HomeMy WebLinkAboutPinney Associates Letter
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The Abuse Potential of 7-
Hydroxymitragynine (7-OH)
According to the 8 Factors of
the Controlled Substances Act
Developed for Submission to the Drug
Enforcement Administration (DEA), Food
and Drug Administration (FDA), and
National Institute on Drug Abuse (NIDA)
Jack E. Henningfield, Daniel W. Wang,
Mark A. Sembower, Steve Pype, Floe
Foxon
September 29, 2025
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Table of Contents
Table of Contents ............................................................................................................ 2
List of Abbreviations ........................................................................................................ 4
1 Introduction .............................................................................................................. 6
2 Factor 1: Actual or Relative Potential for Abuse ....................................................... 9
2.1 Pharmacology ................................................................................................... 9
2.2 Nonclinical Abuse Potential Models (Rewarding Effects) ................................ 11
2.2.1 Self-Administration ................................................................................... 11
2.2.2 Intracranial Self-Stimulation ..................................................................... 11
2.2.3 Drug Discrimination ................................................................................. 11
2.2.4 Conditioned Place Preference ................................................................. 12
2.3 Clinical Studies and Evidence of Abuse Potential in Humans ......................... 12
2.4 Implications for Abuse Potential ...................................................................... 12
3 Factor 2: Scientific Evidence of its Pharmacological Effects .................................. 13
3.1 Mechanism of Action and Opioid Binding ....................................................... 13
3.2 Effects on Other Neurotransmitter Systems .................................................... 14
3.3 Antinociception ................................................................................................ 14
3.4 Respiratory Depression .................................................................................. 14
3.5 Comparison to Morphine ................................................................................. 15
3.6 Implications for Abuse Potential ...................................................................... 15
4 Factor 3: Current State of Scientific Knowledge ..................................................... 16
4.1 Pharmacokinetics ............................................................................................ 16
4.2 Mitragynine Pseudoindoxyl ............................................................................. 18
4.3 Conclusions .................................................................................................... 18
5 Factors 4, 5, and 6: History and Current Patterns of Abuse; The Scope,
Significance and Duration of Abuse; What, if any, Risk is there to the Public Health .... 19
5.1 Factor 4: History and Current Patterns of Abuse ............................................ 19
5.1.1 Reasons for Use ...................................................................................... 20
5.1.2 Dosing, Routes of Administration, and Trajectory of Use......................... 20
5.2 Factor 5: Scope, Duration, and Significance of Abuse .................................... 21
5.2.1 National Surveillance Systems ................................................................ 21
5.2.2 Published Case Reports .......................................................................... 26
5.2.3 Social Media Discussion .......................................................................... 26
5.3 Factor 6: What, if any, Risk is there to the Public Health ................................ 30
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5.3.1 Pharmacological Risks............................................................................. 31
5.3.2 Abuse, Dependence, and Withdrawal Risk .............................................. 31
5.3.3 Potential Benefits to Consumers and Public Health ................................. 32
5.4 Implications ..................................................................................................... 32
6 Factor 7: The Psychic or Physiological Dependence Liability ................................ 33
7 Factor 8: Whether the Substance is an Immediate Precursor of a Substance
Already Controlled ......................................................................................................... 34
8 Scheduling Recommendation ................................................................................ 34
8.1 Policy Implementation Considerations to Minimize Unintended Consequences
35
9 Research Priorities and Policy Considerations ...................................................... 36
9.1 Comparison of 7-OH to Kratom and other Substances ................................... 39
9.2 Potential Unintended Consequences of Schedule I Placement and Policy
Implications ................................................................................................................ 40
9.2.1 Potential Unintended Consequences of Scheduling ................................ 40
10 References ......................................................................................................... 43
11 Appendices ......................................................................................................... 52
11.1 Appendix 1: Published Findings Related to Abuse, Physical Dependence,
Withdrawal, and Safety Signals of 7-OH .................................................................... 52
11.2 Appendix 2: Press Release: FDA Takes Steps to Restrict 7-OH Opioid
Products Threatening American Consumers ............................................................. 73
11.3 Appendix 3: FDA Report: 7-Hydroxymitragyine (7-OH): An Assessment of the
Scientific Data and Toxicological Concerns Around an Emerging Opioid Threat ...... 75
11.4 Appendix 4: FDA Slide Set: Preventing The Next Wave of the Opioid Epidemic:
What You Need to Know About 7-OH ...................................................................... 100
11.5 Appendix 5: Department of Health and Human Services Press Conference
Transcript ................................................................................................................. 106
11.6 Appendix 6: Dr. Martin A. Makary 7-OH Letter to Colleagues ....................... 128
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List of Abbreviations
Abbreviation Definition
Β-arrestin-2 Beta (β)-arrestin-2
7-OH
(7-OH-MG,
7-OH-MIT)
7-hydroxymitragynine
8-FA 8-Factor Analysis
CAMU Commonly Accepted for Medical Use
CNS Central nervous system
CPP Conditioned place preference
CSA Controlled Substances Act
CYP Cytochrome P450 (i.e., 3A, 2D6, 3A4)
DAWN Drug Abuse Warning Network
DEA Drug Enforcement Agency
DHHS Department of Health and Human Services
DOJ Department of Justice
DOR Delta (δ)-opioid receptor
ECDD World Health Organization's Expert Committee on Drug
Dependence
FAERS Food and Drug Administration Adverse Event Reporting System
FDA Food and Drug Administration
GI Gastrointestinal
IC50 Half-maximal inhibitory concentration
ICSS Intracranial self-stimulation
IP intraperitoneal
IQR Interquartile range
IV intravenous
Ki Inhibitor constant
KOR Kappa (κ)-opioid receptor
LSD Lysergic acid diethylamide
MOR Mu (µ)-opioid receptors
NDIN New Dietary Ingredient Notification
NFLIS National Forensic Laboratory Information System
NIDA National Institute on Drug Abuse
NIH National Institutes of Health
NFLIS National Forensic Laboratory Information System
NPDS National Poison Data System
NSDUH National Survey on Drug Use and Health
PO Per oral
TEDS Treatment Episodes Data Set
UGT UDP-glucuronosyltransferase (i.e., UGT1A1, UGT1A3, UGT1A9)
UNODC United Nations Office on Drugs and Crime
U.S. United States
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Disclosure
This report was funded without restrictions by the Center for Plant Science and Health
(CPSH). CPSH had no input into the writing of this report, its methods, or its
conclusions.
Through Pinney Associates, JEH, DWW, MS, SP, and FF consult to CPSH. In addition
to CPSH, in the last 36 months, Pinney Associates has consulted to the Holistic
Alternative Recovery Trust, NP Pharma, and Botanic Tonics LLC (the last
uncompensated) on kratom science and regulatory issues and studies. Through Pinney
Associates, in support of CPSH, JH has commented on kratom pharmacology, public
health, and regulatory needs for state hearings and for a judicial hearing to address
questions raised by the court on these same matters. JEH has also developed reports
and given depositions addressing kratom addictiveness, and risks and benefits to
kratom users, along with regulatory needs on behalf of several defendants in kratom
litigation.
Acknowledgements
The authors are grateful for the care and efforts of Megan S. Harris in the editing and
formatting of the report.
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1 Introduction
On July 29, 2025, the United States (U.S.) Food and Drug Administration (FDA)
presented its assessment of a potential “novel, emerging public health threat”, 7-
hydroxymitragynine (also known as 7-OH), a psychoactive substance that naturally
occurs as a minor constituent of the kratom plant (Mitragyna speciosa) and also forms
in the body as a metabolite of mitragynine, the plant's primary alkaloid. This
assessment, shared as a news release on the FDA website (FDA, 2025a), was based
on epidemiological findings and scientific data on toxicological concerns. FDA’s release
linked to a summary scientific evaluation developed by FDA scientists titled
“Assessment of the Scientific Data and Toxicological Concerns Around an Emerging
Opioid Threat” (Reissig et al., 2025), a slide set titled “Preventing the Next Wave of the
Opioid Epidemic: What You Need to Know about 7-OH” (FDA, 2025b), and a Dear
Colleagues letter by Commissioner Dr. Marty Makary (2025). Additionally, the Secretary
of Health and Human Services, Robert F. Kennedy, Jr., hosted a press conference
described as “measures to safeguard American public from dangerous opioid 7-OH
(DHHS, 2025b). Participants included Secretary Kennedy, Department of Health and
Human Services (DHHS) Deputy Secretary Jim O’Neill, FDA Commissioner Dr. Marty
Makary, U.S. Senator Markwayne Mullin (R-OK), and Melody Woolf (chronic pain
survivor) (DHHS, 2025a).
These scientific analyses and announcements summarized FDA’s findings that 7-OH
binds to morphine opioid receptors (also referred to as “mu (µ)- opioid receptors or
MOR”) with potentially strong effects similar to those that can be produced by morphine
and other classical opioids. Of particular concern to FDA is the increasing proliferation
of products that contain highly concentrated, often semi-synthetically derived 7-OH.
These novel products deliver significantly higher levels of 7-OH than occur naturally or
are found in traditional kratom leaf products. In its July 29, 2025 media release FDA
cites evidence from key studies and assays typically considered in drug scheduling
determinations, including rewarding effects in animal studies, physical dependence and
withdrawal symptoms, respiratory depression (at least when administered
intravenously), and effects in animals generalized to morphine.
Additionally, FDA cites clinical presentations (often referred to as anecdotal reports) and
receptor binding profiles. These data support FDA’s characterization of 7-OH as a
substance with a pharmacological profile that is qualitatively similar to classical opioids
with effects such as “euphoria, sedation, respiratory depression, and opioid-like
withdrawal syndromes, with users acknowledging its significant addiction potential
(Reissig et al., 2025, p. 4). FDA concluded “The pharmacological profile, abuse liability,
and emerging patterns of nonmedical use establish 7-OH as a dangerous substance”
(Reissig et al., 2025, p. 4). As discussed in Factor 8, such data suggest that 7-OH
meets the statutory definition of an opioid as described in the 1970 Controlled
Substances Act (CSA).
Although some kratom products have likely been boosted in their 7-OH concentrations
in the past, the widespread marketing and consumption of concentrated 7-OH products
has emerged nationwide in just the past few years. FDA itself noted a clear “distinction”
between kratom and kratom products that “have been used for centuries in both
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medicinal and recreational settings” containing naturally low occurring levels of 7-OH
compared to what the agency described as the recent widespread appearance of “7-OH
opioid products” (e.g., FDA (2025a). FDA emphasized that “7-OH is found in trace
amounts in the kratom plant leaf. But this is not our focus. Our primary concern is the
concentrated form of 7-OH. This is an important distinction. These concentrated 7-OH
opioid products are far more dangerous than traditional kratom leaf products” (Makary,
2025)
Currently, many kratom and related products, including concentrated 7-OH products are
marketed as dietary ingredients and/or supplements, though to date no New Dietary
Ingredient Notification (NDIN) has been accepted by FDA and the lack of adequately
documented history of use prior to 1994 has precluded its acceptance as an ‘old dietary
ingredient’ that is exempt from the NDIN requirements as described in the 1994 Dietary
Supplement Health and Education Act (DSHEA).
During the FDA’s July 29, 2025, press conference, the DHHS leadership indicated that
the Department would recommend the Drug Enforcement Administration (DEA) place 7-
OH in the CSA. If DEA concurs, then 7-OH would be placed in Schedule I, along with
heroin, LSD, and marijuana as that is the only CSA schedule for substances with high
abuse potential and which are not “Commonly Accepted for Medical Use” (CAMU).
CAMU is typically determined by FDA’s approval as a drug for medical use, or in a rare
recent case with respect to marijuana, a substantial body of medical use, state-level
authorization, and clinical evidence was considered adequate to support the designation
of marijuana as CAMU despite the absence of FDA formal therapeutic/medical approval
(DHHS, 2023a; DEA, 2024).
Permanent placement in Schedule I requires an 8-factor analysis (8-FA), which is the
structured evaluation described in the CSA that is determinative of CSA control and
scheduling. Factors 1, 2, 3, and 7 are based on chemical, pharmacological, and clinical
studies, while Factors 4, 5, and 6 determine public health impact and whether the
substance poses an imminent hazard to public health. Factor 8 examines whether the
substance is a chemical precursor of a substance that is already controlled in the CSA,
or has the same chemical structure, or in the case of opioids is derived from the opium
poppy by extraction, or chemical synthesis based on opium or an opium poppy
constituent such thebaine or morphine or has a pharmacological profile similar to that of
already controlled morphine-like opioids1.
This recent action represents a shift from a 2018 DHHS decision, which rescinded a
prior recommendation to schedule kratom and its alkaloids, including 7-OH. In that
1 In 21 U.S. Code § 802 – Definitions
(17)The term “narcotic drug” means any of the following whether produced directly or indirectly by
extraction from substances of vegetable origin, or independently by means of chemical synthesis, or by a
combination of extraction and chemical synthesis:
(A) Opium, opiates, derivatives of opium and opiates, including their isomers, esters, ethers,
salts, and salts of isomers, esters, and ethers, whenever the existence of such isomers, esters, ethers,
and salts is possible within the specific chemical designation. Such term does not include the isoquinoline
alkaloids of opium.
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decision, U.S. Assistant Secretary for Health Admiral Brett P. Giroir noted that the
existing science did not support a recommendation to place mitragynine and 7-OH in
the CSA because this would have had the effect of banning kratom product and that
carried a “significant risk of immediate adverse public health consequences” if users
were to switch to more lethal opioids (Giroir, 2018).
Similarly, the United Nations Commission on Narcotic Drugs (UNODC) Commission on
Narcotic Drugs (CND) concluded there was insufficient evidence to recommend a
critical review of kratom and its alkaloids, including mitragynine and 7-OH, though it
advised they be kept under surveillance (UNODC, 2021). Since then, in late August
2025, the UNODC published a warning of emerging products containing 7-OH and 7-
OH’s metabolite pseudoindoxyl, recommending further educational awareness
campaigns by healthcare professionals, regulators, and law enforcement, as well as
enhancing surveillance, testing, detection, and epidemiological surveillance of these
products.
The present document provides an 8-FA of 7-OH according to the 1970 Controlled
Substances Act. This 8-FA has been developed following the model laid out in FDA’s
guidance, Assessment of the Abuse Potential of Drugs (FDA, 2017), while also taking
into consideration the experience and evolution in approach to such assessments since
the CSA was signed into law in 1970. The present analysis considered and expands
upon the pharmacological and epidemiological data that were presented in FDA’s July
29, 2025 scientific assessment (Reissig et al., 2025) and incorporates insights from
prior work by Pinney Associates, including the 2018 and 2022 kratom 8-FAs and related
analyses (Henningfield, Fant, & Wang, 2018; Henningfield, Wang, & Huestis, 2022).
The Appendices include four documents released by FDA addressing 7-OH science,
warnings and educational materials (FDA, 2025a, FDA, 2025b, Makary, 2025; Reissig
et al., 2025), as well as the conference transcript in Appendix 5.
The purpose is to provide a structured review of the evidence typically used to inform
the FDA and National Institute on Drug Abuse (NIDA) in their CSA scheduling
recommendations and the DEA in its potential scheduling action, as well as to provide a
resource for public health policymakers, regulators, scientists, and the public in general
to learn about the risks associated with 7-OH and the complexities of its potential
regulatory and legal control. This 8-FA also discusses policy considerations such as
potential scheduling and enforcement approaches; efforts to mitigate unintended
consequences such as fueling the formation of illicit (“black”) 7-OH markets and relapse
to deadlier classical opioid use; and addressing other potential health problems and
medical issues in people who found 7-OH to be more effective, acceptable or
assessable than FDA approved medicines, kratom, or other approaches in addressing
their health needs including opioid dependence and withdrawal.
Table 1 from FDA (2017) summarizes the 8 factors of the CSA as follows:
Under 21 U.S.C. 811(b) of the CSA, the medical and scientific analysis considers
the following eight factors determinative of control of the drug under the CSA (21
U.S.C. 811(c)):
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1. Its actual or relative potential for abuse.
2. Scientific evidence of its pharmacological effect, if known.
3. The state of current scientific knowledge regarding the drug or other
substance.
4. Its history and current pattern of abuse.
5. The scope, duration, and significance of abuse.
6. What, if any, risk there is to the public health.
7. Its psychic or physiological dependence liability.
8. Whether the substance is an immediate precursor of a substance already
controlled.
2 Factor 1: Actual or Relative Potential for Abuse
The actual or relative potential for abuse of a substance is a primary determinant in
scheduling considerations under the CSA. This factor is assessed through a
combination of preclinical studies in animals and an analysis of human use patterns. For
7-OH, a number of nonclinical studies including self-administration, conditioned place
preference, and drug discrimination studies indicate potential for abuse, with effects that
are often comparable to, or more potent than, those of morphine. While controlled
human abuse potential studies have not yet been conducted, emerging data from user
reports and clinical case studies corroborate the findings from animal research,
suggesting that concentrated 7-OH products are being used for their rewarding and
opioid-like effects.
