Bioanalytical method development and validation of corynantheidine, a kratom alkaloid, using UPLC-MS/MS, and its application to preclinical pharmacokinetic studies

King, Tamara I.; Sharma, Abhisheak; Kamble, Shyam H.; León, Francisco; Berthold, Erin C.; Popa, Raluca Andreea; Cerlati, Orélia; Prentice, Boone M.; McCurdy, Christopher R.; Avery, Bonnie A.

doi:10.1016/j.jpba.2019.113019

Cited by 18 publications

(19 citation statements)

References 25 publications

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“… ,, Corynantheidine has the same stereochemistry at C3 (3 S ) and C20 (20 S ) as mitragynine. About 1% of alkaloid extract is believed to be corynantheidine in some extracts according to literature reports . We were not able to find this alkaloid in “Red Indonesian Micro Powder”, so we chemically synthesized corynantheidine from mitragynine as shown in Scheme .…”

Section: Resultsmentioning

confidence: 99%

Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom

Chakraborty

Uprety

Daibani

et al. 2021

ACS Chem. Neurosci.

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Dry leaves of kratom (mitragyna speciosa) are anecdotally consumed as pain relievers and antidotes against opioid withdrawal and alcohol use disorders. There are at least 54 alkaloids in kratom; however, investigations to date have focused around mitragynine, 7-hydroxy mitragynine (7OH), and mitragynine pseudoindoxyl (MP). Herein, we probe a few minor indole and oxindole based alkaloids, reporting the receptor affinity, Gprotein activity, and βarrestin-2 signaling of corynantheidine, corynoxine, corynoxine B, mitraciliatine, and isopaynantheine at mouse and human opioid receptors. We identify corynantheidine as a mu opioid receptor (MOR) partial agonist, whereas its oxindole derivative corynoxine was an MOR full agonist. Similarly, another alkaloid mitraciliatine was found to be an MOR partial agonist, while isopaynantheine was a KOR agonist which showed reduced βarrestin-2 recruitment. Corynantheidine, corynoxine, and mitraciliatine showed MOR dependent antinociception in mice, but mitraciliatine and corynoxine displayed attenuated respiratory depression and hyperlocomotion compared to the prototypic MOR agonist morphine in vivo when administered supraspinally. Isopaynantheine on the other hand was identified as the first kratom derived KOR agonist in vivo. While these minor alkaloids are unlikely to play the majority role in the biological actions of kratom, they represent excellent starting points for further diversification as well as distinct efficacy and signaling profiles with which to probe opioid actions in vivo.

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Section: Resultsmentioning

confidence: 99%

Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom

Chakraborty

Uprety

Daibani

et al. 2021

ACS Chem. Neurosci.

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“…Animal models for kratom alone may not be fully predictive of human effects Factor 3: Current state of scientific knowledge MG and 7-OH-MG PK/PD (Hiranita et al, 2020), (Avery et al, 2019;Jagabalan et al, 2019;Maxwell et al, 2020) Greater exposure observed with natural kratom formulations than with oral MG Minor Alkaloids PK/PD (King et al, 2020;Berthold et al, 2021;Kamble et al, 2021) Approximately one third of minor alkaloids are characterized Clinical Studies (Singh et al, 2018a;Singh et al, 2018b;Singh et al, 2019a;Singh et al, 2020a;Leong Bin Abdullah et al, 2020; Long term users of kratom have no significant differences in most physiological measures compared to nonusers These should not be considered definitive safety data but provide a foundation for further studies…”

Section: Factor/description Citations Main Findings Commentsmentioning

confidence: 99%

“…Similarly, the pharmacokinetics of corynanthidine, a minor kratom alkaloid and perhaps a MOR antagonist, were determined after 2.5 mg/kg IV and 20 mg/kg oral doses to rats, yielding a 50% oral bioavailability, a 4.1 h Tmax and extensive distribution including in brain corpus callosum and hippocampus regions (King et al, 2020).…”

Section: Pharmacokinetic and Pharmacodynamic Findingsmentioning

confidence: 99%

Kratom Abuse Potential 2021: An Updated Eight Factor Analysis

Henningfield¹,

Wang²,

Huestis³

2022

Front. Pharmacol.

