# Kratom alkaloids: in vitro and in vivo pharmacological mechanisms

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $669,920

## Abstract

Mitragyna speciosa (kratom) has exploded onto the US market, with an estimated 55,000 kg entering the US
between 2014 and 2016, corresponding to 12 million kratom doses and one million users. The FDA recently
used computational modeling to predict that 22 kratom constituents bind to opioid receptors; however, these
predictions await translation into whole animals. There is an urgent need for systematic, pharmacological testing
of kratom alkaloids to help inform abuse risk. We feel it is important to assess the behavioral effects of not only
individual alkaloids, but also alkaloid mixtures representative of plant material in commercially used products.
We will extract, isolate, and purify alkaloids from two kratom sources: dried leaf material of Mitragyna speciosa
trees and a US commercial product (i.e., OPMS Gold capsules). We will quantify up to ten kratom alkaloids
simultaneously using our bioanalytical methods. In a pharmacokinetic-based Aim 1, we will quantify kratom
alkaloids in multiple biological matrices (urine, plasma, brain, liver) after p.o. and i.v. administration in rats to
obtain a comprehensive ADME profile. Liver microsomes, recombinant CYP450 enzymes, and specific chemical
CYP450 inhibitors will be used to identify pathways of metabolism and biologically active metabolites. In our
pharmacodynamic-based Aim 2, we will use drug discrimination to identify receptor mechanism(s) underlying
abuse-related effects. Four separate groups of rats will be trained to discriminate one of the following: 1) alkaloid
mixture in proportion to kratom dried leaf material, 2) alkaloid mixture in proportion to commercially available
kratom product (both containing 32 mg/kg mitragynine, 3) 32 mg/kg mitragynine alone, or 4) 3.2 mg/kg 7-
hydroxymitragynine alone. Moreover, we will use i.v. drug self-administration to assess abuse risk, and to assess
how kratom alkaloids modify the reinforcing effects of abused opioids (i.e., heroin). Male and female rats will be
used throughout to assess sex as a biological variable. The overarching hypothesis is that Mitragyna speciosa
has a complex pharmacology resulting from multiple alkaloids differentially interacting with both opioid and non-
opioid receptors. The following specific hypotheses will be tested: 1) alkaloids interact (i.e., exert synergistic and
antagonist effects) with each other and with other abused opioids in drug discrimination and self-administration
assays; 2) some of the interactions are due to PK; 3) behavioral effects of the parent alkaloid are due in part to
both the parent compound and its behaviorally active metabolites; 4) no single alkaloid accounts for the
discriminative stimulus and reinforcing effects of the mixtures; and 5) both opioid and adrenergic receptors
mediate the effects of alkaloid mixtures representative of natural plant material. Subtraction and addition of
individual alkaloids will help identify the alkaloids most responsible for kratom's integrated pharmacology. After
...

## Key facts

- **NIH application ID:** 9913489
- **Project number:** 5R01DA047855-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Christopher R McCurdy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $669,920
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913489

## Citation

> US National Institutes of Health, RePORTER application 9913489, Kratom alkaloids: in vitro and in vivo pharmacological mechanisms (5R01DA047855-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9913489. Licensed CC0.

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