2.1 Pharmacology
7-OH has been shown to naturally occur at de minimis levels in the kratom plant and is
generally formed in vivo from mitragynine, the parent alkaloid, through metabolic
oxidation in the liver, mediated by cytochrome (CYP) P450 3A (Kruegel et al., 2019). It
appears that low levels of 7-OH may also occur post-harvest in leaves by enzymatic
interactions (Karunakaran, Vicknasingam, & Chawarski, 2025; Smith et al., 2024).
7-OH has demonstrated pharmacological properties consistent with potential for
recreational use, abuse, and dependence. However, available evidence indicates that
7-OH acts as a partial agonist at opioid receptors, suggesting that by some measures it
is weaker in its expression or less efficacious compared to morphine, such as opioid-like
effects. Whether the overall abuse potential of 7-OH is most accurately described as
lower, higher, or similar to morphine (the most common standard comparator) is not
clear at present; however, as discussed by FDA (Reissig et al., 2025), 7-OH has
sufficiently similar pharmacology to be characterized as an opioid. Moreover, although
its potency (the amount of drug required to produce a given effect) varies widely across
measures and studies, it requires smaller amounts of 7-OH by weight (e.g., mg) to
produce a variety of abuse-related effects as compared to morphine, therefore
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supporting the general description of 7-OH by FDA as a “potent’ and even “highly
potent” opioid”.
Specifically, 7-OH exhibits high affinity for MORs and acts as a partial agonist,
producing G-protein biased signaling with limited beta- (β) arrestin-2 recruitment
(Kruegel et al., 2016; Todd et al., 2020). This bias is generally associated with reduced
opioid-like effects such as constipation (Gutridge et al., 2020).
The FDA’s 2025 assessment characterizes 7-OH as a potent MOR agonist with high
abuse potential and risk of severe dependence stating, “Critically, 7-OH produces
respiratory depression, physical dependence, and withdrawal symptoms characteristic
of classical opioids, such as morphine, fentanyl, oxycodone, and hydrocodone”. It is
important to note that demonstrations of morphine equivalent reinforcing efficacy and
respiratory depression in rodent models were by the intravenous (IV) route of
administration, whereas virtually all human consumption is by the oral route. Overdose
risk by the oral route would seem to be a plausible risk but has not been well-
documented in animals and the evidence for apparent 7-OH attributed overdose deaths
in humans is not strong. FDA described two cases in which an overdose death occurred
and concluded as follows:
“Although FDA’s Adverse Event Reporting System (FAERS) has documented
cases reporting adverse events (13 cases, including 2 deaths) suspected to
involve 7-OH, ambiguity about the contributory role of 7-OH from uncharacterized
products or concomitant medications and underlying disease limits interpretation”
(Reissig et al., 2025).
Note that these reports are not limited to a single year but rather all the cases that have
been reported to date. Whereas these reports are concerning, and this report agrees
with FDA that adverse events related to 7-OH use have been under-reported, the actual
numbers of such cases are very low as compared to the thousands reported over time
and annually for opioids such as heroin, oxycodone and fentanyl and fentanyl related
substances.
Whereas most animal studies indicated that mitragynine is neither potent, strong, nor
reliable in producing respiratory depression (e.g., (Henningfield, Rodricks, et al., 2022),
7-OH produced stronger morphine-like respiratory depression by the IV route at lower
concentrations than mitragynine (Gonzalez et al., 2025; Harun et al., 2015).
Also, unlike mitragynine, 7-OH reliably substitutes for morphine across antinociception,
discrimination, and self-administration paradigms, showing dose-dependent reinforcing
and conditioned place preference effects with greater potency than morphine in several
animal models (Gutridge et al., 2020; Harun et al., 2015).
7-OH produces strong naloxone-reversible analgesia yet with less respiratory
depression and constipation at equianalgesic doses, and exhibits higher oral
bioavailability than morphine (Kruegel et al., 2016; Matsumoto et al., 2004). In mice,
brain concentrations of 7-OH after mitragynine administration are sufficient to explain
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most or all of the opioid-receptor mediated analgesic effects associated with
mitragynine use (Kruegel et al., 2019).
2.2 Nonclinical Abuse Potential Models (Rewarding Effects)
2.2.1 Self-Administration
A study by Hemby et al. (2019) evaluated the reinforcing effects of 7-OH in rats and
found that 7-OH not only engendered but also maintained self-administration behavior
at intravenous doses ranging from 2.5 to 10 µg/infusion, demonstrating reinforcing
effects comparable to those of morphine when administered at 50 and 100 µg/infusion,
suggesting 7-OH may be 10-20 times more potent than morphine in this test. In
contrast, mitragynine did not maintain self-administration, highlighting a critical
pharmacological distinction between the two compounds. The reinforcing effects of 7-
OH were found to be mediated by both MORs and delta (δ)-opioid receptors (DOR), as
intake was reduced by antagonists for both receptor types (NLXZ and NTI,
respectively). This contrasts with morphine, whose reinforcing effects in the same study
were primarily mediated by MORs.
To contextualize these findings for human risk, an allometric scaling factor can be used
to estimate a human equivalent dose. Based on the rat data, the reinforcing intravenous
dose of 7-OH for a 70 kg person is estimated to be between 0.161 and 0.322 mg,
compared to 1.61 mg for morphine. This calculation suggests that 7-OH might be
between 5-10x more potent than morphine in producing reinforcing effects, a key
indicator of abuse potential though this should be considered a possibility to be tested
and not an established fact. It is crucial to note, however, that the clinical
meaningfulness of such estimates is not clear because the animal data are based on
intravenous administration, whereas human consumption of 7-OH products is typically
oral. The abuse potential of 7-OH in humans has not been directly evaluated in human
abuse potential studies by any route of administration using protocols recommended by
FDA in its 2017 Guidance (FDA, 2017) nor have other potential effects of 7-OH
administration been well characterized in controlled clinical studies.
2.2.2 Intracranial Self-Stimulation
In an intracranial self-stimulation (ICSS) study, neither mitragynine nor 7-OH-MG
showed evidence of brain rewarding effects, whereas morphine robustly and dose
dependently decreased the stimulation threshold (Behnood-Rod et al., 2020). Thus, the
ICSS results suggest lower brain rewarding effects of mitragynine as compared to
morphine. Note that ICSS is not recommended in FDAs guidance for abuse potential
assessment but is considered a potentially informative model (Henningfield, Comer,
Banks, Coe, Collins, Cooper, Fantegrossi, Durgin, Heal, Huskinson, Lanier, Lynch,
Miesch, Rowlett, Strickland, & Gannon, 2025).
2.2.3 Drug Discrimination
Drug discrimination studies assess the interoceptive (subjective) effects of a substance
by training animals to recognize and distinguish the effects of a test drug from a placebo
(saline) or another drug. An animal's ability to generalize the subjective cue of a novel
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compound to that of a known drug of abuse, such as morphine, is considered predictive
of similar subjective effects and abuse potential in humans.
Several studies have shown that 7-OH fully substitutes for the discriminative stimulus
effects of morphine. Harun et al. (2015) trained male Sprague Dawley rats to
discriminate morphine (5.0 mg/kg, intraperitoneal [i.p.]) from saline. In subsequent
substitution tests, the highest dose of 7-OH (3.0 mg/kg) produced complete substitution
for the morphine cue, and this effect was reversed by the opioid antagonist naloxone.
Notably, this study found 7-OH to be more potent than morphine in producing these
subjective effects.
Further research has reinforced these findings. Obeng et al. (2021) reported that 7-OH
fully generalized to morphine in rats, whereas mitragynine only partially generalized.
Similarly, Hemby et al. (2019) found that 7-OH substituted for morphine in a dose-
dependent manner, while mitragynine did not substitute at any dose tested. The
consistent and complete generalization of 7-OH to the morphine cue across multiple
studies provides strong evidence that it may produce subjective effects that are
qualitatively similar to those of classical opioids.
2.2.4 Conditioned Place Preference
Matsumoto et al. (2008) found that 7-OH administered at 2 mg/kg produced conditioned
place preference (CPP) with greater potency than morphine. Similarly, Gutridge et al.
(2020) demonstrated that 7-OH at a dose of 3 mg/kg induced CPP in C57BL/6 mice,
although it required four conditioning sessions compared to 2 sessions for morphine (6
mg/kg) to establish the preference. This suggests that while 7-OH is rewarding, the
onset or strength of the conditioned association may differ from that of morphine under
certain experimental conditions. Another study by Chakraborty, Uprety, et al. (2021)
also confirmed that 7-OH produces significant CPP, whereas its metabolite, mitragynine
pseudoindoxyl, did not, indicating distinct rewarding profiles among related alkaloids.
Collectively, these findings consistently show that 7-OH has rewarding effects sufficient
to establish a conditioned preference, common in drugs with abuse potential.
2.3 Clinical Studies and Evidence of Abuse Potential in Humans
While there have been no controlled human laboratory studies conducted to date
specifically designed to assess the abuse potential of 7-OH, a growing body of
epidemiological data, clinical case reports, and user self-reports provide evidence of its
nonmedical use and abuse. The FDA's 2025 scientific assessment noted clinical
presentations that include reports of “euphoria, sedation, respiratory depression, and
opioid-like withdrawal syndromes, with users acknowledging its significant addiction
potential”. These reports align with the effects predicted by preclinical models and are
characteristic of substances with abuse potential, discussed further in Factors 4-6.
2.4 Implications for Abuse Potential
Taken together, the evidence summarized in Factor 1 suggests that 7-OH has
meaningful abuse potential despite limitations in the breadth of available studies, the
range of study types, and inconsistencies across findings. Preclinical studies suggest
robust reinforcing, rewarding, and subjective effects characteristic of a µ-opioid agonist,
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with potentially a potency greater than morphine, although not necessarily stronger.
This distinction is often misunderstood; potency refers to the amount of drug required to
produce a given effect and not the maximal possible effect that can be produced. Thus,
for example, in a classic study, Matsumoto et al. (2004) found that the potency of 7-OH
varied widely across outcome measures (include guinea-pig ileum contractions, tail flick
and hot plate tests) as compared to morphine and mitragynine, however, whereas 7-OH
and morphine produced similar maximum effects on several measures, mitragynine’s
effects were consistently weaker (producing smaller maximum possible effects) and far
less potent (taking more mg to produce any effect) than 7-OH and morphine.
From an abuse potential perspective, the most important finding is that both 7-OH and
morphine produce a range of qualitatively similar effects, supporting the characterization
of 7-OH as an ‘opioid’ and as a drug with a potential for opioid-like abuse potential.
These findings are also consistent with similarities in receptor binding and mechanism
of action, suggesting that its abuse related pharmacology is sufficiently similar to that of
opioids to warrant considering characterizing of 7-OH as an opioid.
At present, the available evidence does not provide a basis for determining the overall
abuse potential of 7-OH relative to morphine. However, that level of pharmacological
characterization is not critical to determine whether a substance lacking FDA approval
or commonly accepted for medical use meets the requirements for placement into
Schedule I of the Substances Act. That 7-OH as a substance exhibits meaningful abuse
potential and overall morphine-like opioid pharmacology satisfies the statutory criteria
for scheduling.
If 7-OH were to be submitted to FDA as part of a New Drug Application and
subsequently approved for therapeutic use, a quantitative determination of its relative
abuse potential would be important to guide scheduling – for example if it should be
placed alongside morphine in Schedule II, or in a less restrictive schedule (III, IV, or V)
based on the totality of evidence.
3 Factor 2: Scientific Evidence of its Pharmacological Effects
Current scientific evidence shows that 7-OH is pharmacologically active with a distinct
profile of central nervous system (CNS) mediated effects. It acts primarily as a potent
partial agonist at the MOR, but its effects extend to other neurotransmitter systems,
indicating that while its effects appear to warrant the designation as an opioid, it has
additional effects that appear to differentiate 7-OH from morphine-type opioids in its
overall pharmacology.
3.1 Mechanism of Action and Opioid Binding
7-OH’s interactions with opioid receptors appear to be the predominate cause of at least
its abuse related effects. For example, 7-OH consistently demonstrates high affinity for
the MOR, with reported inhibitor constant (Ki) values ranging from approximately 7 nM
to 78 nM, significantly higher than that of mitragynine, its parent alkaloid (1700 nM).
Studies have shown that both 7-OH and mitragynine demonstrate a preference for
activating the G-protein signaling pathway with little to no recruitment of the β-arrestin-2
pathway. This is a significant finding, as β-arrestin-2 recruitment is strongly associated
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with the adverse effects of classical opioids, such as respiratory depression and
constipation. This G-protein bias suggests a potential for a lower risk profile compared
to conventional opioids like morphine, which robustly recruit β-arrestin-2 (Ellis et al.,
2020; Kruegel et al., 2016). Nonetheless, other findings with 7-OH indicate meaningful
opioid-like abuse potential, as discussed in Factor 2.
For example, in addition to its primary action at the MOR, 7-OH also binds with
moderate to high affinity at the kappa (κ-) opioid receptor (KOR) and DOR, where it
appears to function as a competitive antagonist (Obeng et al., 2021). This profile as a
partial MOR agonist and a KOR/DOR antagonist distinguishes it from classical opioids
like morphine, which are full MOR agonists, and may contribute to its unique
pharmacological effects. For instance, KOR antagonism is associated with
antidepressant and anxiolytic effects, which could align with some of the reported
motivations for kratom and 7-OH use (Carlezon, & Krystal, 2016).
3.2 Effects on Other Neurotransmitter Systems
While 7-OH appears to primarily target opioid receptors, there is evidence that it, along
with mitragynine, also interacts with other CNS receptors, including adrenergic,
serotonergic, and dopaminergic systems. This multimodal activity likely contributes to
the complex profile of effects reported by users, which can include both stimulant-like
and sedative properties.
A study by James P. Manus et al. (2025) investigated the effects of 7-OH on dopamine
release in the nucleus accumbens, a key brain region in the reward pathway. The study
found a bidirectional effect: a low dose of 7-OH (0.5 mg/kg) increased dopamine
release, while a high dose (2 mg/kg) decreased it. The authors noted that these
alterations in dopamine function are not necessarily consistent with those of classic
drugs of abuse, suggesting a more complex mechanism of action on the brain's reward
systems. Ellis et al. (2020) found that the oxidation of mitragynine to 7-OH significantly
strengthens its binding affinity at the MOR but weakens its affinity at adrenergic and
serotonin receptors, indicating that the pharmacological profile shifts substantially upon
metabolism.
3.3 Antinociception
Numerous studies have demonstrated that 7-OH produces robust, dose-dependent
antinociceptive effects in animal models such as the hot plate and tail flick tests
(Behnood-Rod et al., 2020; Matsumoto et al., 2004). Its potency in producing analgesia
is consistently reported to be significantly greater than that of morphine. For example,
Kruegel et al. (2016) reported that 7-OH was approximately 10 times more potent than
morphine in producing antinociception. This potent analgesic effect, combined with its
high oral bioavailability compared to morphine, and its lack of measurable β-arrestin-2
recruitment makes 7-OH an interesting subject for potential therapeutic development.
3.4 Respiratory Depression
While studies referenced above determined mitragynine and 7-OH lacked measurable
β-arrestin-2 recruitment, a study by Gonzalez et al. (2025) found that 7-OH caused
dose-dependent reductions in respiratory frequency and minute volume in rats, effects
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fully reversed by naloxone. This is in contrast to mitragynine, which unexpectedly
increased respiratory frequency with no significant depression of tidal/minute volume.
This lack of respiratory depressive effects by mitragynine was confirmed by
Henningfield, Rodricks, et al. (2022)’s study showing no respiratory depression in rats
administered up to 400 mg/kg oral mitragynine. Mitragynine’s stimulant effect was not
blocked by naloxone, suggesting a non-opioid mechanism.
3.5 Comparison to Morphine
Comparing the relative potency of kratom, mitragynine, and 7-OH to morphine is
important in pharmacological evaluations but is often misinterpreted as indicative of
abuse, addiction and/or harm potential. What is more important in abuse potential
assessments is the maximum possible effect of a drug as a reward or euphoriant which
is generally considered a stronger determinant of the overall abuse potential of a drug
and its likelihood of recreational use. Potency should not be considered the same as
maximum possible effect.
Numerous studies have shown that 7-OH is more potent than morphine on several
measures but most of these do not suggest that 7-OH has stronger maximum possible
effects. For example, an in vitro study using electrically stimulated guinea pig ileum, a
classic assay for opioid activity, found that 7-OH was approximately 17 times more
potent than morphine and 30 times more potent than mitragynine (Horie et al., 2005). A
similar study by Takayama et al. (2002) found that 7-OH had 13 times higher potency
than morphine and 46 times more than mitragynine. Studies of 7-OH’s antinociception
potential have reported it at 10 times that of morphine (Kruegel et al., 2016).