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Drugs are regulated in the United States (US) by the Controlled Substances Act (CSA) if assessment of their abuse potential, including public health risks, show such control is warranted. An evaluation via the 8 factors of the CSA provides the comprehensive assessment required for permanent listing of new chemical entities and previously uncontrolled substances. Such an assessment was published for two kratom alkaloids in 2018 that the Food and Drug Administration (FDA) have identified as candidates for CSA listing: mitragynine (MG) and 7-hydroxymitragynine (7-OH-MG) (Henningfield et al., 2018a). That assessment concluded the abuse potential of MG was within the range of many other uncontrolled substances, that there was not evidence of an imminent risk to public health, and that a Schedule I listing (the only option for substances that are not FDA approved for therapeutic use such as kratom) carried public health risks including drug overdoses by people using kratom to abstain from opioids. The purpose of this review is to provide an updated abuse potential assessment reviewing greater than 100 studies published since January 1, 2018. These include studies of abuse potential and physical dependence/withdrawal in animals; in-vitro receptor binding; assessments of potential efficacy treating pain and substance use disorders; pharmacokinetic/pharmacodynamic studies with safety-related findings; clinical studies of long-term users with various physiological endpoints; and surveys of patterns and reasons for use and associated effects including dependence and withdrawal. Findings from these studies suggest that public health is better served by assuring continued access to kratom products by consumers and researchers. Currently, Kratom alkaloids and derivatives are in development as safer and/or more effective medicines for treating pain, substances use disorders, and mood disorders. Placing kratom in the CSA via scheduling would criminalize consumers and possession, seriously impede research, and can be predicted to have serious adverse public health consequences, including potentially thousands of drug overdose deaths. Therefore, CSA listing is not recommended. Regulation to minimize risks of contaminated, adulterated, and inappropriately marketed products is recommended.

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“…Four of kratom’s over 40 known bioactive alkaloids, mitragynine (MG), 7-hydroxymitragynine (7-HG), corynoxine, and speciociliatine, appear to act at μ-opioid receptors. The two most heavily studied, MG and 7-HG, seemingly act as partial opioid receptor agonists, though non-opioid actions are also observed with these and other alkaloids ( Kruegel and Grundmann, 2018 ; Fowble and Musah, 2019 ; Kruegel et al, 2019 ; Obeng et al, 2019 ; King et al, 2020 ; Todd et al, 2020 ; Berthold et al, 2021 ; Chear et al, 2021 ; Kamble et al, 2021 ). MG and 7-HG have been found to produce a range of mostly dose-dependent acute and chronic effects (both adverse and potentially therapeutic) that are consistent with μ-opioid receptor activity in nonhuman animals, including: discriminability as opioids (with partial generalization to psychostimulants); self-administration; conditioned place preference; attenuation of opioid self-administration and opioid withdrawal; and analgesic, antinociceptive, and anxiolytic effects ( Hazim et al, 2014 ; Harun et al, 2015 ; Yusoff et al, 2017 ; Yue et al, 2018 ; Hemby et al, 2019 ; Hiranita et al, 2019 ; Hassan et al, 2020 ; Kamble et al, 2021 ; Obeng et al, 2021 ; Suhaimi et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Searching for a Signal: Self-Reported Kratom Dose-Effect Relationships Among a Sample of US Adults With Regular Kratom Use Histories

et al. 2022

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There is limited understanding regarding kratom use among US adults. Although motivations for use are increasingly understood, typical kratom doses, threshold of (low and high) doses for perceived effectiveness, and effects produced during cessation are not well documented. We aimed to extend prior survey work by recruiting adults with current and past kratom exposure. Our goal was to better understand kratom dosing, changes in routines, and perception of effects, including time to onset, duration, and variability of beneficial and adverse outcomes from use and cessation. Among respondents who reported experiencing acute kratom effects, we also sought to determine if effects were perceived as helpful or unhelpful in meeting daily obligations. Finally, we attempted to detect any signal of a relationship between the amount of kratom consumed weekly and weeks of regular use with ratings of beneficial effects from use and ratings of adverse effects from cessation. We conducted an online survey between April-May 2021 by re-recruiting participants from a separate study who reported lifetime kratom use. A total of 129 evaluable surveys were collected. Most (59.7%) had used kratom >100 times and reported currently or having previously used kratom >4 times per week (62 weeks on average). Under half (41.9%) reported that they considered themselves to be a current “regular kratom user.” A majority (79.8%) reported experiencing acute effects from their typical kratom dose and that onset of effects began in minutes but dissipated within hours. Over a quarter reported that they had increased their kratom dose since use initiation, whereas 18.6% had decreased. Greater severity of unwanted effects from ≥1 day of kratom cessation was predicted by more weeks of regular kratom use (β = 6.74, p = 0.02). Acute kratom effects were largely reported as compatible with, and sometimes helpful in, meeting daily obligations. In the absence of human laboratory studies, survey methods must be refined to more precisely assess dose-effect relationships. These can help inform the development of controlled observational and experimental studies needed to advance the public health understanding of kratom product use.

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Bioanalytical method development and validation of corynantheidine, a kratom alkaloid, using UPLC-MS/MS, and its application to preclinical pharmacokinetic studies

Cited by 18 publications

References 25 publications

Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom

Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom

Kratom Abuse Potential 2021: An Updated Eight Factor Analysis

Searching for a Signal: Self-Reported Kratom Dose-Effect Relationships Among a Sample of US Adults With Regular Kratom Use Histories

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