Kratom-Oxycodone Interaction Study for Herbal Interaction
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: Washington State University
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is studying how kratom tea affects the body's processing and response to the pain medication oxycodone. Healthy adults will take kratom tea and oxycodone in different combinations. Researchers aim to see if kratom changes how oxycodone is broken down and its effects on the body. Kratom is a herb with a long history of traditional use in Southeast Asia, known for its stimulant properties at low doses and effects similar to opioids at higher doses.
Do I have to stop taking my current medications to join the trial?Yes, you must stop taking any medications, including prescription and non-prescription drugs, that are known to alter the pharmacokinetics of kratom or oxycodone. You also need to abstain from dietary supplements, botanical products, and certain other substances for several weeks before participating.
Is Kratom-Oxycodone a promising drug?Kratom, a plant from Southeast Asia, is used for its pain-relieving and opioid-like effects. It has gained popularity in the U.S. for managing pain and opioid withdrawal. Oxycodone is a well-known painkiller. Combining Kratom and Oxycodone could potentially enhance pain relief and help with opioid withdrawal, offering a natural alternative to traditional drugs.23467
What safety data exists for the interaction between Kratom and Oxycodone?Existing safety data indicates that Kratom, particularly its alkaloid mitragynine, can inhibit cytochrome P450 enzymes, notably CYP3A and CYP2D6, which are involved in the metabolism of many drugs, including oxycodone. This inhibition can lead to increased systemic exposure to these drugs, potentially causing adverse effects. Reports of adverse drug reactions and fatalities associated with Kratom, especially when used with other substances, highlight the need for caution. Further research is needed to fully understand the safety and interaction profile of Kratom with drugs like oxycodone.24567
What data supports the idea that Kratom-Oxycodone Interaction Study for Herbal Interaction is an effective treatment?The available research does not provide clear evidence that the Kratom-Oxycodone Interaction Study for Herbal Interaction is an effective treatment. Instead, the studies focus on the potential interactions between kratom and other drugs, highlighting concerns about safety and possible adverse effects. For example, kratom can affect how certain drugs are processed in the body, which might lead to serious interactions. While kratom is used by some people to manage pain and opioid withdrawal, the research emphasizes the need for more studies to understand its safety and effectiveness compared to other treatments.12467
Eligibility Criteria
This trial is for healthy adults aged 21-45, weighing between 130-250 pounds with a BMI of 19-30. Participants must have previously used kratom and opioids without issues or addiction, not be on medications that affect these substances' metabolism, and agree to avoid certain substances like caffeine, alcohol, cannabis products, and dietary supplements before visits.Participant Groups
The study aims to see if kratom affects how the body processes oxycodone. Participants will try four different scenarios: only kratom tea; just an oxycodone tablet; both together; and several days of kratom followed by both. Researchers want to know how this combination impacts drug metabolism and effects on the body.
4Treatment groups
Experimental Treatment
Active Control
Group I: Arm 4Experimental Treatment2 Interventions
The same 16 participants will self-administer a single low dose (2 g) of kratom as a tea once daily at home. On the fifth day, subjects will return to the research setting, where they will be administered a single low dose (2 g) of kratom, followed 15 minutes later by a single low dose (10 mg) of oxycodone by mouth. Plasma, pupil diameter measurements, and urine will be collected from 0-24 hours.
Group II: Arm 3Experimental Treatment2 Interventions
The same 16 participants will be administered a single low dose (2 g) of kratom as a tea. After 15 minutes, the subjects will be administered a single low dose (10 mg) of oxycodone as a tablet by mouth. Plasma, pupil diameter measurements, and urine will be collected from 0-24 hours. A washout of at least 10 days will separate Arms 3 and 4.
Group III: Arm 1Experimental Treatment1 Intervention
Sixteen non-naive\* participants (8 males, 8 females) will be administered a single low dose (2 g) of a well-characterized kratom product by mouth as a tea. Pupil diameter will be measured from 0-12 hours. A washout of at least 10 days will separate Arms 1 and 2.
