitragynine withdrawal effects was described by Harun et al (2020) , suggesting that the mu-opioid receptor is responsible for the development of mitragynine dependence.…”

Section: Discussionmentioning

confidence: 99%

“…All the replacement treatments were applied for four days and then abruptly stopped on day 5 in order to determine whether or not the mitragynine withdrawal signs will resurface. This design followed the replacement routine described by Hassan et al (2020) . In a subsequent test, we examined hematological, biochemical and histopathological effects of the mitragynine and the replacement treatments.…”

Section: Methodsmentioning

confidence: 99%

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Methadone, Buprenorphine, and Clonidine Attenuate Mitragynine Withdrawal in Rats

et al. 2021

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Background: Kratom or Mitragyna speciosa Korth has been widely used to relieve the severity of opioid withdrawal in natural settings. However, several studies have reported that kratom may by itself cause dependence following chronic consumption. Yet, there is currently no formal treatment for kratom dependence. Mitragynine, is the major psychoactive alkaloid in kratom. Chronic mitragynine treatment can cause addiction-like symptoms in rodent models including withdrawal behaviour. In this study we assessed whether the prescription drugs, methadone, buprenorphine and clonidine, could mitigate mitragynine withdrawal effects. In order to assess treatment safety, we also evaluated hematological, biochemical and histopathological treatment effects.Methods: We induced mitragynine withdrawal behaviour in a chronic treatment paradigm in rats. Methadone (1.0 mg/kg), buprenorphine (0.8 mg/kg) and clonidine (0.1 mg/kg) were i.p. administered over four days during mitragynine withdrawal. These treatments were stopped and withdrawal sign assessment continued. Thereafter, toxicological profiles of the treatments were evaluated in the blood and in organs.Results: Chronic mitragynine treatment caused significant withdrawal behaviour lasting at least 5 days. Methadone, buprenorphine, as well as clonidine treatments significantly attenuated these withdrawal signs. No major effects on blood or organ toxicity were observed.Conclusion: These data suggest that the already available prescription medications methadone, buprenorphine, and clonidine are capable to alleviate mitragynine withdrawal signs rats. This may suggest them as treatment options also for problematic mitragynine/kratom use in humans.

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A systematic review of (pre)clinical studies on the therapeutic potential and safety profile of kratom in humans

Prevete

Kuypers

Theunissen

et al. 2021

Human Psychopharmacology

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Introduction: Kratom (Mitragyna speciosa) is a tropical plant traditionally used as an ethnomedicinal remedy for several conditions in South East Asia. Despite the increased interest in its therapeutical benefits in Western countries, little scientific evidence is available to support such claims, and existing data remain limited to kratom's chronic consumption.Objective: Our study aims to investigate (pre)clinical evidence on the efficacy of kratom as a therapeutic aid and its safety profile in humans. Methods: A systematic literature search using PubMed and the Medline database was conducted between April and November 2020. Results: Both preclinical (N = 57) and clinical (N = 18) studies emerged from our search. Preclinical data indicated a therapeutic value in terms of acute/chronic pain (N = 23), morphine/ethanol withdrawal, and dependence (N = 14), among other medical conditions (N = 26). Clinical data included interventional studies (N = 2) reporting reduced pain sensitivity, and observational studies (N = 9) describing the association between kratom's chronic (daily/frequent) use and safety issues, in terms of health consequences (e.g., learning impairment, high cholesterol level, dependence/withdrawal).Conclusions: Although the initial (pre)clinical evidence on kratom's therapeutic potential and its safety profile in humans is encouraging, further validation in large, controlled clinical trials is required.

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Assessing physiological dependence and withdrawal potential of mitragynine using schedule-controlled behaviour in rats

Cited by 28 publications

References 56 publications

Acute mitragynine administration suppresses cortical oscillatory power and systems theta coherence in rats

Acute mitragynine administration suppresses cortical oscillatory power and systems theta coherence in rats

Methadone, Buprenorphine, and Clonidine Attenuate Mitragynine Withdrawal in Rats

A systematic review of (pre)clinical studies on the therapeutic potential and safety profile of kratom in humans

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