However, it is critical to interpret these findings with caution. While informative, results
from in-vitro assays and subsequent in-vivo animal models do not always directly
translate to the complex human experience. Also, while 7-OH’s affinity to opioid
receptors relative to morphine can be quantified in a controlled laboratory setting, their
respective pharmacological profiles merit further study. Factors such as route of
administration, formulation, metabolism rate, bioavailability, blood-blood brain barrier
penetration, and the activation and interactions of multiple neurotransmitter systems
create a more complex web of effects than can be observed in a controlled laboratory
setting. Therefore, while the existing research provides a valuable pharmacological
baseline establishing 7-OH as a potent opioid agonist in some assays, its overall
pharmacological effects in humans have not been well characterized and remains an
area requiring further clinical research.
3.6 Implications for Abuse Potential
Taken together the data reviewed in this factor are consistent with the characterization
of 7-OH as a CNS-acting drug with effects likely to contribute to use and abuse
potential. Data from numerous studies indicate that 7-OH is pharmacologically active
with dose-related effects and mechanisms of action being similar though not identical to
those of morphine-like opioids. The relative potency compared to morphine appears to
vary widely across measures, which is not surprising nor atypical of opioids. However,
its distinct activity and variability (especially its lack of measurable β-arrestin-2
recruitment and activity at KOR and DOR receptors) suggest that direct comparison and
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characterizing 7-OH as an opioid that is up to 13 times more potent than morphine is
misleading as a stand-alone indicator of its abuse potential as these estimates are
based on animal models that may not necessarily relate to human effects.
Moreover, as mentioned earlier, relative potency is not necessarily indicative of abuse
potential. The mixed mechanisms of action of 7-OH may contribute to the diversity of
reasons people report for its use (as discussed in Factors 4, 5, and 6); however, this
pharmacological complexity does not inherently determine its level of abuse potential.
For example, when seeking rewarding and euphoriant effects, many recreational users
prefer opioids with a pharmacological profile characterized predominantly by MOR
agonism, such as morphine, oxycodone, heroin and fentanyl. Overall, the risk profile of
7-OH remains incompletely understood and warrants further study.
4 Factor 3: Current State of Scientific Knowledge
Research on kratom, including research on 7-OH specifically, has increased
enormously in the past decade. For example, the introduction to Kratom: History,
Science, and Therapeutic Potential, a recently published book featuring contributions
from many of the world’s leading kratom researchers, notes the rate of annual kratom
science publications increased from about 20 per year in 2016 to more than 130 per
year by 2024, with the increased fueled heavily by research funding by the National
Institutes of Health (NIH), NIDA (Henningfield, Beyer, & Raffa, 2025). This rapidly
expanding body of research undoubtedly played a significant role in shaping two
important themes in the July 29, 2025 FDA and DHHS documents addressing 7-OH: the
characterization of its abuse potential and safety, and the decision to treat 7-OH as a
public health concern distinct from kratom itself.
One of the most significant advances to emerge from the hundreds of new studies
conducted over the past decade has been the understanding that 7-OH is more
appropriately considered a mitragynine metabolite in humans and animals that are
given or who self-administer kratom. Additionally, while it has been established that it is
either absent from or appears in de minimis levels in freshly harvested kratom leaves, 7-
OH may emerge at low levels in the leaves over time, likely as a result of enzymatic
processes (Karunakaran, Vicknasingam, & Chawarski, 2025; Smith et al., 2024).
Indeed, it was observed several decades ago that 7-OH is less than 2% of the total
content of all of the alkaloids in kratom leaves (Takayama, 2004). In many marketed
kratom products including leaf powder, encapsulated kratom powder and extracts in the
U.S. 7-OH content is lower still ranging from undetectable to about 0.01% to 0.04% by
weight (Kikura-Hanajiri et al., 2009).
4.1 Pharmacokinetics
When kratom or pure, single isolate mitragynine extracts are self-administered or
administered in clinical studies, mitragynine is metabolized in the liver, a conversion
mediated primarily by the CYP3A enzyme, forming 7-OH. A human clinical study by
Mongar et al. (2024) found that co-administration of itraconazole, a potent CYP3A4
inhibitor, decreased the formation of 7-OH from mitragynine, reducing its peak plasma
concentration (i.e., Cmax) by 56% and its total exposure (i.e., area under the curve) by
43%.
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A large scale clinical trial found that after administration of encapsulated kratom leaf
powder, the time to reach maximum plasma concentration (i.e., Tmax) for 7-OH was
between 1.2 and 2.0 hours (Huestis et al., 2024). The elimination half-life (i.e., T1/2) was
found to be 4.7 hours after a single dose and extended to 24.7 hours after multiple daily
doses, indicating potential for accumulation with long term and/or daily use.
A study in beagles found a conversion rate of 23.1% of mitragynine to 7-OH, though this
may not be representative of human conversion rates. For instance, Hiranita et al.
(2020) reported “the conversion rate of 7‐hydroxymitragynine from per oral (PO)
mitragynine is low. In a study of pharmacokinetic interaction of kratom and cannabidiol
in male rats, the metabolite to parent (mitragynine) exposure ratio percentage of 7-OH-
MG remained similar (3.5 and 3.1 with and without cannabidiol, respectively). As there
was an increase in mitragynine exposure during this study, it was expected that this
would be due to a decrease in metabolism, but this was not the case for 7-OH-MG
despite it being primarily metabolized by CYP3A and cannabidiol being a competitive
inhibitor of CYP3A (Berthold et al., 2024).
Further rat studies support this finding, showing that 7-OH and mitragynine are
quantifiable 8 hours after consumption, and accumulation of mitragynine and 7-OH after
multiple oral doses (Chiang et al., 2024; Kamble et al., 2021). Another study by Tanna
et al. (2022) reported a similar half-life of 5.67 hours after a single oral 2 g dose of
kratom tea. This tea was tested and found to have contained only trace amounts of 7-
OH (i.e., less than the limit of quantitation [< LOQ]) in the starting product; therefore, the
assumption was made that 7-OH was generated from the metabolism of mitragynine in
vivo. Concerningly, there appear to be some 7-OH formulations that have been
designed to bypass first pass metabolism, artificially increasing bioavailability (Smith et
al., 2025).
Kruegel et al. (2019) found that brain concentrations of 7-OH formed from mitragynine
in mice are sufficient to explain most or all of the opioid-receptor-mediated analgesic
activity of mitragynine. At the same time, mitragynine is found in the brains of mice at
very high concentrations relative to its opioid receptor binding affinity, suggesting that it
does not directly activate opioid receptors (Kruegel et al., 2019).
Uchaipichat (2025) found that 7-OH-MG exhibited inhibitory potency on UGT1A9, with a
half-maximal inhibitory concentration (IC50) value of 51 µM, while moderate potency was
observed for UGT1A1 and UGT1A3, with IC50 values of 196 and 141 µM, suggesting
the potential for herb-drug interactions in individuals consuming high doses of 7-OH-
MG. However, the experimental Ki values found in this study were relatively high
compared to the maximum plasma concentrations of mitragynine and 7-OH reported in
humans.
In a study relevant to breast cancer treatment medications are potential effects of 7-OH
(and mitragynine) on as HER2 inhibitors. This in silico study (involving computer
simulations to predict pharmacological effects) suggested that the molecular docking
included binding energies of −7.56 kcal/mol and −8.77 kcal/mol, respectively, with key
interactions involving residues such as Leu726, Val734, Ala751, Lys753, Thr798, and
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Asp863. Akbar et al. (2025) found both mitragynine and 7-OH were inhibitors of
CYP2D6 and CYP3A4, though neither were found to be P-glycoprotein substrates,
which minimizes the risk of efflux-related bioavailability issues. Both studies confirm the
potential for significant drug-drug interactions with other substances that are substrates,
inhibitors, or inducers of these systems. These should be considered preliminary
findings and not necessarily related to abuse potential or safety but provide an example
of other research that involves 7-OH and other mitragynine related substances.
While Akbar et al. (2025)’s Absorption, Distribution, Metabolism, Excretion, and Toxicity
analysis found that both mitragynine and 7-OH demonstrated high gastrointestinal (GI)
absorption, suggesting high oral bioavailability (also a conclusion by Chakraborty,
Uprety, et al. (2021), a study in rats reported a low oral bioavailability of only 2.7%,
possibly due to poor water solubility, indicating that formulation and species differences
may significantly impact absorption (Chiang et al., 2025).
A recent case report that has been accepted for publication at the time of this writing
described a patient admitted to a hospital emergency department following "cardio-
pulmonary arrest”. He was found unresponsive and received approximately 10 min of
cardiopulmonary resuscitation; he was successfully revived with two doses of naloxone
4mg intravenously." The patient reported ongoing use of other substances that may
have contributed to this event, as well having ingested several times the recommended
serving size labeled on the 7-OH product. Thus, whereas causality cannot be
definitively determined beyond a likely poly-pharmaceutical contribution is not clear, the
responsiveness to naloxone suggests that 7-OH’s opioid receptor-mediated activity may
have played a role, particularly since no other conventionally screened 'opiates' were
detected in the blood (Pullman, Kanumuri, Leon et al. 2025).
4.2 Mitragynine Pseudoindoxyl
Kamble et al. (2020) further discovered that 7-OH is itself converted to mitragynine
pseudoindoxyl in human plasma, and to a greater extent than is produced in mice, rats,
dogs, and cynomolgus monkeys, possibly explaining potential human effects that may
not be predicted in animal studies alone. Mitragynine pseudoindoxyl’s effects, however,
are still mostly unclear; for instance while 7-OH-MG and mitragynine have shown
significant conditioned place preference (Section 2.2.4), mitragynine pseudoindoxyl did
not (Chakraborty, DiBerto, et al., 2021).
4.3 Conclusions
The available evidence shows that 7-OH is a potent, orally bioavailable, µ-opioid partial
agonist with a G-protein bias that can accumulate in the body upon daily and/or chronic
use. Its metabolism is heavily dependent on the CYP3A4 enzyme processes. Its
complex pharmacology, involving interactions with multiple opioid receptor subtypes
and other neurotransmitter systems, underlies its opioid-like effects, including analgesia,
euphoria, and sedation, as well as its potential for abuse and dependence.
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5 Factors 4, 5, and 6: History and Current Patterns of Abuse; The
Scope, Significance and Duration of Abuse; What, if any, Risk is
there to the Public Health
5.1 Factor 4: History and Current Patterns of Abuse
The marketing and apparent sales and consumption of 7-OH have increased rapidly
since about 2022, and 7-OH has progressed over the past several years from a minor,
little known alkaloid with little to no independent history of use to a commercially
available, highly concentrated product at the center of what FDA deems an “emerging
public health threat”. This has been driven in part by growing awareness of its
potentially potent opioid pharmacology though current use patterns (as gleaned from
national surveys, surveillance systems, and online user communities) reveal a user
base with diverse motivations. However, these data sources also highlight an escalating
pattern of high-dose use of concentrated products that is associated with dependence,
withdrawal, and other adverse outcomes.
Traditional use of kratom in Southeast Asia, which involves chewing fresh leaves or
brewing them into tea, results in ingestion of only trace amounts of 7-OH. The primary
psychoactive effects from traditional kratom preparations are attributed primarily to its
most abundant alkaloid mitragynine and the complex interactions of the many other
alkaloids in the plant leaves. The market for kratom began to rapidly evolve with the rise
of its popularity in the U.S. in the mid-2000s, though use likely dates back as early as
the 1980s, brought back by American veterans returning from Southeast Asia and
immigrants from those areas. Consumer demand for alternative kratom products,
combined with scientific and manufacturing resources and innovation from American
entrepreneurs led to explosive growth in the number of kratom extracts and other
products artificially enhanced with non-natural amounts of kratom alkaloids and/or other
substances.
A pivotal shift occurred with the proliferation of products specifically marketed as “7-OH”
products. These products often contain artificially elevated levels of 7-OH, often created
through synthetic or semi-synthetic means, such as chemical oxidation of mitragynine,
which is much more readily abundant naturally and economically viable than isolating
from kratom leaves.
Analysis of these commercial products revealed concentrations of 7-OH that are
hundreds of times higher than would be expected in natural kratom leaf. For example,
one analysis reported that 7 of 8 products tested contained 109-509% more 7-OH than
would be expected in a natural product (Ogozalek, 2023), and news reports identified
pill products containing 15 mg of 7-OH per pill, a dose far exceeding natural levels and
one that is likely pharmacologically significant. This is in contrast to an analysis of 13
commercial kratom products, which found 7-OH at 0.01-0.04% by weight, aligning with
reports that 7-OH represents less than 0.05% of the alkaloid content, substantially lower
than mitragynine. This indicates that naturally occurring levels of 7-OH in kratom are
minimal compared to the primary alkaloid (Kikura-Hanajiri et al., 2009; Kruegel et al.,
2019). These 7-OH products are now readily available online and in retail locations such
as gas stations, vape shops, convenience stores, and corner shops, often in a vast
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array of formulations like gummies, tablets, and liquid shots (Hill, Henderson, et al.,
2025).
5.1.1 Reasons for Use
While national surveys like the National Survey on Drug Use and Health (NSDUH) track
kratom use, they do not yet specifically distinguish users of traditional kratom from users
of concentrated 7-OH products. General kratom user demographics from the 2019
NSDUH and other surveys indicate that users are generally somewhat more male than
female users, with most identifying as “White” or Caucasian, and between the ages of
18 and 49, though results vary widely. The most recent largescale kratom survey at this
writing reported the majority of kratom users were males between 30-49 years old who
identify as Caucasian (Grundmann et al., 2025). There is evidence that kratom users
are generally older, often reporting reasons for use related to potential therapeutic
effects (relief of common pain symptoms, elevating energy); there is little evidence of
youth use.
However, none of these surveys addressed people who are primarily 7-OH consumers,
a critical area in need of research. Thus, extrapolations from kratom-focused surveys
are not necessarily representative. This caveat applies to reasons for use as well,
although some anecdotal data described below suggest that at least some 7-OH users
are people who found it to be more effective or satisfying than kratom for pain and self-
management of their opioid use disorder and/or opioid withdrawal.
Those who use kratom and 7-OH report a diverse range of motivations, including for
therapeutic or self-medication purposes, such as for pain relief, anxiety, and depression.
A significant portion of users, particularly those with a history of opioid use, report using
kratom to address opioid withdrawal symptoms or as a substitute for more dangerous
illicit opioids. Additionally, current opioid users were more likely to report use kratom for
opioid withdrawal, while former opioid users were more likely to report mood elevation
as their reason for use (Singh et al., 2020).
The emergence of concentrated 7-OH products appears to be attracting both existing
kratom users and new consumers. Analysis of Reddit discussions reveals two primary
user groups for 7-OH: individuals seeking potent relief for chronic pain, and individuals
seeking strong, opioid-like recreational effects. For example, one Reddit user in a
chronic pain forum reported using 7-OH for pain management, often at lower daily
doses (e.g., 11 mg/day) without reporting significant adverse effects. In contrast,
discussions in subreddits focused on substance use and quitting kratom describe
patterns of high-dose, frequent use for euphoric effects, leading to rapid development of
dependence and severe withdrawal. This bifurcation suggests that the availability of a
more potent, isolated compound is creating distinct patterns of use and risk profiles
compared to traditional kratom.
5.1.2 Dosing, Routes of Administration, and Trajectory of Use
Information from online user reports provides detailed, albeit anecdotal, data on current
use patterns for 7-OH products. An analysis of 6 Erowid experience reports found a
median oral dose of 13.5 mg (range 6.9 mg - 16.9 mg), with a maximum reported dose
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of 120 mg. Most reports described oral administration of pills, capsules, or tablets,
though sublingual and insufflation (snorting) routes were also mentioned.
A concerning pattern emerging from these reports is the trajectory of use. While some
reports describe single-dose experiences, a significant portion describe daily use,
escalating over periods from a few days to several months. Reddit users in the “Quitting
Kratom” subreddit describe daily use, sometimes up to 5× per day, with doses
associated with withdrawal symptoms ranging from 30 mg/day to as high as 500
mg/day. This pattern of escalating, high-frequency dosing is a classic hallmark of
substance use disorders and is consistent with the development of tolerance to 7-OH's
effects. The availability of 7-OH in discrete, high-dose units like pills and liquid shots
facilitates this pattern of use in a way that traditional kratom use (i.e., consuming dried
kratom leaf powder) does not.
5.2 Factor 5: Scope, Duration, and Significance of Abuse
National surveillance systems in the U.S. have in recent years begun tracking use of
kratom; however, the majority of these systems have yet to track data as it relates to 7-
OH use, and attempts at analysis with current data are complicated by these systems
combining 7-OH and kratom cases as one category. However, recent efforts to monitor
7-OH specifically, combined with analyses of existing data, reveal concerning signals of
increasing human exposure and associated risk as discussed by FDA (Reissig et al.
2025) and in this Factor. The scope of use appears to be significant and growing,
marked by a sharp increase in incidents beginning in late 2023 and continuing through
2025.
Adding to the domestic data, the UNODC has noted that since 2024, the U.S. and other
jurisdictions worldwide have reported toxicology cases involving high-concentration 7-
OH products to its Early Warning Advisory on New Psychoactive Substances (UNODC,
2025).
See further discussion relevant to scope and significance in Factors 4 and 6.
