Preclinical in vivo
Explore the preclinical in vivo studies of kratom and the active compounds extracted from the plant, alkaloids.
To determine the safety and efficacy of any compound, preclinical in vivo testing in mammalian species must be performed. For a compound to become recognized as safe, approved as a dietary supplement, or sold as a drug product (over the counter or prescription) it must undergo a variety of studies to ensure its long-term safe use and recommended use levels. When it comes to products derived from botanicals or botanicals themselves, testing becomes even more complicated, as plants may contain numerous bioactive compounds.
Testing is performed in rodents first (mice or rats) prior to being carried out in larger nonrodent species (dogs, monkeys). The following will explore the preclinical work performed for kratom and its isolated alkaloids.
Preclinical in vivo receptor pharmacology, efficacy, and abuse potential
Receptor Pharmacology
In preclinical in vivo research, rodent and nonrodent models are used to determine safety and efficacy of compounds. In rodent models, rats and mice are used to determine the mechanism of action of a compound using various methods. For opioid receptor studies, hot-plate assays or other measures of analgesia are used to determine if a compound is acting with the central opioid system. The compound is measured against a gold-standard compound (for these studies usually morphine) and an antagonist is used to ensure that the mechanism of action is through the receptor system being explored.
VIDEO: In Vivo Receptor Pharmacology
Kratom extracts, as well as isolated mitragynine, show central analgesia in rodents which is fully antagonized by non-selective opioid antagonists (i.e., naloxone or naltrexone) suggesting that analgesia from kratom is primarily driven by the opioid receptor system (1-4). Other isolated alkaloids have been tested with speciociliatine and corynoxine, two other minor indole alkaloids found in kratom, having equal or more potency than morphine (5). Another kratom alkaloid, corynantheidine was found to be an antagonist at opioid receptors (6). Mitragynine has also been found to act through central adrenergic analgesic pathways in rodents indicating its pain relieving/reducing properties occur through activation of multiple receptor systems (7, 8).
As kratom is also used traditionally to increase mood, activity of kratom and its alkaloids at serotonin and dopamine receptors has been researched in vivo. Serotonin receptors play an important role in regulation of mood, cognition, and sleep, among other physiological processes. A measure of in vivo serotonin activity in rodents is the lower lip retraction test. In this test, the alkaloids paynantheine and speciogynine demonstrated the greatest activity and this activity was antagonized by WAY100635, a serotonin receptor antagonist, so both alkaloids act as either agonists or partial agonists at serotonin receptors (9). Dopamine receptors are important for regulation of emotion, learning, and play a role in reward systems among other functions and have been studied in rodent models with kratom extract and isolated mitragynine. Mitragynine shows anxiolytic properties in rodents that are reversed by opioid, GABA, and dopamine antagonists which indicates that mitragynine may decrease anxiety through a variety of receptor subtypes, as it does with analgesia (10, Hazim, 2011 #593, 11) On the other hand, kratom methanolic extracts have shown an interesting duality when tested in rodent models of psychosis. In certain instances, kratom exacerbated symptoms of psychosis while in other tests it decreased psychosis through the dopaminergic system which underlines the need for more study to understand the dose-response relationship of individual kratom alkaloids and full kratom products (12).
Efficacy for substance use disorders
VIDEO: Efficacy for substance use disorders
In addition to the preclinical work described above that shows kratom and/or its alkaloids have potential for pain and mental health, research studying kratom and its alkaloids for substance use disorders has been performed. A lyophilized kratom tea preparation significantly decreased opioid withdrawal in morphine dependent mice indicating that full leaf kratom preparations may be useful for opioid withdrawal symptoms. Importantly, the kratom tea preparation did not produce any physical dependence in mice when administered chronically (13).
In another study, kratom extract and mitragynine were separately investigated to determine if they reduced withdrawal symptoms in morphine dependent mice. Whole kratom extract and mitragynine isolate both decrease withdrawal in opioid dependent subjects and the effect of mitragynine resembled that produced by methadone and buprenorphine, two currently approved medications for opioid use disorder (14, 15). Mitragynine has also demonstrated attenuation of morphine dependence, reduction in response rates of heroin induced conditioned place preference, and reduction of morphine tolerance (16-20).
Kratom extracts and alkaloids have also demonstrated utility in alcohol withdrawal, decreasing alcohol seeking behaviors, and decreasing alcohol intake in rodents (21-24).
Abuse Potential
When the United States Drug Enforcement Agency considers a compound for scheduling as part of the Controlled Substances Act, eight factor analysis is performed. This analysis includes the abuse potential, pharmacology, current scientific knowledge, history and patterns of abuse, significance of abuse, risk to public health, dependence, and comparison to already controlled substances. The abuse potential of kratom and its alkaloids have been assessed preclinically using self-administration, drug discrimination, conditioned place preference, dependence, and withdrawal assays.
VIDEO: Abuse Potential
In intravenous self-administration studies of mitragynine, no abuse potential is signaled and mitragynine pretreatment decreased heroin self-administration (19, 20). But the metabolite of mitragynine, 7-hydroxymitragynine, does show abuse potential when measured against morphine in self-administration procedures (20). In tests of drug-discrimination, mitragynine has the strongest generalization to lofexidine (an α-2 adrenergic receptor agonist used for acute opioid withdrawal symptoms) and phenylephrine (found in many over the counter cold medications as a nasal decongestant) both of which are not controlled substances (25). High doses of kratom methanolic extract achieved conditioned place preference while lower doses of lyophilized kratom tea did not produce conditioned place preference which is a measure of the rewarding properties of a compound (13, 24). Mitragynine causes no spontaneous withdrawal upon cessation, but naloxone precipitated withdrawal symptoms are apparent though weaker and short-lived compared to the morphine control group (26).
Overall, though dependence and withdrawal can be simulated in rodent models, it is modest and manageable compared to other opioids, so the abuse liability of kratom does not warrant it becoming a controlled substance.
Preclinical in vivo pharmacokinetics and safety
Preclinically, short-term or single doses of kratom and individual alkaloids are well tolerated in mice, rats, dogs, and monkeys (27-31), (9, 32-35). Preclinical safety studies in rodent and nonrodent species are lacking for kratom and its alkaloids. No acute or chronic toxicity or carcinogenicity studies have been performed. To better understand the safety profile of kratom, clinical data in humans from long-term users is analyzed.