Kratom Component in Clinical Trial for Opioid Use Disorder

SPECIAL REPORT: SUBSTANCE USE

The recent US Food and Drug Administration acceptance of an investigational new drug application for mitragynine, a psychoactive alkaloid from the leaf of the kratom tree (Mitragyna speciosa), for opioid use disorder (OUD) has cleared the way for a National Institutes of Health (NIH)–led randomized clinical trial.¹

"We have seen the potential of mitragynine in the lab, and now we are finally able to examine its potential in people," stated Joni Rutter, PhD, director of the National Center for Advancing Translational Sciences at NIH. "Hopefully, this work will lead to a new treatment option for people with opioid use disorder and support a path to recovery."

The phase 1 clinical trial will be conducted as part of the HEAL (Helping to End Addiction Long-Term) Initiative of the NIH, under the direction of Julia Solarczyk Donnelly, MS, RAC, who is chief of regulatory affairs at the National Institute on Drug Abuse at NIH. The double-blind, placebo-controlled, single–ascending dose study will assess safety and tolerability of an oral mitragynine formulation, MG001, developed by researchers at NIH and the University of Florida.

Interestingly, just weeks after the NIH announced the trial with mitragynine, the US Drug Enforcement Administration (DEA) filed notice of its intent to designate the metabolite of mitragynine, 7-hydroxymitragynine (7-OH), and 3 related compounds as Schedule I substances. This designation applies only to the synthesized and concentrated forms.²

The Schedule I classification and restrictions do not, in the current filing, affect products containing the kratom botanical leaf, as the total and peak amounts of the metabolite yielded after ingesting whole leaf products are lower than the thresholds set by the DEA. This designation will also not affect the clinical trial with the mitragynine isolate from kratom, as the dose and the rate of metabolism are also insufficient to produce the peak concentrations associated with ingestion of synthetic 7-OH.

The potential use of mitragynine in treating OUD is based on preclinical characterization of neuroreceptor site activity and on reports from experimentation and traditional medicine. In addition to being a partial opioid μ receptor agonist and competitive antagonist at the opioid κ and δ receptors, mitragynine and 7-OH also bind to adrenergic and serotonergic receptors.³ The range of purported effects includes antinociceptive, anxiolytic, and sedative effects; opioid craving and withdrawal are among an array of conditions for which it has been used.⁴

Determining Dose Response

The NIH-led trial will be conducted with approximately 32 healthy adult volunteers, randomly assigned to receive a single dose of either inactive placebo or 25, 50, 75, or 100 mg of MG001.⁵ Participants will remain in the research clinic under medical observation for 4 days and return to the clinic on day 7 for additional follow-up. Health assessments will include vital signs, electrocardiogram, determination of corrected QT interval, measures of pupil constriction, and degree of sedation by visual analog scale score. Serum will be drawn for multiple clinical laboratory values and to establish pharmacokinetics (PK). Incidence of treatment-emergent adverse events will be identified through either self-report or abnormal findings.

Although the NIH news release claims that "the compound in isolation has yet to be studied in humans,"¹ that was rebutted by Elisabeth Prevete, MD, PhD, from the Department of Neuropsychology and Psychopharmacology at Maastricht University in the Netherlands, and colleagues, who earlier published findings from a phase 1 trial of mitragynine.⁶ Theirs was a placebo-controlled, single-blind, within-participants study. It was conducted in 2 parts, with 8 healthy adult volunteers receiving placebo and 3 doses of mitragynine (5, 10, and 20 mg) in sequential dosing on separate days and another group of 7 volunteers receiving placebo and then 40 mg of mitragynine. Assessments measured at regular intervals for 7 hours after drug administration included vital signs, subjective drug experience, neurocognitive function, and pain tolerance.

"Overall, mitragynine did not affect most of the outcome measures at any dose," Prevete and colleagues reported. "Yet the lowest dose (5 mg) of mitragynine increased subjective ratings of arousal and attention, accuracy in sustained attention tasks, and motor inhibition. The highest dose (40 mg) of mitragynine increased subjective ratings of amnesia and produced mild psychopathological symptoms."

Prevete and colleagues suggest their findings support earlier claims that kratom exerts a "double action" as a psychostimulant at low doses and a sedative at higher doses. They posit that stimulant effect and enhanced mood may arise through adrenergic, opioidergic, and serotonergic receptors. There could be impaired cognition and memory at the higher dose, they suggest, citing findings from preclinical studies that relate these to changes in cortical neural activity and interference with hippocampal synaptic transmission. Prevete and colleagues acknowledge the limitations of the small phase 1 trial and indicate they look forward to "further investigations with higher mitragynine doses, larger sample sizes, and full PK analysis."

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. NIH research clears way for study of experimental treatment for opioid use disorder. News release. National Institutes of Health. June 1, 2026. Accessed July 6, 2026. https://www.nih.gov/news-events/news-releases/nih-research-clears-way-study-experimental-treatment-opioid-use-disorder

2. DEA to temporarily schedule 7-OH and related substances to protect public safety. News release. US Drug Enforcement Administration. July 1, 2026. Accessed July 6, 2026. https://www.dea.gov/press-releases/2026/07/01/dea-temporarily-schedule-7-oh-and-related-substances-protect-public

3. Annuar NAK, Azlan UK, Mediani A, et al. An insight review on the neuropharmacological effects, mechanisms of action, pharmacokinetics and toxicity of mitragynine. Biomed Pharmacother. 2024;171:116134.

4. Prevete E, Kuypers KPC, Theunissen EL, et al. Clinical implications of kratom (Mitragyna speciosa) use: a literature review. Curr Addict Rep. 2023;10(2):317-334.

5. Phase 1 study of oral MG001. ClinicalTrials.gov. Updated June 16, 2026. Accessed July 6, 2026. https://clinicaltrials.gov/study/NCT07204171

6. Prevete E, Theunissen EL, Kuypers KPC, et al. An exploratory study of the safety profile and neurocognitive function after single doses of mitragynine in humans. Psychopharmacology (Berl). 2025;242(6):1363-1376.