\*Non-naive subjects are defined as intermittent users who consume 2-8 g kratom at least once per month but no more than three times daily within the last six months prior to screening and are willing to abstain for several weeks
Group IV: Arm 2Active Control1 Intervention
The same 16 participants will be administered a single low dose (10 mg) of immediate-release oxycodone by mouth as a tablet. Plasma, pupil diameter measurements, and urine will be collected from 0-24 hours. A washout of at least 2 days will separate Arms 2 and 3.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Washington State University College of Pharmacy and Pharmaceutical SciencesSpokane, WA
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Who is running the clinical trial?
Washington State UniversityLead Sponsor
National Center for Complementary and Integrative Health (NCCIH)Collaborator
References
Herb-drug interactions and mechanistic and clinical considerations. [2022]Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herbdrug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.
Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations. [2022]Preparations from the leaves of the kratom plant (Mitragyna speciosa) are consumed for their opioid-like effects. Several deaths have been associated with kratom used concomitantly with some drugs. Pharmacokinetic interactions are potential underlying mechanisms of these fatalities. Accumulating in vitro evidence has demonstrated select kratom alkaloids, including the abundant indole alkaloid mitragynine, as reversible inhibitors of several cytochromes P450 (CYPs). The objective of this work was to refine the mechanistic understanding of potential kratom-drug interactions by considering both reversible and time-dependent inhibition (TDI) of CYPs in the liver and intestine. Mitragynine was tested against CYP2C9 (diclofenac 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), and CYP3A (midazolam 1'-hydroxylation) activities in human liver microsomes (HLMs) and CYP3A activity in human intestinal microsomes (HIMs). Comparing the absence to presence of NADPH during preincubation of mitragynine with HLMs or HIMs, an ∼7-fold leftward shift in IC50 (∼20 to 3 μM) toward CYP3A resulted, prompting determination of TDI parameters (HLMs: K I , 4.1 ± 0.9 μM; k inact , 0.068 ± 0.01 min-1; HIMs: K I , 4.2 ± 2.5 μM; k inact , 0.079 ± 0.02 min-1). Mitragynine caused no leftward shift in IC50 toward CYP2C9 (∼40 μM) and CYP2D6 (∼1 μM) but was a strong competitive inhibitor of CYP2D6 (K i , 1.17 ± 0.07 μM). Using a recommended mechanistic static model, mitragynine (2-g kratom dose) was predicted to increase dextromethorphan and midazolam area under the plasma concentration-time curve by 1.06- and 5.69-fold, respectively. The predicted midazolam area under the plasma concentration-time curve ratio exceeded the recommended cutoff (1.25), which would have been missed if TDI was not considered. SIGNIFICANCE STATEMENT: Kratom, a botanical natural product increasingly consumed for its opioid-like effects, may precipitate potentially serious pharmacokinetic interactions with drugs. The abundant kratom indole alkaloid mitragynine was shown to be a time-dependent inhibitor of hepatic and intestinal cytochrome P450 3A activity. A mechanistic static model predicted mitragynine to increase systemic exposure to the probe drug substrate midazolam by 5.7-fold, necessitating further evaluation via dynamic models and clinical assessment to advance the understanding of consumer safety associated with kratom use.
A Case of Potential Pharmacokinetic Kratom-drug Interactions Resulting in Toxicity and Subsequent Treatment of Kratom Use Disorder With Buprenorphine/Naloxone. [2022]The botanical product kratom produces opioid-like effects at high doses and is sometimes used for opioid replacement by individuals with opioid use disorder. Mitragynine, a major alkaloid contained in kratom leaves, has been shown to inhibit multiple cytochromes P450 (CYPs) in vitro, including CYP2D6 and CYP3A. As such, kratom may precipitate pharmacokinetic drug interactions when co-consumed with certain medications. We present a case of a patient taking 150 mg venlafaxine (CYP2D6/3A substrate), 300 mg quetiapine (CYP3A substrate), and a high amount of kratom (~90 g) daily. The patient presented to the emergency department with serotonin syndrome and corrected electrocardiogram abnormalities that may have been secondary to supratherapeutic exposure to venlafaxine and/or quetiapine. The patient's symptoms resolved after discontinuation of venlafaxine and quetiapine. He was amenable to medication therapy for kratom discontinuation and successfully completed an at-home induction with buprenorphine/naloxone. This case report adds to the literature about potential pharmacokinetic kratom-drug interactions and suggests that buprenorphine/naloxone can facilitate recovery from kratom use disorder.