5.2.1 National Surveillance Systems
5.2.1.1 FAERS
FAERS reports involving 7-OH were identified through searches of the FAERS Public
Dashboard and open FDA using the term “7-Hydroxymitragynine,” limited to cases in
which 7-OH was designated as the primary suspect drug. No date restrictions or
deduplication procedures were applied. The two sources largely overlapped, though 2
cases appeared exclusively in the Public Dashboard. In total, 14 unique cases were
identified. Corresponding data were extracted from open FDA and qualitatively
reviewed. A summary of findings is presented below.
The 14 FAERS case reports involving 7-OH primarily describe patterns of dependence,
withdrawal, and psychiatric disturbances. Across patients ranging from their early 20s to
mid-60s, reactions commonly included drug dependence, withdrawal syndrome,
depression, anxiety, insomnia, somnolence, and impaired quality of life. Several cases
noted GI complaints (e.g., nausea, vomiting, diarrhea, constipation), neurological issues
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(e.g., dyskinesia, memory problems, dizziness), or musculoskeletal symptoms (e.g.,
myalgia, restless legs). Some patients reported product quality concerns or suspected
tampering, suggesting variability in supply or formulation. Many cases involved
concomitant use of prescription medications (e.g., clonidine, gabapentin,
antidepressants, Suboxone, benzodiazepines) or other herbal mitragynine products,
complicating causality assessments.
Importantly, 2 fatal cases associated with 7-OH consumption were recorded: one
involving toxicity from multiple agents including opioids and mitragynine in a 38-year-old
male, and another describing accidental poisoning and respiratory depression in
association with polypharmacy (including citalopram, lamotrigine, and zopiclone) in a
male from Norway. These highlight potential risks of combining 7-OH with other CNS-
active substances. Overall, the data remain sparse but suggest that 7-OH is more
frequently linked to dependence, withdrawal, psychiatric symptoms, and – in rare but
severe cases – fatal outcomes, warranting continued monitoring and further
investigation.
5.2.1.2 National Poison Data System
Between February 1, 2025 and April 30, 2025, the National Poison Data System
(NPDS) recorded 53 closed human exposure cases involving 7-OH (Table 1). Of these,
24 were classified as abuse cases, and 37 involved single-substance exposures,
including 16 single-substance abuse cases. The most common reasons for exposure
were intentional abuse (24 cases, 16 single-substance), withdrawal-related use (8
cases, 6 single-substance), and unintentional general exposure (4 cases, all single-
substance). Smaller numbers were attributed to suspected suicide (2 cases), adverse
drug reactions (4 cases), misuse (3 total cases), therapeutic error (4 cases), and
unknown reasons (2 cases).
Most reported clinical effects were moderate (13 cases, 6 single-substance) or minor (6
cases, 3 single-substance), with 3 major outcomes (including 1 single-substance). Five
cases were judged as having minimal effects, and one was considered a potentially
toxic exposure but could not be followed.
Age distribution showed that the majority of cases occurred in adults (≥18 years; 46
cases, including 23 abuse cases and 32 single-substance exposures), while 6 cases
involved individuals under 18, and 1 case had unknown age.
Table 1. National Poison Data System Closed Human Exposure Casesa
(01Feb2025-30Apr2025)
Number of
Exposure
Casesb
Number of
Abuse Casesc
Single
Substance
Exposure
Cases
Single
Substance
Abuse Cases
Total cases involving 7-OH 53 24 37 16
Reason
Page 23 of 128
Number of
Exposure
Casesb
Number of
Abuse Casesc
Single
Substance
Exposure
Cases
Single
Substance
Abuse Cases
Adverse drug reaction 4 2
Intentional- abuse 24 16
Intentional- misuse 4 3
Intentional- suspected suicide 2 0
Other- withdrawal 8 6
Unintentional- general 4 4
Unintentional- misuse 1 1
Unintentional therapeutic error 4 3
Unknown reason 2 2
Related Clinical Outcomes
Minor 6 3
Moderate 13 6
Major 3 1
Note followed, minimal clinical
effects possible 5 3
Unable to follow, judged as
potentially toxic exposure 1 0
Age
< 18 years 6 1 5 0
≤ 18 years 46 23 32 16
Unknown age 1 0 0 0
Abbreviations: 7-OH = 7-hydroxymitragynine; NPDS = National Poison Data System.
Note: Related clinical outcomes includes cases with clinical effects deemed “related” to exposure based
on timing, severity, and assessment of clinical effects by Poison Center Specialists. Definitions available
from America’s Poison Centers: NPDS Full Report 2023 (Gummin et al., 2024, p. 235).
a Excludes cases classified as ‘confirmed non-exposure’.
b Cases may involve other substances, besides 7-OH.
Source: Adapted from NPDS dataset.
5.2.1.3 National Forensic Laboratory Information System (NFLIS)
The National Forensic Laboratory Information System (NFLIS) collects drug
identification results obtained during law enforcement investigations involving potential
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criminal possession and distribution of illicit drugs and substance seizures collected
during those operations. Historically, mitragynine has never reached the threshold to be
listed among the top 25 most frequently identified drugs, though it has appeared in
lower-level reports. Mitragynine has not been reported in annual NFLIS reports because
its levels have been relatively stable and low since about 2015. However, data can be
obtained from the NFLIS Public Data Query System. As of August 2025, data from the
NFLIS Public Data Query System showed 253 mitragynine drug reports in 2024, but
specific data for 7-OH seizures are not yet separately reported in publicly available
annual summaries. The lack of 7-OH specific data in law enforcement seizure reports
represents an important current gap in surveillance.
5.2.1.4 DEA Toxicology Testing Program (DEA TOX)
The DEA TOX program analyzes toxicological evidence from death investigations.
Between 2019 and 2025, 103 cases were identified where mitragynine, 7-OH, or
mitragynine pseudoindoxyl were detected. A significant limitation of this data is the
difficulty in discerning whether deaths are related to one specific alkaloid, as 7-OH is a
metabolite of mitragynine. However, the report notes a trend: the number of fatal
overdose cases in which one or more of these substances were detected was
approximately 3-fold higher for the years 2023 to 2025 compared to the period from
2019 through 2022. This increase coincides directly with the recent market entry of
concentrated 7-OH products, suggesting a strong temporal association between the
availability of these new products and fatal outcomes.
It is important to note that many reported kratom-associated deaths involve toxic levels
of other substances, and many lack the comprehensive toxicological testing needed to
confirm a causal role for either mitragynine or 7-OH. Kratom products may also be
present at opioid-related fatalities because they are often used to manage opioid use
disorder or withdrawal. Additionally, routine toxicology screens may miss novel
psychoactive substances, such as designer opioids or benzodiazepines, requiring more
specialized and costly testing (Henningfield, Grundmann, Huestis, and Smith, 2024)
5.2.1.5 Other National Surveillance Data
Two important national surveillance systems that monitor substance use trends,
NSDUH and the proprietary Researched Abuse, Diversion and Addiction-Related
Surveillance (RADARS) (which also receives federal funding), have included “kratom”
as a tracked substance” but have not differentiated traditional kratom products from
concentrated 7-OH products. NSDUH provides prevalence estimates for kratom use
(0.6% past-year use in 2024) but does not yet differentiate 7-OH use. As a result, their
reported “kratom” data likely represent a combined population of kratom users and
those using 7-OH products, a segment that appears to have emerged and grown rapidly
in recent years. A further challenge in these surveillance efforts is that some individuals
who use 7-OH may continue to report their past or current use simply as “kratom”, even
when the product in question would more accurately be classified as a 7-OH product.
These two surveillance systems also likely underestimate kratom use overall, possibly
due to their survey designs and sampling approaches that primarily target major illicit
and prescription drug use (see discussion in Henningfield, Grundmann, et al. (2022).
These Kratom focused reports suggested estimates of approximately 1.7 to 2.0 million
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past-year kratom consumers from 2019–2021 (Palamar, 2021; SAMHSA, 2023, 2024),
with an estimated lifetime prevalence at 3.4 million based on 2018–2019 data
(Schimmel, & Dart, 2020).
Other major surveillance systems, such as the Drug Abuse Warning Network (DAWN),
which tracks drug-related emergency department visits, and the Treatment Episodes
Data Set (TEDS), have not yet reported specific data for 7-OH, though the “New
DAWN” system recently identified “7-OH” as a new slang term to monitor.
A more recent nationally representative survey suggests past 30 day (‘current use’)
prevalence suggests potentially more than 20 million kratom users ages 18 and older
(Grundmann et al., 2025).The recency of this survey conducted in 2024 makes it likely
that some respondents were actually primary 7-OH users, possibly contributing to the
larger estimated population of kratom consumption in earlier surveys.
Similarly, it is possible if not plausible that some fraction of adverse events reported to
FDA’s Adverse Event Reporting System, to the poison control centers, and possibly
deaths associated with kratom consumption involved consumption of 7-OH products in
addition to or in place of kratom products that do not contain artificially boosted or high
concentrations of 7-OH. This conclusion is consistent with the following observations by
FDA in its Reissig-led scientific evaluation (Reissig et al., 2025):
“Available surveillance data indicate that abuse of 7-OH is occurring and is
associated with serious harms; however, as noted previously, it is difficult to
quantify the public health burden because surveillance systems do not provide
estimates for the prevalence of 7-OH use and are only beginning to track the
specific involvement of 7-OH enhanced products in exposure cases and
overdoses. The current epidemiologic data on 7-OH exposures often lack
sufficient detail to distinguish with confidence involvement of botanical kratom
products from 7-OH enhanced products.” (Reissig et al., 2025, p. 14)
And in its Conclusions section:
“Due to the fact that 7-OH is both a metabolite of mitragynine and naturally
present in low amounts in botanical kratom, using toxicology results to identify 7-
OH as a primary or sole contributor in human exposures is challenging. There is
also a need for improved clinical awareness and population surveillance to better
characterize patterns of 7-OH use, the products that people are obtaining, and
individual treatment needs following 7-OH exposure. Additionally, questions on 7-
OH are not generally included in national surveys, and other data sources that
rely on self-reported use of 7-OH likely underestimate the number of 7-OH
exposure cases, as individuals may be unaware of the distinction from kratom
products. Nonetheless, since specific codes were added earlier this year to
document 7-OH exposure cases, U.S. poison centers have identified multiple
single-substance cases of 7-OH exposure resulting in serious adverse clinical
outcomes.” (Reissig et al., 2025, p. 18)
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The foregoing observations of this report and those of Reissig et al. above are
consistent with recent conclusions and evaluations by other experts which suggest that
some fraction of the adverse events and possibly deaths that have been reported and or
interpreted as involving or even caused by kratom, were actually more likely attributable
to the consumption of 7-OH products in addition to or in place of kratom (Grundmann et
al., 2024; Hill, Boyer, et al., 2025; Papsun et al., 2023; Smith et al., 2025; Vadiei, Evoy,
& Grundmann, 2025).
Taken together, the foregoing observations support the conclusion that it is urgent to
add 7-OH to relevant substance surveillance systems including NSDUH, RADARS,
FAERS, and poison control. Similarly, assessment of 7-OH in blood plasma in forensic
toxicology examinations as well as kratom research in general is a critical need.
It is beyond the scope of this report to specify how surveillance systems should be
designed to distinguish between kratom products and those containing 7-OH, including
the precise wording of survey questions or the analytical methods to detect 7-OH.
These should be developed with input from appropriate experts and stakeholders,
ideally with a fast-track approach with a proposal from FDA and request for comments.
A public meeting for comment convened by FDA, ideally with NIDA and DEA
involvement may also help to ensure that the approaches to surveillance and biological
assessment will be scientifically reliable, valid, and relevant to the emerging
marketplace, regardless of whether or not 7-OH is ultimately scheduled.
5.2.2 Published Case Reports
Published case reports provide clinical evidence recorded and reported by trained
healthcare professionals; however, these accounts are considered anecdotal and may
not be representative of common experiences.
A case report by Wightman and Hu (2025) detailed the experience of a 38-year-old man
with a history of opioid use disorder who escalated his use from kratom to concentrated
7-OH products, consuming up to eight 30 mg tablets daily. Upon stopping, he
experienced a clear opioid withdrawal syndrome, with a peak Clinical Opiate Withdrawal
Scale (i.e., COWS) score of 14. His symptoms, which included anxiety, insomnia, and
restlessness, were successfully managed with buprenorphine during an inpatient stay.
Another case report described a 31-year-old who suffered severe substance-induced
psychosis involving both kratom and cannabis, which resulted in self-amputation of his
ears and penis (Broul et al., 2025).
5.2.3 Social Media Discussion
To investigate online sources of discussion around 7-OH, the search terms “7-OH”, “7-
OH-MG”, “7-OH-MIT”, and “7-Hydroxymitragynine” were included in a boolean search of
Erowid (erowid.org) using the Google search term “7-OH OR 7-OH-MG OR 7-OH-MIT
OR 7-Hydroxymitragynine site:erowid.org”, and of Reddit (reddit.com) using the Google
search term “7-OH OR 7-OH-MG OR 7-OH-MIT OR 7-Hydroxymitragynine
site:reddit.com”. The searches were completed in August 2025.
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Six experience reports in the Erowid vault were found. Where provided, information on
sex, age, body mass index, dose, route of administration, formulation, duration, and
effects were recorded. Most (3/5 experience reports with dates) were recent (i.e., since
2024). The remaining 2 experience reports with dates described experiences from more
than a decade ago (2007-2010). One experience report did not report its date.
In terms of demographics, all 6 reports came from males aged 22 years to 39 years
(i.e., younger adults). Across these 6 experiences, the median dose was 13.5 mg
(interquartile range [IQR]: 6.9 mg – 16.9 mg) or 0.15 mg/kg body mass (IQR: 0.09
mg/kg – 0.19 mg). The maximum dose was 120 mg or 1.5 mg/kg. Two reports (33%)
described single-dose experiences, 2 reports (33%) described daily use for 2 days, and
2 reports (33%) described longer-term, daily use from 2 weeks to 6 months. The
majority (67% of reports) described oral administration of 7-OH, while the remaining
reports described sublingual administration (n=1; 17%) and insufflation (n=1; 17%). The
majority (67% of reports) described pill/capsule/tablet formulations, while the remaining
2 (33%) described tincture/liquid formulations. Experiences lasted from 3-6 hours.
Only one report described concomitant substances, namely cannabis (smoked), though
this does not necessarily mean that no other substances were taken. Effects included
euphoria (83% of reports), cravings (50%), increased heart rate (33%), itch (33%),
tiredness, lethargy, or sedation (33%), constipation (17%), self-reported “withdrawal”
(17%), body shakes (17%), numbness (17%), weightlessness (17%), sick feeling (17%),
feeling of relaxation (17%), aphrodisia (17%), analgesia (17%), loss of balance (17%),
visual distortion (17%), and most significantly, hospitalization (17%) and self-reported
“respiratory depression” (17%).
The following review of Reddit posts and comments on 7-OH is non-exhaustive. On
Reddit, 7-OH was discussed in the Quitting Kratom subreddit
(www.reddit.com/r/quittingkratom). Reddit posts and comments were much less
descriptive than Erowid experience reports making inferences difficult. Nevertheless, a
number of Reddit users reported using or formerly using kratom and being offered 7-
OH, sometimes for free, from stores where they would typically purchase kratom. Most
users who reported 7-OH use reported pill/capsule/tablet forms; tinctures/liquid
formulations were relatively rare. Most posts reported daily use, up to 5 × daily, with use
duration from 5 days to 8 months. Some users attempted to dissuade others from 7-OH
use. Effects were consistent with Erowid experience reports, including euphoria,
withdrawal, anxiety, insomnia, restlessness, involuntary arm and leg movement,
abdominal pain, vomiting, body shakes, tightness in chest, tachycardia, diarrhoea,
fatigue, sedation, dizziness, paranoia, anhedonia, kidney pain, and 1 case of
hospitalization. Some Reddit users compared the severity of withdrawal from 7-OH to
other substances; these included “worse than how I was with the oxy withdrawal” and
“50% as bad as Fentanyl withdrawal”. Some Reddit users described stopping 7-OH use
“cold turkey”, or using kratom or other substances including suboxone to “taper off” of 7-
OH. Many posts and comments were missing data on dose. Among comments
reporting withdrawal symptoms and dose, these ranged from 30 mg/day to 500 mg/day.
Many posts and comments were missing data on dose. Among comments reporting
withdrawal symptoms and dose, these ranged from 30 mg/day to 500 mg/day. Many
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posts and comments were missing data on dose. Among comments reporting
withdrawal symptoms and dose, these ranged from 30 mg/day to 500 mg/day.
7-OH was also discussed by a number of Reddit users in the Chronic Pain subreddit
(https://www.reddit.com/r/ChronicPain) who reported using 7-OH for chronic pain
management. Only one Reddit user discussing 7-OH for chronic pain reported dose;
they reported taking 5.5 mg tablets twice daily (11 mg/day) and did not report adverse
effects or withdrawal or withdrawal. This is lower than the doses reported by Reddit
users experiencing withdrawal.
