Preclinical pharmacokinetic study of speciociliatine, a kratom alkaloid, in rats using an UPLC-MS/MS method

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

doi:10.1016/j.jpba.2020.113778

Cited by 13 publications

(12 citation statements)

References 19 publications

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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%

“…Speciociliatine pharmacokinetics were characterized following IV and oral dosing to help understand the potential contribution of this alkaloid to in vivo kratom administration effects (Berthold et al, 2021). Speciociliatine had higher systemic exposure and lower clearance compared to the other kratom alkaloids mitragynine and corynantheidine.…”

Section: Pharmacokinetic and Pharmacodynamic Findingsmentioning

confidence: 99%

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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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Section: Factor/description Citations Main Findings Commentsmentioning

confidence: 99%

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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“…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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“…According to the results obtained in Table 7 , the binding affinities of speciociliatine (3) (K i (MOR): 116 ± 36 nM, K i (KOR): 54.5 ± 4.4 nM) at both opioid receptors are higher than mitragynine (1) (K i (MOR): 198 ± 30 nM, K i (KOR): 161 ± 10 nM). Berthold et al (2021) also found that the binding affinity of speciociliatine (3) at MOR and KOR was 3.0- and 1.7-fold higher than that of mitragynine (1) . Based on the two studies, it is suggested that the conversion of the configuration at position 3 from S [mitragynine (1) ] to R [speciociliatine (3) ] causes a significant change in terms of the binding affinities.…”

Section: Pharmacology/structure Activity Relationship Study (Sars)mentioning

confidence: 83%

“…In addition, speciociliatine (3) has a different spatial arrangement in comparison with mitragynine (1) , where both structures can be distinguished by a switch in the configuration from R [speciociliatine (3) ] to S (mitragynine (1) ) of the hydrogen moiety positioned at C-3. This configurational inversion from R to S will induce significant spatial change in the core skeleton (ring C and D) of speciociliatine (3) , where it will enhance its molecular volume while the inversion to mitragynine (1) will cause the β -methoxy acrylate moiety in the compound to adopt an axial position ( Berthold et al, 2021 ).…”

Section: Chemistrymentioning

confidence: 99%

The Chemical and Pharmacological Properties of Mitragynine and Its Diastereomers: An Insight Review

et al. 2022

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Mitragynine, is a naturally occurring indole alkaloid that can be isolated from the leaves of a psychoactive medicinal plant. Mitragyna speciosa, also known as kratom, is found to possess promising analgesic effects on mediating the opioid receptors such as µ (MOR), δ (DOR), and κ (KOR). This alkaloid has therapeutic potential for pain management as it has limited adverse effect compared to a classical opioid, morphine. Mitragynine is frequently regarded to behave like an opioid but possesses milder withdrawal symptoms. The use of this alkaloid as the source of an analgesic candidate has been proven through comprehensive preclinical and clinical studies. The present data have shown that mitragynine is able to bind to opioid receptors, particularly MOR, to exhibit the analgesic effect. Moreover, the chemical and pharmacological aspects of mitragynine and its diastereomers, speciogynine, speciociliatine, and mitraciliatine, are discussed. It is interesting to know how the difference in stereochemical configuration could lead to the difference in the bioactivity of the respective compounds. Hence, in this review, the updated pharmacological and toxicological properties of mitragynine and its diastereomers are discussed to render a comprehensive understanding of the pharmacological properties of mitragynine and its diastereomers based on their structure–activity relationship study.

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Preclinical pharmacokinetic study of speciociliatine, a kratom alkaloid, in rats using an UPLC-MS/MS method

Cited by 13 publications

References 19 publications

Kratom Abuse Potential 2021: An Updated Eight Factor Analysis

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

The Chemical and Pharmacological Properties of Mitragynine and Its Diastereomers: An Insight Review

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