Adverse Drug Interaction Between Kratom and Amitriptyline With Gastrointestinal and Mild Hepatic Effects. [2023]Kratom (Mitragyna speciosa) is a tropical evergreen plant native to Southeast Asia, where it has been used historically for its various psychoactive and analgesic properties. In recent years, the popularity of kratom has surged in the United States as a supplement for treating opioid withdrawal/addiction, anxiety, depression, and chronic pain, among others. However, much of Kratom processing and sales remain largely unregulated, with little clinical research to demonstrate the effects of kratom on physiologic processes such as potential drug interactions. Here, we present a case of Kratom interaction with Amitriptyline in a patient recovering from Opioid Use Disorder.
An evaluation of adverse drug reactions and outcomes attributed to kratom in the US Food and Drug Administration Adverse Event Reporting System from January 2004 through September 2021. [2023]Kratom is a widely used Asian botanical that has gained popularity in the United States due to a perception that it can treat pain, anxiety, and opioid withdrawal symptoms. The American Kratom Association estimates 10-16 million people use kratom. Kratom-associated adverse drug reactions (ADRs) continue to be reported and raise concerns about the safety profile of kratom. However, studies are lacking that describe the overall pattern of kratom-associated adverse events and quantify the association between kratom and adverse events. ADRs reported to the US Food and Drug Administration Adverse Event Reporting System from January 2004 through September 2021 were used to address these knowledge gaps. Descriptive analysis was conducted to analyze kratom-related adverse reactions. Conservative pharmacovigilance signals based on observed-to-expected ratios with shrinkage were estimated by comparing kratom to all other natural products and drugs. Based on 489 deduplicated kratom-related ADR reports, users were young (mean age 35.5 years), and more often male (67.5%) than female patients (23.5%). Cases were predominantly reported since 2018 (94.2%). Fifty-two disproportionate reporting signals in 17 system-organ-class categories were generated. The observed/reported number of kratom-related accidental death reports was 63-fold greater than expected. There were eight strong signals related to addiction or drug withdrawal. An excess proportion of ADR reports were about kratom-related drug complaints, toxicity to various agents, and seizures. Although further research is needed to assess the safety of kratom, clinicians and consumers should be aware that real-world evidence points to potential safety threats.
Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom. [2023]Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (Cmax ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and Cmax (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (KI , ~4 μM; kinact , ~0.07 min-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.
Translating Kratom-Drug Interactions: From Bedside to Bench and Back. [2023]Kratom is a botanical natural product belonging to the coffee family, with stimulant effects at low doses and opioid-like effects at higher doses. During the last two decades, kratom has been purported as a safer alternative to pharmaceutical and illicit drugs to self-manage pain and opioid withdrawal symptoms. Kratom alkaloids, typically mitragynine, have been detected in biologic samples from overdose deaths. These deaths are often observed in combination with other drugs and are suspected to result from polyintoxications. This review focuses on the potential for kratom to precipitate pharmacokinetic interactions with object drugs involved in these reported polyintoxications. The legal status, chemistry, pharmacology, and toxicology are also summarized. The aggregate in vitro and clinical data identified kratom and select kratom alkaloids as modulators of cytochrome P450 (P450) enzyme activity, notably as inhibitors of CYP2D6 and CYP3A, as well as P-glycoprotein-mediated efflux activity. These inhibitory effects could increase the systemic exposure to co-consumed object drugs, which may lead to adverse effects. Collectively, the evidence to date warrants further evaluation of potential kratom-drug interactions using an iterative approach involving additional mechanistic in vitro studies, well designed clinical studies, and physiologically based pharmacokinetic modeling and simulation. This critical information is needed to fill knowledge gaps regarding the safe and effective use of kratom, thereby addressing ongoing public health concerns. SIGNIFICANCE STATEMENT: The botanical kratom is increasingly used to self-manage pain and opioid withdrawal symptoms due to having opioid-like effects. The legal status, chemistry, pharmacology, toxicology, and drug interaction potential of kratom are reviewed. Kratom-associated polyintoxications and in vitro-in vivo extrapolations suggest that kratom can precipitate pharmacokinetic drug interactions by inhibiting CYP2D6, CYP3A, and P-glycoprotein. An iterative approach that includes clinical studies and physiologically based pharmacokinetic modeling and simulation is recommended for further evaluation of potential unwanted kratom-drug interactions.