To quantify interest in 7-OH over time, Google Trends was used. Google search interest
(i.e., the relative volume of Google searches) for “7-OH”, “7-OH-MG”, “7-OH-MIT”, and
“7-Hydroxymitragynine” was extracted (Figure 1). Search interest in these search terms
was zero from 2004 through 2010. Beginning in 2011, minimal search interest in “7-OH”
and “7-Hydroxymitragynine” began, staying low through the end of 2023. Beginning in
2024 however, search interest in “7-OH” and “7-Hydroxymitragynine” grew rapidly,
peaking in August 2025 shortly after FDA announced action on 7-OH products, which
are the latest available data; search interest may continue to rise in the months
following August 2025. Search interest in “7-OH-MIT” and “7-OH-MG” remained
negligibly low throughout.
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Figure 1. Google Search Interest in 7-OH-Related Search Terms
Note: 7-OH-mitragynine may be referred to by the short-hand versions “7-OH”, “7-OH-MIT”, or “7-OH-MG”.
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There are many websites that focus specifically on drug misuse and abuse, some
intended to discourage such use as well as those that appear dedicated to providing
information in support of, if not to encourage, misuse and abuse of drugs. Many of the
kratom-related postings involve what appear to be extremely high dosages of kratom
substances and extracts, and self-made extracts from a variety of kratom sources. For
example, users may combine several grams of kratom powder, several ounces of
kratom leaves, and indeterminate forms of this or other substances. Some people have
reported experiencing intoxication, euphoria, and other effects at these very high
dosages, though typically their comparisons to other drugs provide a basis for
understanding why kratom and kratom products apparently are rarely the substance of
choice among people who seek abused drugs and are in search of better ways to get
better highs and euphoria. There are self-reports of dependence and withdrawal, but
these tended to involve extremely high intakes of kratom, apparently along with other
substances.
5.3 Factor 6: What, if any, Risk is there to the Public Health
Factor 6 requires an integrated assessment of the overall risk a substance poses to
public health. This involves synthesizing the pharmacological data on its intrinsic
pharmacological risks (Factor 2), its potential for abuse and dependence (Factors 1 and
7), and the real-world evidence of its harm (Factors 4 and 5). For 7-OH, the available
data indicate a potential risk to public health, which has led the FDA to conclude that it
is a “dangerous substance” that poses an “emerging public health threat” and an
“imminent hazard”. This risk is fundamentally driven by the substance's potent opioid
pharmacology, exacerbated by its increasing availability in highly concentrated,
unregulated products.
Evaluation of Factor 6 can include individual and public health benefits evidence as well
because real and perceived benefits can contribute to evaluating FDA approved
pharmaceuticals as well as substances that have not been approved for therapeutic use
(Henningfield, Coe, et al., 2022; Henningfield et al., 2025).
FDA’s July 29, 2025 summary of the science (Reissig et al., 2025) and other FDA
documents release on July 29 made clear the concerns of FDA and the DHHS have
about the risks of 7-OH. In FDA’s July 29, 2025 educational slide set “Preventing the
Next Wave of the Opioid Epidemic: What You Need to Know about 7-OH (FDA,
2025b), the second slide depicted four waves of the opioid crisis of approximately equal
size and shape. These were labeled “prescription pills”, “heroin”, “fentanyl”, and “7-OH’,
respectively. While the conclusion that 7-OH presents a potential and imminent public
health risk necessitating regulatory attention is supported, caution is warranted against
overstating the overdose risk, particularly given the likelihood of misinterpretation by the
public and media when hearing references to 7-OH as “more potent than morphine”,
even though the term “overdose” is not used in the figure.
Despite evidence suggesting thousands of individuals are currently using 7-OH –
including some who appear to be consuming highly concentrated preparations and
substantial total doses – the documented incidence of fatalities directly attributable to 7-
OH remains very low. Even if, as FDA has suggested, 7-OH-related deaths are
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underreported, it is notable that such cases appear to be rare. This low apparent
lethality may be explained by two key factors: first, the predominant route of
administration among users is oral rather than intravenous; and second, 7-OH exhibits
the pharmacological profile of a partial MOR agonist by several measures, as discussed
in Factor 2.
The available evidence indicates that 7-OH may indeed pose a “risk to public health” or
a “national drug threat”, thereby warranting regulatory attention and interventions as
discussed in Factors 4 and 5 and below. However, it remains uncertain whether 7-OH
poses a population-level overdose risk comparable to that of other opioids. This
uncertainty does not diminish the case for control measures; this report concurs that
such measures – including potential scheduling under the CSA – are justified. However,
it is important to recognize that some individuals report using 7-OH as their preferred
and/or most effective alternative to opioids known to carry high risks of fatal overdose,
or as a means of self-managing other serious disorders. Considering this population
should inform any policy approaches, particularly those involving criminal penalties for
possession if 7-OH is placed in Schedule I, as discussed in the policy section of this
report.
5.3.1 Pharmacological Risks
The primary risk inherent to 7-OH is its potent activity at the MOR, which mediates not
only its abuse-related effects but also its most dangerous potential adverse effect:
respiratory depression. As reported by Gonzalez et al. (2025), 7-OH produces dose-
dependent respiratory depression that is reversible with naloxone, a classic feature of
opioid toxicity. While some research suggests its G-protein bias and lack of measurable
β-arrestin-2 recruitment may confer a degree of safety relative to classical opioids at
equianalgesic doses, this risk may preclude 7-OH to be marketed as a dietary
ingredient to be used in supplements regardless of whether it is placed in Schedule I.
5.3.2 Abuse, Dependence, and Withdrawal Risk
While the abuse-related risk of 7-OH is primarily attributed to its effects at the MOR
receptors, its pharmacology is not identical to that of classical opioids that are primarily
active at the MOR (Factor 2). The FDA's 2025 assessment states that 7-OH produces
“physical dependence, and withdrawal symptoms characteristic of classical opioids” and
notes that clinical presentations include “opioid-like withdrawal syndromes” (Reissig et
al., 2025). This is supported by published case reports in the medical literature, with
reports of symptoms associated with opioid withdrawal including anxiety, insomnia,
rhinorrhea, abdominal discomfort, restlessness, diaphoresis, and chills that were
successfully managed with buprenorphine, a standard treatment for opioid withdrawal
and dependence (Wightman, & Hu, 2025). However, these preliminary findings merit
further study.
As evidenced by user reports, the availability of potent products with concentrations of
7-OH that is far higher than is found naturally may be facilitating patterns of chronic,
escalating dose use that can lead to dependence, withdrawal, and other symptoms
associated with drugs of abuse. The consequences of this include not only the direct
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risk of harm from the substance itself but also the broader medical, psychological, and
social harms associated with addiction.
The opioid-like withdrawal syndromes associated with 7-OH dependence presents
another risk. Individuals attempting cessation may experience physical and
psychological symptoms, which can be detrimental to their work and personal lives, a
major barrier to recovery, and a cause to relapse. In some cases, individuals may
require medically supervised withdrawal and medication-assisted treatment (e.g., with
buprenorphine), placing additional burden on the healthcare system.
5.3.3 Potential Benefits to Consumers and Public Health
Anecdotal reports in public media and other sources indicate that some 7-OH users
perceive it to be more effective, acceptable, or accessible than FDA approved
medicines, kratom, or other approaches for their conditions. Similar conclusions for
kratom were reached in 2016 (Henningfield and Fant, 2016), and in subsequent
analyses (Giroir, 2018; UNODC, 2021). Consequently, removal of 7-OH from the licit
marketplace without simultaneously ensuring the availability of viable accessible
alternatives carries the risks of unintended consequences. These include the risk that
current 7-OH consumers may relapse to potentially deadlier opioid use, as well as the
likely emergence of an illicit market in which 7-OH products would proliferate without the
quality standards that some 7-OH makers and marketers appear to voluntarily adhere.
An illicit 7-OH market also raises the potential, if not likelihood, of 7-OH products being
replaced or adulterated with fentanyl related substances. While 7-OH’s potential
benefits do not necessarily affect whether substances or products should be scheduled,
these issues should be considered in how scheduling actions are implemented to
minimize unintended individual and public health consequences.
5.4 Implications
The widespread use of highly concentrated 7-OH products is a relatively new
phenomenon in the U.S., but it appears to be growing rapidly. Since about 2022, data
from surveillance systems and user reports from social media, surveys, and case
studies provide valuable insights into the patterns of 7-OH use, with users reporting that
they are using it for pain management, to self-treat opioid withdrawal, and for
recreational purposes. Data from America's Poison Centers also indicate a growing
public health problem, with a rising number of exposure cases involving 7-OH and
serious health effects. The FDA has also issued warnings about the public health risks
associated with 7-OH, citing the high concentrations of the substance in some products
and the lack of regulation and quality control.
It is important to note that 7-OH associated outcomes, both at the individual and
population levels, have likely been underreported and instead attributed broadly to
“kratom”. This underestimation arises because current surveillance methodology does
not distinguish 7-OH products from traditional kratom preparations, instead aggregating
them into a single “kratom” category. This problem is exacerbated by marketing and
labeling of many 7-OH products as “kratom” or “kratom derived” with implied safety
statements based on studies of kratom and its far more widely studied naturally
occurring constituent, mitragynine.
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Despite limitations, it is clear that 7-OH is becoming more of a concern and priority for
regulatory, law enforcement, and surveillance authorities. Available evidence suggests
that there are signals of meaningful real-world nonmedical use and abuse with
potentially significant medical outcomes, such as dependence, withdrawal, and
development of substance use disorder. However, it is still not clear the severity of the
risk posed to the public health by 7-OH. While surveillance systems are capturing an
increasing number of cases regarding kratom, this coincides with a rapidly growing
kratom market with some estimates suggesting the total market size to be 1-1.5 billion
USD. Presumably, a proportion of these cases are due to consumption of concentrated
7-OH products, as many of these cases have been included as “kratom” cases, though
this figure is unclear based on current surveillance capabilities.
For example, the 44th WHO Expert Committee on Drug Dependence (ECDD) reviewed
the available evidence on kratom and its alkaloids in 2020 (UNODC, 2021). It concluded
that there was insufficient evidence to recommend a critical review of these substances.
However, the committee also noted the increasing availability of concentrated kratom
products and the potential for these products to pose a public health risk. The UNODC
has also issued an announcement about new kratom-related products, expressing
concern about their potential health effects. However, this report was focused on kratom
plant products and extracts and mitragynine studies and not the subcategory of high-
concentration 7-OH products, which had not yet emerged as a significant or substantial
category of product in the U.S. or globally.
It is critical to characterize the relative risk of 7-OH to that of kratom products that are
consistent with the natural constitution of the kratom plant, and to classical drugs of
abuse. Despite a growing kratom market, there have been few signals of risk to the
public health from natural kratom products, and a number of reports and surveys
showing consumers using them for therapeutic purposes (Grundmann et al., 2022;
Smith, & Lawson, 2017). FDA in its 2018 determination to rescind the recommendation
for CSA control of mitragynine and 7-OH cited a “potentially substantial risk to public
health if these chemicals were scheduled at this time” due to potential adverse
consequences if kratom is no longer available for people using for symptoms such as
intractable pain, psychological distress, risk for suicide, transition from opioids or other
potential or harmful drugs (Giroir, 2018). Similarly, reported use of 7-OH includes
consumers and patients using for therapeutic purposes, and who may suffer unintended
adverse consequences from its sudden removal from the market. Given its distinct risk
profile, especially in the context of highly concentrated 7-OH products, careful
surveillance and research are necessary and warranted including but not limited to
studying 7-OH using accepted FDA toxicological standards (e.g., through NIH funded
research or through development as an FDA approved drug).
6 Factor 7: The Psychic or Physiological Dependence Liability
As discussed in Factor 1 and elsewhere, this report agrees with FDA regarding the
evidence that some 7-OH consumers can become psychologically and physically
dependent and develop substance use and withdrawal disorders, respectively.
However, the level of risk and an evidence-based characterization of 7-OH dependency,
use disorder, or withdrawal has received little study and more research is warranted,
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regardless of the scheduling action and approach. The existing data are likely to be
considered insufficient to conclude at present that the 7-OH withdrawal syndrome is
sufficiently similar to classical opioids to warrant inclusion in a diagnostic manual.
7 Factor 8: Whether the Substance is an Immediate Precursor of a
Substance Already Controlled
It is important to note that 7-OH does not meet the prototypical criteria of Factor 8 as an
immediate precursor of a substance already controlled as it is neither an immediate
precursor of a substance already controlled, nor is it an opioid based on its botanical
origin or chemical structure. It is not an immediate chemical precursor used in the
synthesis of any currently controlled substance. Furthermore, 7-OH is a metabolite of
mitragynine, a naturally occurring alkaloid from the Mitragyna speciosa plant, which is
botanically unrelated to the opium poppy (Papaver somniferum). Therefore, it is not an
opiate derived by extraction or chemical synthesis from opium or its constituents, such
as morphine or thebaine.
However, the CSA includes a provision (21 U.S.C. § 802(18)) that guides determination
of whether a substance can be determined to be sufficiently pharmacologically
equivalent to morphine with respect to key effects related to “addiction liability” to be
designated and regulated as an opioid. Specifically, no. 18 states:
“The term ‘opiate’ or ‘opioid’ means any drug or other substance having an
addiction-forming or addiction-sustaining liability similar to morphine or being
capable of conversion into a drug having such addiction-forming or addiction-
sustaining liability.”
This pharmacological definition is critical to the regulatory consideration of 7-OH. It
allows the DEA, upon recommendation from DHHS, to classify a substance as an opioid
based on its effects, even if it does not meet the structural or precursor criteria of Factor
8. The determination of whether a substance has an “addiction-forming or addiction-
sustaining liability similar to morphine” is based on the scientific and medical evidence
evaluated under the other factors of the 8-FA, particularly Factors 1, 2, 3, and 7.
An example of this in pharmaceutical development was tapentadol. During its evaluation
and development as an analgesic, it was not designated as an opioid based on its
chemical structure; however, based on its overall pharmacological profile and similarity
to morphine and related opioids, tapentadol was placed in Schedule II of the CSA, along
with morphine and oxycodone, following its approval for therapeutic use and is now
widely classified as an “opioid”.
8 Scheduling Recommendation
This 8-FA supports FDA’s preliminary July 29, 2025 recommendation that placement of
7-OH in the CSA is warranted. Moreover, because 7-OH has not been approved by
FDA for therapeutic use and has not been determined by FDA and DHHS to be
commonly accepted for medical use (i.e., CAMU), the only CSA scheduling option is
Schedule I.
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Specifically, the present analysis supports FDA’s “Assessment of the Scientific Data
and Toxicological Concerns” which included the following conclusions:
“Based on demonstrated pharmacology, repeated or prolonged use of 7-OH
would lead to tolerance, physical dependence, and potentially to opioid addiction
— typical of mu opioid agonist drugs of abuse.”
The analysis of Factors 1, 2, 3 and 7 in the present report and the FDA analysis both
support the conclusion that 7-OH meets the statutory criteria of the Controlled
Substances Act’s specific provision (at 21 U.S.C. § 802(18)) that guides determination
of whether a substance can be determined to be sufficiently pharmacologically
equivalent to morphine with respect to key effects related to “addiction liability”. Thus, 7-
OH can be designated and regulated as an opioid as discussed above in Factor 8.
Moreover, with respect to the determination of whether 7-OH poses a known or
imminent public health threat, which is among the criteria for both temporary (i.e.,
“emergency”) scheduling and permanent scheduling, FDA’s July 29th analysis
concluded as follows:
“The pharmacological profile, abuse liability, and emerging patterns of non-
medical use establish 7-OH as a dangerous substance. Current regulatory gaps
have enabled widespread availability of these products despite their opioid-like
properties and necessitate immediate policy intervention to address this
emerging threat to American public health.”
Factors 4, 5, and 6 in the present report supports FDA’s conclusion that 7-OH poses a
likely imminent public health threat, thus supporting the known or imminent public health
threat criteria for temporary and permanent scheduling.
8.1 Policy Implementation Considerations to Minimize Unintended
Consequences
Evidence suggests that there is likely a proportion of individuals who may benefit from
their use of 7-OH, with some considering it a life-saving path away from more deadly
illicit opioids. While such reports may not, on their own, be sufficient justification to avoid
scheduling 7-OH, they should be considered in how such a regulatory policy is
implemented and enforced. As discussed in greater detail in the Research Priorities and
Policy Considerations section below, some 7-OH consumers may need time, support,
and assistance to identify effective alternatives, and to reduce the likelihood that a
significant illicit market for 7-OH will emerge if 7-OH is scheduled.
The FDA appeared careful in its July 29th documents and press conference to
distinguish between concentrated 7-OH products and natural kratom products, which it
acknowledges often contains detectable levels of 7-OH. For controlled substances the
CSA does not set a level of for controlled substances that can be marketed without
control. However, there are examples of substances and products that contain low
levels of substances. For example, FDA has not banned, and DEA has not scheduled,
poppy seeds used in cooking even though their consumption can produce detectable
levels of morphine following consumption of poppy seed pastries, curries and other
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foods. Other examples include a Parkinson’s Disease diagnostic scanning assay that
includes small amounts of cocaine related substances that DEA determined did not
require scheduling. Implementation may include a performance standard for kratom
products such as the maximum allowable amount per serving size.
