Pharmacokinetics of Eleven Kratom Alkaloids Following an Oral Dose of Either Traditional or Commercial Kratom Products in Rats

Kamble, Shyam H.; Berthold, Erin C.; King, Tamara I.; Raju, K. Kanaka; Popa, Raluca Andreea; Herting, Julius R; León, Francisco; Sharma, Abhisheak; Avery, Bonnie A.; McCurdy, Christopher R.

doi:10.1021/acs.jnatprod.0c01163

Cited by 37 publications

(35 citation statements)

References 27 publications

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“…Paynatheine, at a 10 mg∙kg −1 dose, only blocks morphine hyper-ambulation within the first 15–20 min of the 40-min conditioning session. Detailed pharmacokinetic data for paynantheine have yet to be reported, but a recent study has shown that following oral administration in rats, a 1.1 mg∙kg −1 dose of paynantheine had a T max of 10 min in plasma and was undetectable after an hour ( Kamble et al, 2021 ). We suspect that in our hands paynantheine is similarly being rapidly metabolized and/or cleared from the brain and plasma, such that it may not block morphine’s CPP long enough to inhibit it significantly.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder

et al. 2021

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Background and Purpose:Mitragyna speciosa extract and kratom alkaloids decrease alcohol consumption in mice at least in part through actions at the δ-opioid receptor (δOR). However, the most potent opioidergic kratom alkaloid, 7-hydroxymitragynine, exhibits rewarding properties and hyperlocomotion presumably due to preferred affinity for the mu opioid receptor (µOR). We hypothesized that opioidergic kratom alkaloids like paynantheine and speciogynine with reduced µOR potency could provide a starting point for developing opioids with an improved therapeutic window to treat alcohol use disorder.Experimental Approach: We characterized paynantheine, speciociliatine, and four novel kratom-derived analogs for their ability to bind and activate δOR, µOR, and κOR. Select opioids were assessed in behavioral assays in male C57BL/6N WT and δOR knockout mice.Key Results: Paynantheine (10 mg∙kg−1, i.p.) produced aversion in a limited conditioned place preference (CPP) paradigm but did not produce CPP with additional conditioning sessions. Paynantheine did not produce robust antinociception but did block morphine-induced antinociception and hyperlocomotion. Yet, at 10 and 30 mg∙kg−1 doses (i.p.), paynantheine did not counteract morphine CPP. 7-hydroxypaynantheine and 7-hydroxyspeciogynine displayed potency at δOR but limited µOR potency relative to 7-hydroxymitragynine in vitro, and dose-dependently decreased voluntary alcohol consumption in WT but not δOR in KO mice. 7-hydroxyspeciogynine has a maximally tolerated dose of at least 10 mg∙kg−1 (s.c.) at which it did not produce significant CPP neither alter general locomotion nor induce noticeable seizures.Conclusion and Implications: Derivatizing kratom alkaloids with the goal of enhancing δOR potency and reducing off-target effects could provide a pathway to develop novel lead compounds to treat alcohol use disorder with an improved therapeutic window.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder

et al. 2021

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“…Concomitant use of kratom with other substances and dietary habits that could potentiate or attenuate kratom effects may also have occurred, thus limiting conclusions that might be drawn, including kratom's beneficial or adverse effects and effectiveness when used alone. Lastly, it is critical to keep in mind that heterogeneity of kratom products within the US is considerable, but also that commercialized and processed kratom products consumed in the US likely differ from fresh kratom preparations available and used in Southeast Asia (Saref et al, 2019;Charoenratana et al, 2021;Kamble et al, 2021). The regular use of kratom in the US continues to grow at unknown rates, making it incumbent upon researchers and healthcare providers to include kratom use history items on broader surveys related to substance use or clinical assessments.…”

Section: Limitationsmentioning

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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“…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%

“…With Kratom's Minor Alkaloids MG, 7-OH-MG, corynantheidine, speciogynine, speciociliatine, paynantheine, corynoxine, corynoxine-B, mitraphylline, ajmalicine, and isospeciofoline were analyzed in rat plasma after a variety of oral kratom products, with only MG, 7-OH-MG, speciociliatine, and corynantheidine quantifiable at 8 h (Kamble et al, 2021).…”

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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Pharmacokinetics of Eleven Kratom Alkaloids Following an Oral Dose of Either Traditional or Commercial Kratom Products in Rats

Cited by 37 publications

References 27 publications

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder

Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder

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

Kratom Abuse Potential 2021: An Updated Eight Factor Analysis

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