🇺🇸 Informational public health resource. Educational reference for legislative and regulatory review.

Randomized Safety & Tolerability Trial (Huestis et al., 2026)

This was a randomized, double-blind, placebo-controlled study evaluating single and repeated daily oral doses of dried kratom leaf powder (MitraLeaf) in healthy adult volunteers.

Study Design

  • 116 participants total (49 active kratom; 67 placebo)
  • Four escalating mitragynine dose levels: 6.65, 13.3, 26.6, and 53.2 mg
  • Single dose phase followed by 15 consecutive daily doses
  • 23-day follow-up period
  • Participants were healthy, nonsmoking adults who had not used kratom in ≥12 months

7-Hydroxymitragynine (7-OH) Formation

The MitraLeaf product contained <0.01% 7-OH. The paper confirms that 7-OH detected in plasma primarily results from metabolic conversion of mitragynine (via CYP3A4), not from high 7-OH content in the plant material.

Adverse Events (TEAEs)

No serious adverse events or deaths were reported. Treatment-emergent adverse events (TEAEs) generally increased with higher dose levels.

Most common after single dose:

  • Nausea
  • Dizziness
  • Headache

Most common after 15 daily doses:

  • Headache
  • Feeling hot
  • Nausea
  • Somnolence
  • Increased ALT (alanine aminotransferase)

Most TEAEs were mild in severity (approximately 90%+). A small number were moderate. Severe events were rare and resolved.

Drug Liking / Abuse-Related Signals

Abuse potential–related adverse events were monitored. Euphoric mood was reported in only three participants total (one in each active single-dose cohort and one in placebo).

No participant reported euphoric mood during the multiple-dose phase after receiving active kratom.

Only one withdrawal-related event (mild diarrhea) was reported during follow-up.

Early Terminations

Six participants were withdrawn early:

  • Two due to elevated ALT (liver enzyme) increases
  • One due to severe gastroenteritis
  • One due to vasovagal syncope during blood draw
  • One due to ALT increase not meeting Hy’s Law criteria
  • One withdrew voluntarily after reporting multiple side effects

ALT and AST elevations at the highest dose resolved after stopping dosing. No cases met FDA criteria for drug-induced liver injury (Hy’s Law).

Cardiovascular and Respiratory Findings

No clinically significant changes were observed in blood pressure, heart rate, respiratory rate, oxygen saturation, or ECG parameters. No QTc prolongation above regulatory concern thresholds was reported.

Sponsorship and Disclosure

The study was funded by NP Pharma. The clinical trial was conducted under institutional review board approval. Authors disclosed consultant relationships with the sponsor.

Open PDF: Huestis study 2026 →

Human Pharmacokinetics of Mitragynine and 7-OH (Huestis et al., 2024)

This study measured how mitragynine and 7-hydroxymitragynine (7-OH) appear in blood after a single dose and after repeated daily dosing (15 days) of oral, encapsulated dried kratom leaf powder.

Why this matters

The kratom powder contained very little pre-formed 7-OH (<0.01%), yet measurable 7-OH was still detected in plasma after dosing. This indicates 7-OH exposure largely reflects metabolic conversion of mitragynine inside the body.

Key findings in plain language

  • Both mitragynine and 7-OH increased with higher doses.
  • Steady-state concentrations were reached in about 8–9 days for mitragynine.
  • 7-OH steady state was reached in about 7 days at the higher dose levels (trough data were limited at the lowest doses).
  • The 7-OH/mitragynine ratio was higher after single dosing and decreased somewhat after repeated dosing.

Half-life and accumulation

Mitragynine showed a long terminal half-life that increased with dose (reported up to ~43 hours after the highest single dose and ~61 hours after repeated dosing in one cohort). 7-OH had a shorter half-life than mitragynine, but also increased with dose and showed variability at higher doses.

With repeated daily dosing, mitragynine accumulation was described as low to moderate, while 7-OH showed minimal accumulation compared with mitragynine.

Sponsorship and conduct

The study reports it was funded by Johnson Foods, LLC (manufacturer of the MitraLeaf dried kratom leaf powder), and the clinical study was performed by SGS Nutrasource in Ontario, Canada. Authors disclosed consulting relationships with the sponsor.

Open PDF: Huestis PK 2024 →

FDA-Registered Human Study (ClinicalTrials.gov: NCT06072170)

This study is registered on ClinicalTrials.gov and evaluates single-dose oral kratom administration under controlled laboratory conditions. The results are publicly available in standardized reporting format.

Participants

The study enrolled healthy adult volunteers who met predefined eligibility criteria. Participants were screened for medical stability prior to enrollment. The registry does not indicate that this was a chronic-use or dependence study.

Sponsorship and Conduct

According to the ClinicalTrials.gov record, this study was sponsored by the U.S. Food and Drug Administration (FDA). The study was conducted in a controlled clinical research setting under federal oversight.

Measured Outcomes

  • Plasma concentrations of mitragynine following dosing
  • Detection of 7-hydroxymitragynine (7-OH) formed through metabolism
  • Standardized subjective effect ratings (including “drug liking” and “feeling high”)
  • Adverse event reporting and safety monitoring
  • Participant discontinuations, when applicable

Why This Is Relevant

The ClinicalTrials.gov results page provides structured tables showing dose levels, laboratory measurements, subjective ratings, and safety events. These data characterize short-term pharmacologic effects under supervised conditions.

The study does not evaluate long-term daily use, dependence development, adolescent exposure, or retail product variability.

View Results on ClinicalTrials.gov →

Summary Across Controlled Human Studies

Controlled human studies of kratom remain limited in number, but the studies summarized here provide structured information on metabolism, short-term tolerability, and measurable subjective effects under supervised conditions.

Key Findings (Plain Language)

  • 7-hydroxymitragynine (7-OH) is produced in the body. Even when the kratom product contains very little 7-OH, participants still develop measurable 7-OH in blood, indicating metabolic conversion from mitragynine.
  • Higher doses increase exposure. Both mitragynine and 7-OH blood levels rise with dose, and repeated dosing results in sustained exposure.
  • Drug-effect ratings increase at higher doses. In the FDA-registered single-dose study, higher doses were associated with statistically significant increases in subjective ratings such as “drug liking” and “feeling high.”
  • Short-term side effects were common and dose-related. Nausea, dizziness, headache, sleepiness, and similar effects were reported more often at higher doses.
  • Some participants were withdrawn. Withdrawals occurred for reasons including elevated liver enzymes at higher doses and gastrointestinal intolerance.

What These Studies Do Not Evaluate

  • Long-term, high-frequency chronic use over months or years
  • Adolescents and pediatric exposures
  • Population-level incidence (how common events are in the general public)
  • Real-world retail variability, including concentrated extracts and polydrug use
  • Development of dependence and withdrawal under long-term daily use

Controlled trials are designed to measure effects under specific conditions. Surveillance systems (mortality, poison control, adverse event reporting) capture broader real-world patterns and are presented elsewhere on this site.