As discussed in Factor 4, 5 and 6 and in the policy implications of this report, a subset
of 7-OH users consider it to be their path away from illicit or pharmaceutical opioids that
likely carry greater risks of overdose death than 7-OH. Individuals also report benefits
such as relief of pain, sometimes describing 7-OH as more effective or preferred to FDA
approved medicines or kratom. Although there are significant gaps in the current body
of evidence that do not allow credible estimates of the incidence of such cases or the
prevalence among 7-OH users, these reports underscore the importance of carefully
planning and implementing any scheduling action. Enforcement priorities should aim to
minimize the risks of 7-OH users relapsing to more deadly opioid use, and prevent the
emergence of an illicit market in which trafficking organizations such as cartels
manufacture and distribute unregulated 7-OH products. Such illicit products may lack
the quality controls observed by at least some current manufacturers. Such illicit
marketers may also add fentanyl related substances to 7-OH for boosted effects or
even replace 7-OH with fentanyl related substances.
To be clear, this discussion of potential unintended public health consequences does
not mean that scheduling is not warranted; rather, it underscores the need for thoughtful
implementation giving consideration to the potentially thousands of current 7-OH
consumers. The timing, scope, and enforcement approach to scheduling and policy
implementation should be carefully considered by the DEA/Department of Justice (DOJ)
ideally in coordination with CDC, FDA, and NIH, with diverse stakeholder input
(including 7-OH consumers). Such coordination would provide the umbrella of
supporting surveillance, assistance, and research to detect and minimize unintended
consequences, and provide time and assistance to current 7-OH users to find
alternatives to 7-OH.
9 Research Priorities and Policy Considerations
The recommendation by the FDA to the DEA of a scheduling action to control 7-OH
under the CSA represents a significant federal response to what the agency has
deemed an “emerging public health threat”. This action is a continuation of a complex
history of regulatory considerations for kratom and its alkaloids and has continued to
highlight gaps in the regulatory and legal framework for regulating novel botanical
psychoactive substances. Some experts may feel that potentially lower real-world risks
of addiction, abuse, and overdose exist for 7-OH and therefore warrant less restrictive
scheduling than those drugs that are placed in Schedule II (i.e., fentanyl and
oxycodone) and Schedule I (i.e., heroin).
However, under current law, Schedule I is the only option for 7-OH. The CSA makes
clear that if a drug has sufficient abuse potential to warrant scheduling and it is not
approved by FDA or designated as CAMU, then placement in Schedule I is required.
Further, while the evidence of overdose risk is primarily by the intravenous route and
real world-use is primarily by the potentially lower risk oral route, the pharmacological
Page 37 of 128
and toxicological profile of the ‘substance’ or ‘chemical entity’ is the basis for scheduling
– regardless of route. If 7-OH is placed in Schedule I, and then in the future, a New
Drug Application for a 7-OH containing product is developed and approved by FDA, that
product will be removed from Schedule I and rescheduled or removed from CSA control
as informed by an 8-FA for that product and other considerations.
Specifically, as per the CSA, approved drugs are scheduled according to their abuse-
related risks as guided by the 8-FA in which Schedule V is least restrictive (e.g., cough
preparations with less than 200 milligrams of codeine or per 100 milliliters, and
pregabalin) and Schedule II is most restrictive (e.g., morphine, oxycodone,
amphetamine, cocaine and fentanyl).
Thus, FDA’s report, “7-Hydroxymitragynine (7-OH): An Assessment of the Scientific
Data and Toxicological Concerns Around an Emerging Opioid Threat”, summarizes the
chemical, pharmacological and epidemiological evidence related to 7-OH safety and
abuse potential. Although not structured as a formal 8-FA, it includes key data which
formed the basis for its determination that:
(a) 7-OH demonstrates sufficient pharmacological equivalence on key abuse and
safety related variables to be considered an “opioid”, thus triggering CSA’s
statutory implications that include placement in Schedule I if not approved as a
drug, and placement in Schedule II if under development with an Investigational
New Drug (IND) application that has been accepted; and,
(b) 7-OH is “dangerous” and poses an imminent hazard to public health which
satisfies a key criterion for temporary (aka “emergency”) drug scheduling.
A critical implication of these two determinations is that to warrant scheduling, the
substance does not need to carry the same or equivalent abuse potential or overdose
risk as classical opioids (e.g., frequent reference standards morphine and oxycodone,
or epidemiological comparators such as heroin and fentanyl). However, in practice, the
greater the risk to public health, the greater the urgency and justification for rapid action.
It is important to note that the definition of CAMU has been recently evolving, as
evidenced by the 2024 DEA recommendation to place marijuana into Schedule III of the
CSA (DEA, 2024), which states:
“In its most recent evaluation, HHS informed DEA of its view that DEA's previous
approach to determining whether a drug has a CAMU does not adequately
account for certain indicia of medical use that, where present, are relevant to
determining whether a substance has a CAMU for purposes of scheduling under
the CSA. Specifically, HHS observed that DEA's tests left no room for an
evaluation of (1) whether there is widespread medical use of a drug under the
supervision of licensed health care practitioners under State-authorized programs
and, (2) if so, whether there is credible scientific evidence supporting such medical
use.”
DHHS therefore developed an alternative test wherein:
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“Under Part 1 of the HHS CAMU test, the Office of the Assistant Secretary for
Health (“OASH”) considered whether there is widespread current experience with
medical use of marijuana in the United States by licensed [healthcare providers]
HCPs operating in accordance with implemented State-authorized programs,
where such medical use is recognized by entities that regulate the practice of
medicine under these State jurisdictions. Part 2 of the CAMU test evaluated
whether there exists some credible scientific support for at least one of the medical
conditions for which the Part 1 test is satisfied. The evaluation in Part 2,
undertaken by FDA, was not meant to be, nor is it, a determination of safety and
efficacy under the Federal Food, Drug, and Cosmetic Act's drug approval standard
for new human or animal drugs. Rather, HHS's two-part test is designed to
evaluate whether a substance, in this case marijuana, has a CAMU for purposes
of drug scheduling recommendations and placement in a drug schedule consistent
with criteria set forth in 21 U.S.C. 812(b).”
While there are reports of consumers using 7-OH for therapeutic purposes, the
available body of evidence falls far short of the level that supported DHHS/FDA
designation of “marijuana” as CAMU in its 2023 analysis, led by the Office of the
Assistant Secretary of Health (OASH). The analysis included extensive data which
confirmed “that more than 30,000 HCPs [health care providers] across 43 U.S.
jurisdictions are authorized to recommend the medical use of marijuana for more than
six million registered patients for at least 15 medical conditions. OASH’s Part 1 analysis,
therefore, supports the finding that marijuana has at least one CAMU in the United
States.” Note this evaluation does not mean marijuana has been approved as a drug for
any given condition. Rather, the widespread and well-documented medical use was
deemed sufficient to satisfy the CAMU requirement and provide the basis for removal of
marijuana from Schedule I – a recommendation that is presently under consideration by
the DEA. Currently, no comparable body of evidence exists to support a similar CAMU
designation for 7-OH
Likewise, neither kratom nor any of its alkaloids (including mitragynine, the predominant
active constituent in most kratom products and extracts) have been designated as
CAMU. Further, kratom and its alkaloids have not been designated as ‘opioids’ based
on botanical origin, chemical structure, or sufficient pharmacological equivalence to
morphine. Moreover, several prior 8-FAs have determined that they do not warrant
scheduling under the Controlled Substances Act. This includes the 2018 analysis by
Assistant Secretary Brett Giroir (Giroir, 2018), which rescinded an earlier
recommendation to schedule kratom's main alkaloids, mitragynine and 7-OH. That
rescission was based on the determination that the scientific evidence at the time was
underdeveloped and insufficient, and that scheduling carried a “significant risk of
immediate adverse public health consequences,” such as driving users to more lethal
opioids.
Similarly, the in 2020, the World Health Organization's Expert Committee on Drug
Dependence (ECDD), found insufficient evidence to recommend a critical review of
kratom, mitragynine, and 7-OH for international scheduling, though it recommended
continued surveillance (UNODC, 2021). Three other 8-FA (one submitted as a comment
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to DEA in 2016 [Henningfield and Fant, 2016], and two as peer reviewed publications
(Henningfield, Fant, and Wang, 2017; Henningfield, Wang, and Huestis, 2021) also
concluded that kratom did not warrant CSA scheduling.
Although these prior evaluations included consideration of 7-OH, they did not find
sufficient basis for scheduling at the time. However, the science has advanced
significantly in recent years as discussed in Factor 3. Specifically, the introduction to
Kratom: History, Science, and Therapeutic Potential, a recently published book
featuring contributions from many of the world’s leading kratom researchers, notes the
rate of annual kratom science publications increased from about 20 per year in 2016 to
more than 130 per year by 2024, with the increased fueled heavily by research funding
by the National Institutes of Health (NIH), NIDA (Henningfield, Beyer, & Raffa, 2025).
The rapid growth in 7-OH marketing and consumption since 2022, coupled with an
expanding body of research addressing its abuse potential and safety (Reissig et al.
2025), in addition to the increased body of evidence regarding kratom in general, has
altered the public health context. Accordingly, this report concurs with the July 2025
FDA’s evaluation that potential and increasing public health risks – exacerbated by
extensive 7-OH product marketing and consumer consumption, rising consumer
exposure, and new scientific evidence – support the recommendations for scheduling.
As discussed earlier, the foregoing observations of this report and those of Reissig et al.
above are consistent with recent conclusions and evaluations by other experts which
suggest that some fraction of the adverse events and possibly deaths that have been
reported and or interpreted as involving or even caused by kratom, were actually more
likely attributable to the consumption of 7-OH products in addition to or in place of
kratom (Grundmann et al., 2024; Hill, Boyer, et al., 2025; Papsun et al., 2023; Smith et
al., 2025; Vadiei, Evoy, & Grundmann, 2025).
Taken together, the foregoing observations support the conclusion that it is urgent to
add 7-OH to relevant substance surveillance systems including NSDUH, RADARS,
FAERS, and poison control. Similarly, assessment of 7-OH in blood plasma in forensic
toxicology examinations as well as kratom research in general is a critical need. As
discussed in Factor 5, it is beyond the scope of this report to specify how surveillance
systems should be designed to distinguish between kratom products and those
containing 7-OH, including the precise wording of survey questions or the analytical
methods to detect 7-OH, which should be developed with input from appropriate experts
and stakeholders.
9.1 Comparison of 7-OH to Kratom and other Substances
Currently, many kratom and related products, including concentrated 7-OH products are
marketed as dietary ingredients and/or supplements, though to date no NDIN has been
accepted by FDA and the lack of documented history of use prior to 1994 has precluded
its acceptance as an ingredient exempt from the NDIN requirements as described in the
Dietary Supplement Health and Education Act (DSHEA) of 1994. A crucial aspect to
determine 7-OH’s risk to the public health is the distinction between traditional kratom
and concentrated 7-OH products. The FDA has explicitly stated that its primary concern
Page 40 of 128
is not with natural kratom leaf, where 7-OH is present in only trace amounts, but with
the “concentrated 7-OH opioid products” that are ‘far more dangerous”. While traditional
kratom is not without risks and has been associated with dependence and adverse
events, its risk profile appears to be substantially lower than that of concentrated 7-OH.
The limiting nature of consuming bulky plant powder and the complex interplay of
dozens of alkaloids in traditional kratom may moderate its effects and abuse potential
compared to isolated 7-OH.
However, neither these statements from FDA nor kratom’s apparent lack of signal of
risk to public health should be misinterpreted that the Agency accepts kratom as safe. It
has not accepted any submitted NDINs in which the standard for acceptance is that the
products specified in the NDIN’s were found to be “acceptably safe”, though this has not
been a standard that FDA has formally defined. In December 2023, FDA stated in a
federal court hearing in the Southern District of California that the Agency had not yet
determined if kratom was hazardous (United States v. Nine2Five, LLC, No. 3:23-CR-
00179-TWR [S.D. Cal.], ECF No. 110-8). FDA also reminds the public on its kratom
website page that kratom has not been approved for therapeutic use. While this is not
directly relevant to the legality or safety of kratom as approval for therapeutic use is not
a standard for accepting a substance as a dietary substance, it means that products
cannot legally be marketed with disease treatment and prevention claims.
When compared to illicit opioids, FDA describes the risk of 7-OH as a potential “new
wave of the opioid epidemic”, and implies the potential risk of fueling an overdose
epidemic rivaling that by three earlier waves of prescription drugs, heroin, and fentanyl
(and related substances) - a message reinforced by recent pharmacological and
epidemiological data presented by FDA (Reissig et al., 2025) and portrayed in a graphic
in its educational materials (FDA, 2025b).
9.2 Potential Unintended Consequences of Schedule I Placement and Policy
Implications
9.2.1 Potential Unintended Consequences of Scheduling
While scheduling 7-OH under the CSA is intended to mitigate public health risks, such
an action has the potential to create unintended negative outcomes. A comprehensive
policy analysis must consider potential unintended consequences, which could, in some
cases, undermine the primary goal of protecting public health.
9.2.1.1 Relapse by Patients and Consumers to Harmful Opioids
A key consideration in the 2018 DHHS decision not to schedule kratom or its alkaloids
was the concern that a ban would cause individuals using kratom to manage opioid
withdrawal symptoms or chronic pain to switch to more dangerous and harmful
substances such as heroin and fentanyl (Giroir, 2018). These risks and others
described by Giroir (see also Henningfield, Fant and Wang (2018); Henningfield,
Grundmann, et al. (2019); Henningfield and Fant (2016)) appear plausible if 7-OH is
scheduled.
Page 41 of 128
As discussed in Factor 6 of this report, a similar conclusion as pertains to 7-OH is based
on admittedly limited anecdotal evidence suggesting that some 7-OH users report that
7-OH to be more effective, acceptable, or assessable than FDA approved medicines,
kratom, or other approaches, as was similarly concluded for kratom in 2016
(Henningfield and Fant, 2016), and in subsequent analyses (Giroir, 2018; UNODC,
2021). Nonetheless, it is foreseeable that removal of 7-OH from the licit marketplace
carries the risks of unintended consequences of 7-OH consumers relapsing to
potentially deadlier opioid use, and resulting in an illicit market in which 7-OH products
would proliferate without the quality standards that some 7-OH makers and marketers
appear to voluntarily adhere.
An illicit 7-OH market also raises the potential if not likelihood of 7-OH products being
replaced or adulterated with fentanyl related substances. This risk is not theoretical and
decades of experience with opioids have elucidated what is sometimes referred to as
the “whack A mole” effect, whereby reduction in access to one opioid has little effect on
overall opioid use as people simply migrate to other opioids. Thus, for example, when
the abuse deterrent formulation of OxyContin was marketed in August 2010 and the
original OxyContin removed from the market, OxyContin abuse actually decreased.
However, surveillance studies over the next two years revealed there was no reduction
in opioid use but rather use of other opioids (including fentanyl and hydromorphone
selection) rose markedly from 20% to 32% and heroin use nearly doubled (Cicero, Ellis,
& Surratt, 2012). Even more sobering is that although high dose and Schedule II opioid
prescribing rates have declined in the U.S. since about 2012, annual opioid overdose
deaths have continued to increase primarily due to heroin and fentanyl related
substances (Henningfield, Ashworth, et al., 2019; Strickler et al., 2020).
9.2.1.2 Restrictions and Impediments to Scientific Research
Placing 7-OH in Schedule I would impose significant regulatory barriers on scientific
research. Investigators wishing to study the substance – whether for its risks or its
potential therapeutic benefits – would face stringent registration, security, and record-
keeping requirements from the DEA, as well as funding limitations in procuring, storing,
or administrating these substances in research settings (Andreae et al., 2016). This
could stifle much-needed research into 7-OH's pharmacology, safety profile, and
potential as a lead compound for developing safer analgesics. The G-protein biased
agonism of 7-OH is of significant scientific interest for the development of novel pain
medications with fewer side effects, and a Schedule I designation could severely
hamper progress in this area.
9.2.1.3 Criminalization and Enforcement
Placement in Schedule I could have profound consequences including potentially
severe restrictions and criminal penalties for possession and distribution. As the
benefits and risks of 7-OH and the extent to which consumers are using 7-OH for
therapeutic purposes have yet to be determined, it’s important for policy decisions to
consider the actions and effects that may have potential unintended consequences and
how to minimize the risks.
Page 42 of 128
While there are no reliable estimates of how many people use 7-OH for therapeutic
purposes, the potentially thousands of people using 7-OH to refrain from harmful opioid
use may benefit from additional federal resources, funding treatment and harm
reduction for substance use issues, as well as the DOJ deprioritizing individual
possession while prioritizing inappropriate marketing and sales. The specific options
and approaches for policy to minimize unintended consequences are beyond the scope
of this report; however, this report recommends consideration should be given to risk
mitigation before 7-OH is scheduled. A request for comment and possibly a public
hearing to give consumers and various important stakeholders consideration is
recommended, because preliminary anecdotal reports suggest that for some people 7-
OH is their lifeline away from potentially more deadly opioid such as fentanyl. They may
need time and assistance to find alternative, acceptable, and effective therapeutic
strategies and support.
Page 43 of 128
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11 Appendices
11.1 Appendix 1: Published Findings Related to Abuse, Physical Dependence,
Withdrawal, and Safety Signals of 7-OH
Page 53 of 128
Table 2. Published Findings Related to Abuse, Physical Dependence, Withdrawal, and Safety Signals of 7-OH
Publication or
Source
Short Title or
Description
Comparators
Studied or
Mentioned
Abuse-related
Variables
Physical
Dependence &
Withdrawal
Safety Individual
Population
Comments
Factor 1: Actual or Relative Potential for Abuse
Gonzalez et al.
(2025)
Mitragynine and
7-
Hydroxymitragyni
ne: Bidirectional
Effects on
Breathing in
Rats.
MG: 5.6, 10, 17.8
mg/kg, IV
7-HMG: 1, 3.2, 10
mg/kg, IV
Positive control
opioid: morphine
(10, 32 mg/kg IV).
Antagonist:
naloxone (1 mg/kg
IV).
NA Did not assess
withdrawal
Morphine caused dose-
dependent respiratory
depression while mitragynine
unexpectedly increased
respiratory frequency at 10
mg/kg, with no significant
depression of tidal/minute
volume. High dose (17.8
mg/kg) caused seizures in
some rats without respiratory
depression. MG’s stimulant
effect was not blocked by
naloxone, suggesting a non-
opioid mechanism.
7-OH-MG caused dose-
dependent respiratory
depression: reduced
frequency and minute volume
at 3.2 and 10 mg/kg, tidal
volume trends toward
depression. Naloxone fully
reversed 7-HMG-induced
respiratory depression (tidal
and minute volume restored).
NA
Sudmoon et al.
(2025)
Discovery of
rhynchophylline
and
mitraphylline in
two Thai
Toxicity testing of
two Thai
Mitragyna
species and the
investigation of
their biological
activity via opioid
MG, 7-OH-MG,
mitraphylline, and
rhynchophylline
NA NA Mild motor impairment seen
at ≥50 mg/kg IP, no lethal
effects
MG exhibited moderate affinity for
the MOR and KOR, whereas 7-OH-
MG had 14x greater binding affinity
than MG.
Rhynchophylline, MG, and 7-OH-
MG were found in other Mitragyna
species.
Page 54 of 128
Publication or
Source
Short Title or
Description
Comparators
Studied or
Mentioned
Abuse-related
Variables
Physical
Dependence &
Withdrawal
Safety Individual
Population
Comments
Mitragyna
species and the
investigation of
their biological
activity via
opioid gene
expression
analysis.
gene expression
analysis
Henningfield,
Rodricks, et al.
(2022)
Rat respiratory
effects & plasma
MG & 7-OH-MG
Oxy & MG General
behavior (e.g.,
sedation)
NA Oxy: respiratory depression &
deaths;
MG: no respiratory effect
Plasma MG & 7-OH-MG confirmed
high-dose exposure.
Chakraborty,
Uprety, et al.
(2021)
Oxidative
metabolism as a
modulator of
kratom’s
biological actions
MG, 7-OH-MG,
MGP
7-OH-MG &
MG showed
significant
CPP, though
MGP did not
NA 7-OH-MG inhibited GI transit.
7-OH-MG produced from MG via
CYP3A mediated oxidation.
Acts as a MOR agonist and
produced dose-dependent
antinociception in tail flick and hot
plate.
Higher potency by the oral route vs
morphine which was higher via SC
admin.
Obeng et al.
(2021)
Pharmacological
comparison of
Mitragynine and
7-OH-MG
DAMGO, morphine,
fentanyl,
buprenorphine,
nalbuphine,
naltrexone, U69,593;
SNC-80
MG, 7-OH-MG
7-OH-MG
produced a
maximum of
100% drug
lever
responding in
morphine
trained rats
In MG-trained
rats, 7-OH-MG
produced a
maximum of
NA 100 mg/kg MG lethal (IP),
even with 10 mg/kg
naltrexone.
7-OH-MG produced significant
naltrexone- and naloxone-reversible
antinociception in rats in hot plate
test.
Page 55 of 128
Publication or
Source
Short Title or
Description
Comparators
Studied or
Mentioned
Abuse-related
Variables
Physical
Dependence &
Withdrawal
Safety Individual
Population
Comments
98% drug lever
responding
Gutridge et al.
(2020)
G protein-biased
kratom-alkaloids
and synthetic
carfentanilamide
opioids as
potential
treatments for
alcohol use
disorder
Kratom extract,
mitragynine,
paynantheine,
speciogynine, 7-OH-
MG (3 mg/kg, IP)
MP102, MP103,
MP105, TRV130
morphine, DAMGO,
Leu-enkephalin,
U50,488
CPP findings
show reward
potential for
kratom extract
and 7-OH-MG
NA NA MG, paynantheine, and
speciogynine reduced ethanol intake
at 10-30 mg/kg in mice.
7-OH-MG reduced intake at 1-3
mg/kg (male) and 3 mg/kg (female).
Speciogynine (30 mg/kg) decreased
activity.
7-OH-MG (3 mg/kg) increased
locomotor activity.
Kratom extract #1 (30 mg/kg) and 7-
OH-MG (3–10 mg/kg) induced CPP.
Morphine induced CPP as expected.
Obeng et al.
(2020)
Adrenergic and
opioid binding
affinities,
metabolic
stability, plasma
protein binding
properties, and
functional effects
of selected
indole-based
kratom alkaloids
MG, 7-OH-MG,
speciociliatine,
corynantheidine, 9-
hydroxycorynantheid
ine
NA NA NA 7-OH-MG had the highest affinity
among tested alkaloids at the MOR,
and showed high affinity at the KOR
and moderate affinity at the DOR.
In rat hot plate tests, 7-OH-MG
produced greater potency than
morphine and speciociliatine but
lower than fentanyl.
Analgesic effect blocked by
naltrexone.
Did not produce hypothermia.
Todd et al.
(2020)
Receptor binding
of 7-OH-MG,
7-OH-MG,
mitragynine,
speciofoline
Binding affinity
to opioid
receptors
NA Not population-specific MG and 7-OH function as partial
agonists of the human MOR, while
speciociliatine does not exhibit
measurable binding affinity at the
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mitragynine, and
speciofoline
MOR, DOR, or KORs. MG and 7-OH
demonstrate functional selectivity for
G-protein signaling, with no
measurable recruitment of β-
arrestin.
Hemby et al.
(2019)
Abuse
liability and
therapeutic
potential of the
Mitragyna
speciosa
(kratom)
alkaloids
mitragynine and
7-
hydroxymitragyni
ne.
MG: 25-150
µg/infusion,
7-OH-MG: 2.5-20
µg/infusion
Morphine: 50-100
µg/infusion
Experiment 1:
MG did not
substitute for
morphine at
any dose.
7-OH-MG
substituted for
morphine in a
dose-
dependent
manner (2.5–
20
µg/infusion),
with an
inverted U-
shaped curve
and maximal
response at 5–
10 µg/infusion
Experiment 2:
Morphine and
7-OH-MG both
engendered
and
maintained self
admin. MG did
not
NA No lethality reported NA
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7-HMG
maintained
intake at 2.5-
10 µg/infusion,
comparable to
morphine
Experiment 3:
Morphine
intake reduced
by NLXZ (μ1
antagonist) but
not NTI.
7-HMG intake
reduced by
both NLXZ and
NTI,
suggesting
reinforcement
mediated by
MOR and
DOR.
Kruegel et al.
(2019)
Hydroxymitragyni
ne is an active
metabolite of
mitragynine and
a key mediator of
its analgesic
effects.
MG, 7-OH-MG,
MGP
NA NA NA MG is converted in vitro in both
mouse and human liver preparations
to 7-OH-MG, mediated by CYP
P450 3A
7-OH is formed from MG in mice
and that brain concentrations of this
metabolite are sufficient to explain
most or all of the opioid-receptor-
mediated analgesic activity of MG.
At the same time, MG is found in the
brains of mice at very high
concentrations relative to its opioid
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receptor binding affinity, suggesting
that it does not directly activate
opioid receptors.
Kruegel et al.
(2016)
Synthetic and
Receptor
Signaling
Explorations of
the Mitragyna
Alkaloids:
Mitragynine as
an Atypical
Molecular
Framework for
Opioid Receptor
Modulators
MG, paynantheine,
speciogynine,
speciociliatine, 7-
OH, morphine,
DAMGO, fentanyl,
HEK293
Characterizatio
n of 7-OH's
activity at
MOR, KOR,
DOR.
7-OH-MG
bound MOR
with high
affinity (Ki ~ 30
nM).
Showed G-
protein biased
signaling
NA Both 7-OH and MG were
found to elicit no measurable
β-arrestin recruitment
7-OH-MG produced potent
antinociception, 10x more potent
than morphine, blocked by
naloxone.
At equianalgesic doses, 7-OH-MG
caused less respiratory depression
and constipation than morphine.
Harun et al.
(2015)
Discriminative
stimulus
properties of
mitragynine
(kratom) in rats.
MG: 3-56 mg/kg IP),
7-HMG: 0.3–3 mg/kg
IP,
Morphine, codeine,
cocaine, diazepam,
U50,488H
MG did not
substitute for
morphine.
7-OH-MG fully
substituted for
morphine.
Effects were
dose
dependent and
naloxone
reversible
NA No lethal toxicity.
MG at high doses produced
sedation and reduced
response.
7-OH-MG elicited responses
at much lower doses (0.3-3
mg/kg).
NA
Matsumoto et
al. (2004)
Antinociceptive
effect of 7-OH-
MG in mice
7-OH-MG, MG,
morphine
NA NA No safety-related signals or
adverse effects reported
7-OH-MG showed dose-dependent
antinociceptive properties when
subcutaneously and orally
administered to mice. Also suggests
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7-OH-MG may be more orally
bioavailable than morphine.
Factor 2 Scientific Evidence of its Pharmacological Effects
J. P. Manus et
al. (2025)
Effects of kratom
alkaloids on
mesolimbic
dopamine
release.
MG, 7-OH-MG,
(cocaine,
amphetamine,
opioids mentioned
but not directly
compared)
NA NA NA Fixed potential amperometry was
used to quantify stimulation-evoked
phasic dopamine release in the
nucleus accumbens (NAc) of
anesthetized male and female mice
before and after MG (1, 15, or 30
mg/kg, IP), 7-OH-MG (0.5, 1, or 2
mg/kg, IP), or vehicle.
MG reduced dopamine release over
the recording period (90 min) in a
dose-dependent manner, and the
low dose of MG significantly
increased dopamine autoreceptor
functioning in males.
Both sexes responded similarly to 7-
OH-MG with the low dose of 7-OH-
MG increasing dopamine release
while the high dose decreased
dopamine release.
7-OH-MG did not alter dopamine
autoreceptor functioning for either
sex. Neither MG nor 7-OH-MG
altered the clearance rate of
stimulation-evoked dopamine.
Findings suggest that these kratom
alkaloids do alter dopamine
functioning, although potentially not
in a way consistent with classic
drugs of abuse.
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Comments
Obeng et al.
(2022)
Interactive
Effects of m-
Opioid and
Adrenergic a2
Receptor
Agonists
in Rats
Pharmacological
investigation of
the primary
kratom alkaloid
mitragynine and
its metabolite 7-
hydroxymitragyni
ne
MG, 7-OH-MG,
morphine,
methadone,
clonidine, lofexidine,
U69,593, naltrexone,
yohimbine
MG showed
low affinity at
α2A and α2C
receptors
MG bound
MOR with Ki
~1700 nM.
7-OH-MG
showed
stronger MOR
affinity (Ki ~78
nM) but no α2
binding at ≤10
μM.
NA No toxicity or lethality
reported.
MG has weak affinity for MOR but
meaningful interactions with α2-
adrenergic systems. Combined
activity may account for kratom’s
mixed reported stimulant/analgesic
profile.
In hot plate tests, MG did not
produce significant antinociception
across routes (IP, SC, oral). In
contrast, 7-OH-MG produced robust,
naloxone-sensitive antinociception.
MG and 7-OH-MG enhanced
potency of α2 agonists
(clonidine/lofexidine)
Maxwell et al.
(2021)
Oral
pharmacokinetics
in beagle dogs of
the
mitragynine
metabolite, 7-
hydroxymitragyni
ne.
MG, 7-OH-MG NA NA NA Following a single oral dose (1
mg/kg) of 7-HMG, plasma samples
were obtained from healthy female
beagle dogs.
Absorption of 7-HMG was rapid, with
a peak plasma concentration (Cmax,
56.4 ± 1.6 ng/mL) observed within
15 min post-dose. In contrast, 7-
HMG elimination was slow,
exhibiting a mono-exponential
distribution and mean t1/2 of 3.6 ±
0.5 h. Oral dosing of 1 mg/kg 7-
HMG was well-tolerated with no
observed AEs or significant changes
to clinical laboratory tests.
The exposure of 7-HMG after MG
dosing due to metabolism
corresponds to a 0.24 mg/kg dose of
7-HMG indicating a 23.1%
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conversion of MG to 7-HMG in
beagle dogs.
Ellis et al.
(2020)
Receptor binding
and signaling of
kratom
MG, 7-OH-MG,
other alkaloids
Binding affinity
to opioid
receptors
NA Not population-specific Identified MOR partial agonism for
7-OH-MG and MG, biased signaling.
Takayama et al.
(2002)
Synthesis and
Opioid Agonistic
Activities of
Mitragynine-
Related Indole
Alkaloids
MG, 7-OH-MG,
pseudoindoxyl
Morphine
NA NA NA In vitro tissue assays and in vivo
mouse hot plate and tail-flick tests
showed potent naloxone reversible
antinociception
Factor 3 Current State of Scientific Knowledge
Akbar et al.
(2025)
Screening,
docking, and
molecular
dynamics
analysis of
Mitragyna
speciosa (Korth.)
compounds for
targeting HER2
in breast cancer.
MG, 7-OH-MG,
paynantheine,
speciociliatine,
speciogynine
NA NA NA MG was found to be BBB permeant,
whereas 7-OH-MG was not BBB
permeant, which could reduce the
likelihood of CNS-related side
effects.
Neither were found to be P-gp
substrates, which minimizes the risk
of efflux-related bioavailability
issues.
However, both were inhibitors of
CYP2D6 and CYP3A4 enzymes.
7-OH-MG demonstrated MOR
binding and partial agonist activity.
7-OH-MG showed potent G-protein
biased MOR agonism.
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7-OH-MG and MG both
demonstrated high GI absorption,
suggesting high oral bioavailability.
Docked to HER2 binding pocket with
lower binding energies, and 7-OH-
MG demonstrated stable hydrogen-
bond interactions with residues
critical for HER2 inhibition.
Chiang et al.
(2025)
In Vitro and In
Vivo
Pharmacokinetic
Characterization
of 7-
Hydroxymitragyni
ne, an Active
Metabolite of
Mitragynine, in
Sprague-Dawley
Rats.
MG
MGP, 7-OH-MG
NA NA NA 7-OH-MG exhibited high
permeability in Caco-2 cells
7-OH-MG exhibited lower plasma
protein binding in rats compared to
MTG. Lower plasma protein binding
of 7-OH-MG may lead to a larger
volume of distribution and a shorter
t1/2 than MTG.
7-HMG showed a rapid elimination
with short metabolic half-lives in
rat liver microsomes (0.4 ± 0.0 h)
and hepatocytes (0.3 ±0.0 h).
After oral dosing, the Cmax was 28.5
± 5.0 ng/ml, and Tmax was 0.3 ± 0.1
h, which indicated rapid absorption
of 7-HMG. The t1/2 of 7-HMG was
0.5 ± 0.0 and 1.7 ± 0.5 h after IV and
oral dosing, respectively, which
indicated 7-HMG eliminates rapidly
from the systemic circulation.
In contrast to other studies, this
study found poor oral bioavailability
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of 7-OH-MG, though this may be
due to poor water solubility.
The concentration of 7-HMG fell
below the LLOQ after 8 h following
IV administration and 4 h following
oral administration.
Uchaipichat
(2025)
Inhibitory effects
of Kratom
constituents,
mitragynine and
7-
hydroxymitragyni
ne, on 4-
methylumbellifer
one
glucuronidation
by human UDP-
glucuronosyltran
sferases.
MG, 7-OH-MG NA NA NA 7-OH exhibited the highest inhibitory
potency on UGT1A9, with IC50 value
of 51 µM, while moderate potency
was observed for UGT1A1 and
UGT1A3, with IC50 value of 196 and
141 µM, respectively. The inhibitory
potency of 7-OH on UGT2B15 was
low (IC50 > 200 µM), while negligible
effects were observed for UGT1A6
and UGT2B7.
7-OH competitively inhibited
UGT1A3 (Ki = 33 µM) and
noncompetitively inhibited UGT1A9
(Ki = 29 µM).
Values are relatively high compared
to the maximum plasma
concentrations reported in humans,
suggesting an unlikely potential for
herb-drug interactions via UGT
inhibition.
Berthold et al.
(2024)
Pharmacokinetic
Interaction of
Kratom and
Cannabidiol in
Male Rats
MG, 7-OH-MG,
speciociliaine,
paynantheine,
speciogynine,
corynantheidine
measured
NA NA NA The metabolite to parent (i.e.,
mitragynine) exposure ratio
percentage of 7-OH-MG remained
similar (3.5 and 3.1 with and without
cannabidiol, respectively). As there
was an increase in MG exposure
during this study, it was expected
that this would be due to a decrease
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OPMSS Gold
kratom extract (11.8
mg/mL MG,
2.8 mg/mL
speciociliatine,
2.2 mg/mL
paynantheine,
1.5 mg/mL
speciogynine).
CBD (33.3 mg/mL
cannabidiol)
in metabolism, but this was not the
case for 7-OH-MG despite it being
primarily metabolized by CYP3A and
cannabidiol being a competitive
inhibitor of CYP3A
Chiang et al.
(2024)
Multiple-Dose
Pharmacokinetic
s and Safety of
Mitragynine, the
Major Alkaloid of
Kratom, in Rats.
MG, 7-OH-MG
(Morphine,
oxycodone,
methadone
mentioned but not
directly compared)
NA NA NA Female rats showed significantly
higher exposure to 7-OH-MG
compared to male rats after multiple
doses of MTG; similar results in
mice (may not be applicable to
humans, as women have higher
expression of CYP3A activity than
men); whereas male rats have
higher expression than female rats.
Huestis et al.
(2024)
Human
Mitragynine and
7-
Hydroxymitragyni
ne
Pharmacokinetic
s after Single and
Multiple Daily
Doses of Oral
Encapsulated
Dried Kratom
Leaf Powder.
Kratom leaf powder
Measured MG and
7-OH-MG
NA COWS and
SOWS
No opioid-like
withdrawal
observed after
cessation of
either single or
15 day dosing.
Mild AEs including GI upset
(vomiting, nausea), dizziness,
fatigue. No serious AEs
reported.
Hematology, liver/kidney
panels normal.
Controlled clinical PK study of
kratom leaf capsules — first large
double-blind, placebo-controlled
trial with single and repeated dosing
Mean metabolite ratio of 7-OH-MG
ranged from 21-31% after a single
oral dose of kratom capsules (MTG
content 6.7-53.2mg) and 15-18%
after multiple doses of kratom.
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Mongar et al.
(2024)
Effects of
Itraconazole on
Pharmacokinetic
s of Mitragynine
and 7-
Hydroxymitragyni
ne in Healthy
Volunteers.
Kratom tea, MG, 7-
OH-MG
NA NA
Only single
dose study, no
tapering or
withdrawal
monitoring
Total of 15 AEs were
recorded during
period 1: drowsiness (56.2%),
vomiting (31.2%), dizziness
(31.2%), headache (18.7%),
fatigue (18.7%), and nausea
(12.5%), while other typical
AEs such as diarrhea, fever,
skin itchy, irritation,
constipation, anorexia, and
heartburn were not observed.
In period 2, the only AE
observed was vomiting
(6.3%).
All events were resolved
on the same day without any
treatment and did not lead to
any drop outs
After oral administration of kratom
tea (MTG content 23.6 mg), the
mean metabolite ratio of 7-OH-MG
was 11.5-16.2%.
The median Cmax for MTG of 159.12
± 8.68 ng/mL was attained in 0.84 h.
While median Cmax for 7-OH of
12.81 ± 3.39 ng/mL was observed at
1.77 h.
Tanna et al.
(2022)
Clinical
Pharmacokinetic
Assessment of
Kratom
(Mitragyna
speciosa), a
Botanical
Product with
Opioid-like
Effects, in
Healthy Adult
Participants
Kratom tea from
purified Mitragyna
speciosa (2 g)
NA NA Kratom tea was well-tolerated
in 5 of 7 enrolled participants.
2 participants experienced
nausea and vomiting; 1
withdrew due to these AEs,
and 1 was withdrawn due to
abnormal appearing urine
deemed likely unrelated to
kratom consumption.
2 participants experienced
lightheadedness and
headache, deemed unrelated
to kratom and related to
placement of IV catheter.
PK results of 3S and 3R alkaloids
included the following:
Plasma concentrations for 3S/3R
alkaloids were quantifiable 15 min
after consumption, suggesting rapid
absorption. Multiple peaks during
absorption reflected delayed GI
emptying common with opioids.
Minimal 3S/3R alkaloids were
excreted unchanged in urine.
3S alkaloids (MG, speciogynine, and
paynantheine) followed biphasic
concentration-time profile; displayed
higher peripheral volumes of
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No patients experienced
severe AEs.
distribution and clearance than 3R
alkaloids; exhibited longer terminal
t1/2, higher CL/F and Vz/F, lower
dose-normalized AUCinf and Cmax,
shorter Tmax than 3R alkaloids.
3R alkaloids (mitraciliatine,
speciociliatine, isopaynantheine)
followed monophasic concentration-
time profile.
Kamble et al.
(2021)
Pharmacokinetic
s of Eleven
Kratom Alkaloids
Following an Oral
Dose of Either
Traditional or
Commercial
Kratom Products
in Rats
Traditional Kratom
(lyophilized kratom
tea)
Commercial Kratom
(OPMS liquid shot)
NA NA NA Among the 11 alkaloids, only MG, 7-
OH-MG, speciociliatine, and
corynantheidine showed systemic
exposure 8 h postdose, and the
dose-normalized systemic exposure
of these four alkaloids was higher
(1.6−2.4-fold) following the
administration of the commercial
OPMS liquid. Paynantheine and
speciogynine levels were
quantifiable up to 1 h postdose,
whereas none of the other alkaloids
were detected.
Hiranita et al.
(2020)
Potential
Contribution of 7-
Hydroxymitragyni
ne, a Metabolite
of the Primary
Kratom
(Mitragyna
Speciosa)
Alkaloid
Mitragynine, to
the μ-Opioid
Activity of
MG and 7-OH
binding activity and
efficacy at the MOR
were compared
Plasma levels
following PO MG
administration were
measured
Antinociception in
In rats
discriminating
morphine (3.2
mg/kg, IP)
from vehicle,
the
discriminative
stimulus
effects of MG
were assessed
90 min after
PO
administration.
NA 32 mg/kg MG was lethal. Binding activity of 7-OH at MOR (Ki
= 78 nm) was 22-fold lower than
morphine and 9-0 fold higher than
MG.
Following PO administration of MG
(HCl salt, 55 mg/kg), Cmax of 7-OH
(85 ng/mL) was 14-fold less than
MG. Tmax of 7-OH and MG were 30
and 84 min, respectively.
7-OH is a more potent and
efficacious MOR agonist than MG,
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Mitragynine in
Rats
hotplate assay was
assessed
MG (up to 178
mg/kg)
produced 76%
morphine-lever
responding
(ED50=51
mg/kg).
suggesting that conversion to this
metabolite may contribute to the in
vivo MOR of MG.
Kamble et al.
(2020)
Metabolism of a
Kratom Alkaloid
Metabolite in
Human Plasma
Increases Its
Opioid Potency
and Efficacy
7-HMG in pooled
mouse, dog,
monkey, and human
plasma was
evaluated
NA NA NA Stability varied across species with
high stability in mouse, rat, and
monkey plasma (>80% 7-HMG
remained after 120 min),
intermediate stability in dog plasma
(>61% remaining after 120 min), and
low stability in human plasma (~40%
7-HMG remaining after 120 min).
Incubation of human plasma
produced an unknown converted
metabolite with NMR data matching
MGP.
Study findings suggest potential for
human plasma to form MGP.
Factor 4 History and Current Patterns of Abuse
Factor 5 The Scope, Significance and Duration of Abuse
Factor 6 What, if any, Risk is there to the Public Health
Broul et al.
(2025)
Case Report:
Cannabis and
kratom-induced
self-amputation
of ears and
penis.
NA NA NA NA 31 year old suffered severe
substance-induced psychosis
involving kratom and cannabis that
resulted in self-amputation.
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Grundmann et
al. (2025)
Prevalence and
Use Patterns of
Kratom
(Mitragyna
speciosa Korth.)
in a US
Nationally
Representative
Sample.
NA NA NA Adverse events more
frequently reported with
gummies/capsules/tablets/pill
s at higher doses
No 7-OH-MG specific data
Survey of 11,545 respondents,
1,049 current kratom users (9.1%
prevalence)
Motivations for use (among users):
Pain relief: 57.5% (n=603).
Relaxation/stress relief: 53.6%
(n=562).
Energy boost: 49.6% (n=520).
Higher reported frequency of kratom
shots/extract powder consumed was
correlated with use for pain relief
Hill, Boyer, et al.
(2025)
De facto opioids:
Characterization
of novel 7-
hydroxymitragyni
ne and
mitragynine
pseudoindoxyl
product
marketing.
7-OH-MG, MGP NA NA Did not assess withdrawal
directly, but authors noted
widespread online reports of
7-OH-MG dependence and
withdrawal
Identified 304 marketed 7-OH and/or
MGP products.
82.2% = 7-OH alone.
14.5% = 7-OH + MGP combos.
3.3% = MGP alone.
Formulations: chewable/sublingual
tablets (60.2%), liquid shots
(20.7%), gummies (4.3%), drink
mixes (4.0%), vapes (3.0%), syrups
(2.3%), capsules (2.0%), strips
(2.0%), food (1.3%), powder (0.3%).
Claims:
73.4% made “general wellbeing”
claims (focus ↑ 58%, relaxation
47%, energy boost 39%).
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37.8% made “functional” claims
(pain relief 26%, anxiety/stress
reduction 21%).
12.5% made explicit “drug” claims
(opioid receptor activity, analgesia,
sedation).
Dosing/costs:
Recommended dose range = 1-700
mg; mean = 20 mg/dose (7-OH
higher than MP).
MP mean recommended dose =
10.1 mg.
Mean cost per recommended dose
= $3.97 (7-OH); ~$5 for MP.
Marketing: 93.1% falsely marketed
as “kratom” despite being semi-
synthetic opioids. Many brands
mimic prescription medications
(names like “Curevana,” “Pain
Crusher Rx,” packaging like blister
packs or syrups).
Osawa and
Johnson (2025)
Postmortem
distribution of
mitragynine
and 7-
hydroxymitragyni
ne in 51 cases
Fluid and tissue
specimens from 51
postmortem cases to
investigate the
distribution of MG
and its active
metabolite 7-OH.
NA NA NA Central and peripheral blood
concentrations were compared, with
an average heart blood to femoral
blood ratio being 1.37 for MG and
1.08 for 7-OH. This ratio >1.0
suggests that MG has some
propensity toward postmortem
redistribution; however, the
difference in concentrations of MG
and 7-OH was not statistically
significant.
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Publication or
Source
Short Title or
Description
Comparators
Studied or
Mentioned
Abuse-related
Variables
Physical
Dependence &
Withdrawal
Safety Individual
Population
Comments
Large average MG to 7-OH ratios of
30.9 in femoral blood and 32.4 in
heart blood were observed
compared to average ratios of 14.8
in vitreous humor and 16.9 in urine.
Smith et al.
(2025)
The rise of novel,
semi-synthetic 7-
hydroxymitragnin
e products.
NA NA NA NA Letter to editor
Began marketing novel semi-
synthetic products with varying
routes of administration (e.g.
sublingual tablets, nasal sprays)
containing 14-25 mg.
7-OH-MG per labeled dose, often
with brand names alluding to
narcotics. These newly marketed
products may contain up to
98% 7-OH-MG, together with other
kratom alkaloids.
Concerningly, some product
formulations circumvent first-pass
metabolism, increasing
bioavailability.
Chronic 7-OH product use could
result in opioid-like physical
dependence and possibly addiction.
Scale and severity may be distinct
from kratom leaf-based and extract
products, which have not produced
widespread severe addiction, but
rather mild–moderate physical
dependence.
Currently, 7-OH products contain
trace amounts of MG and ‘new’
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Publication or
Source
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Description
Comparators
Studied or
Mentioned
Abuse-related
Variables
Physical
Dependence &
Withdrawal
Safety Individual
Population
Comments
chemicals yet to be identified. The
safety of these unknown chemicals
are unknown
Vadiei, Evoy
and Grundmann
(2025)
The Impact of
Diverse Kratom
Products on Use
Patterns,
Dependence,
and Toxicity
NA NA NA NA Although alkaloid content naturally
ranges from 2-5% in native leaf
material, it can be up to 60% in
concentrated extracts. Concentrated
kratom products may pose risks not
comparable to traditional use, and
may require regulatory oversight and
clinical evaluation before marketing
and therapeutic use.
White (2025)
Kratom's Use
and Impact on
Pediatric
Populations.
MG and 7-OH-MG NA NA Reviewed a case series of 6
neonates exposed prenatally:
withdrawal onset ~24 h after
birth (jitteriness, irritability,
vomiting, poor feeding,
crying). Treated successfully
with morphine or
buprenorphine taper .
Review/Letter
Poison control (2011–2017, n=1,807
exposures):
10.2% <20 years old.
48 children <13 (42 used kratom
only); 137 adolescents 13–19 (80
kratom only).
Admission rates after kratom-only
exposure: 14.3% (<13 yr), 21.3%
(13–19 yr), 27% (≥20 yr).
Symptoms: opioid-like (confusion,
drowsiness, nausea, vomiting),
stimulant-like (agitation, seizures,
tremor, tachycardia, hypertension,
chest pain, tachypnea). Respiratory
depression rare.
Children/adolescents may use as a
simulant “smart drug” or by athletes
for pain/stamina reasons.
Page 72 of 128
Publication or
Source
Short Title or
Description
Comparators
Studied or
Mentioned
Abuse-related
Variables
Physical
Dependence &
Withdrawal
Safety Individual
Population
Comments
Wightman and
Hu (2025)
A Case of 7-OH
Mitragynine Use
Requiring
Inpatient
Medically
Managed
Withdrawal.
NA NA NA Patient reported withdrawal
symptoms upon cessation of
7-OH use including anxiety,
insomnia, rhinorrhea,
abdominal discomfort,
restlessness, diaphoresis,
and chills
COWS score peaked at 14 on
day 2
38 year old man with history of
opioid use disorder reported
escalation of use including kratom to
7-OH.
Abstinent from opioids then started
using kratom at 31 (30 g a day)
3 months before presentation,
switched to 7-OH, with escalating
use (up to eight 30 mg tablets daily,
taking them every 1-2 hours).
Patient received buprenorphine and
transitioned to residential care.
Abbreviations: 7-OH-MG (7-HMG; 7-OH) = 7-hydroxymitragynine; AE(s) = adverse event(s)/adverse effect(s); BBB = blood brain barrier; Cmax = maximum concentration;
CNS = central nervous system; COWS = Clinical Opiate Withdrawal Scale; CPP = conditioned place preference; CYP = cytochrome; DOR = delta (δ)- opioid receptor; GI
= gastrointestinal; IC50 = half maximal inhibitory concentration; IP = intraperitoneal; Ki = inhibitor constant; IV = intravenous; KOR = kappa (ƙ)- opioid receptor; LLOQ =
lower limit of quantitation; MG (MTG) = mitragynine; MGP (MP) = mitragynine pseudoindoxyl; MOR = mu (µ)- opioid receptor; NA = not available; Oxy = oxycodone; P-gp
= P-glycoprotein; PK = pharmacokinetic; SC = subcutaneous; SOWS = Subjective Opiate Withdrawal Scale; t1/2 = half life; Tmax = time to maximum concentration.
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11.2 Appendix 2: Press Release: FDA Takes Steps to Restrict 7-OH Opioid
Products Threatening American Consumers
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11.3 Appendix 3: FDA Report: 7-Hydroxymitragyine (7-OH): An Assessment of the
Scientific Data and Toxicological Concerns Around an Emerging Opioid
Threat
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11.4 Appendix 4: FDA Slide Set: Preventing The Next Wave of the Opioid
Epidemic: What You Need to Know About 7-OH
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11.5 Appendix 5: Department of Health and Human Services Press Conference
Transcript
Measures to Safeguard American Public from Dangerous Opioid 7-OH
Participants:
HHS Secretary Robert F. Kennedy, Jr.
HHS Deputy Secretary Jim O’Neill
FDA Commissioner Dr. Marty Makary
Melody Woolf (chronic pain survivor).
Hubert H. Humphrey Building Auditorium
200 Independence Ave SW Washington, D.C.
Tuesday, July 29 at 10:30 AM Eastern Daylight Time.
Announcement accessed at https://www.hhs.gov/press-room/hhs-opioid-7oh-press-
conference-kennedy.html
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11.6 Appendix 6: Dr. Martin A. Makary 7-OH Letter to Colleagues