# EusomniaMD 7-Hydroxymitragynine Resource Center **Version:** 1.2 **Last reviewed:** August 8, 2026 **Author:** Brian Harris, MD **Contact:** bharris@eusomniamd.com > This combined editorial master contains the 12 core sections and appendices. The modular files remain canonical for individual webpage updates. ## Contents - [7-OH in 5 Minutes](#7-oh-in-5-minutes) - [What 7-OH Actually Is](#what-7-oh-actually-is) - [Pharmacology and Pharmacodynamics](#pharmacology-and-pharmacodynamics) - [Pharmacokinetics and Metabolism](#pharmacokinetics-and-metabolism) - [Toxicity and Overdose](#toxicity-and-overdose) - [Dependence and Withdrawal](#dependence-and-withdrawal) - [Treatment Framework for Clinicians](#treatment-framework-for-clinicians) - [Guide for Patients and Families](#guide-for-patients-and-families) - [Special Populations and Drug Interactions](#special-populations-and-drug-interactions) - [Public-Health and Legal Tracker](#public-health-and-legal-tracker) - [Evidence Library](#evidence-library) - [About the Author and Clinical Experience](#about-the-author-and-clinical-experience) - [Appendix A: Chemistry, Metabolism, and Detection](#appendix-a-chemistry-metabolism-and-detection) - [Appendix B: Clinical Assessment Template](#appendix-b-clinical-assessment-template) - [Appendix C: Source and Publication Notes](#appendix-c-source-and-publication-notes) - [Appendix D: Receptor and Target Catalogue](#appendix-d-receptor-and-target-catalogue) --- ## 7-OH in 5 Minutes *Source module: `01-7-oh-in-5-minutes.md`* **Public-health overview and PSA** **Audience:** patients, clinicians, treatment programs, journalists, and policymakers **Last reviewed:** August 8, 2026 > **The essential warning:** Concentrated commercial 7-hydroxymitragynine is not ordinary kratom leaf. It is a potent opioid-active drug sold in tablets, gummies, shots, powders, and sublingual products. Dependence, withdrawal, overdose, and naloxone-responsive respiratory toxicity are real. Regulation is warranted. People who are already dependent still need a treatment bridge rather than a legal cliff. ![Commercial products have been sold in ordinary retail settings](assets/retail_products.png) ### Who The immediate concern is not every person who has ever used botanical kratom. It is the growing population using **concentrated or semisynthetic 7-OH products**, sometimes every few hours, often without understanding that they are taking an opioid-active drug. The clinical population is heterogeneous: adolescents and older adults, people using it for pain or mood, people with prior opioid exposure, people who believed it was a safer supplement, and professionals who never expected a smoke-shop product to reorganize their day around withdrawal. America's Poison Centers recorded **593 reports involving 7-OH in all of 2025 and 901 reports from January through June 2026**. Among reports involving 7-OH alone, 38.8% were classified as serious, 63.8% were treated at a healthcare facility, and 20.5% were hospitalized. These are surveillance reports, not incidence estimates, but the direction of travel is not subtle. ([E01](11-evidence-library.md#e01)) ### What 7-hydroxymitragynine, usually called **7-OH**, is a minor natural kratom alkaloid and an active metabolite of mitragynine. Commercial products can contain concentrations far above botanical leaf exposure and may be produced by chemical conversion of mitragynine. Some products contain or are sold alongside **mitragynine pseudoindoxyl**, **MGM-15**, **MGM-16**, undeclared alkaloids, or oxidation products. Product labels are not reliable substitutes for chemical analysis. ([E09](11-evidence-library.md#e09), [E10](11-evidence-library.md#e10), [E11](11-evidence-library.md#e11), [E39](11-evidence-library.md#e39)) At the receptor level, 7-OH is a high-potency mu-opioid receptor agonist. Its measured intrinsic efficacy varies by assay and receptor reserve; it should not be dismissed as a weak drug merely because some systems describe partial agonism. G-protein-biased signaling is scientifically interesting, but it is not a certificate of respiratory safety. ([E12](11-evidence-library.md#e12), [E23](11-evidence-library.md#e23)) ### When Federal law has not changed merely because the waiting period expired. DEA published two **notices of intent** on July 6, 2026. One targets 7-OH above defined concentration or quantity thresholds; the other targets mitragynine pseudoindoxyl, MGM-15, and MGM-16 by name. DEA stated that temporary orders could be published on or after August 5, 2026 and would take effect upon publication. **No final federal temporary scheduling order was located during the last verification on August 8, 2026 at 07:43 UTC.** That status must be rechecked before publication or clinical/legal counseling. ([E02](11-evidence-library.md#e02), [E03](11-evidence-library.md#e03), [E04](11-evidence-library.md#e04)) California has already taken a different route. The California Department of Public Health states that kratom- and 7-OH-containing products are illegal to manufacture or sell **for consumption** under state food-and-drug law, and it is actively using embargoes, seizures, retailer enforcement, and litigation. That is not the same thing as saying California has placed every kratom product into the controlled-substances schedule. ([E06](11-evidence-library.md#e06), [E07](11-evidence-library.md#e07), [E08](11-evidence-library.md#e08)) ### Where These products have been sold online and through gas stations, convenience stores, smoke shops, vape stores, and specialty retailers. The ordinary retail setting is part of the hazard. It communicates legitimacy to consumers who would never purchase a bag of powder from an illicit dealer but will purchase a brightly labeled tablet next to the register. ### Why it matters Two public-health problems can occur simultaneously. The first is **treatment demand**. People who are already physiologically dependent may abruptly lose access, and many do not identify themselves as opioid users. Emergency departments, detoxification programs, outpatient addiction practices, poison centers, and low-barrier buprenorphine clinics may see an influx that is difficult to estimate because no credible national denominator exists. The second is **substitution risk**. Some patients will stop. Some will seek care. Some will stockpile. Others may turn to counterfeit pills, heroin, or fentanyl. There are not yet epidemiologic data proving how many will make that transition, so it should be described as a foreseeable risk rather than a measured outcome. Clinically, however, it is exactly the failure mode worth preventing. ### What clinicians should do now Ask directly about **7-OH, 7-hydroxy, kratom extracts, tablets, shots, films, gummies, and smoke-shop opioid-like products**. Document the product, labeled milligrams per unit, actual units per day, dosing interval, duration, nocturnal or interdose withdrawal, co-exposures, and whether loss of access might lead the patient to seek illicit opioids. Do not assume a negative routine opioid screen excludes exposure. Do not assume the label is accurate. Do not assume COWS captures the full syndrome. Do not assume that a fixed number of hours after the last dose makes buprenorphine automatically safe. The clinical state of the patient matters more than a stopwatch. ### What patients and families should do now Do not panic, stockpile, or switch to non-prescribed opioids. Do not mix 7-OH with alcohol, benzodiazepines, other opioids, or sedating drugs. If daily use has become difficult to stop, arrange medical care before supply disappears. Bring the package or a photograph of it to the appointment. If someone is difficult to awaken, breathing slowly or abnormally, turning blue or gray, having a seizure, or severely confused, administer naloxone if available and call 911. Poison Help in the United States is **1-800-222-1222**. ### LinkedIn-ready PSA **A public-health warning for clinicians, patients, detox programs, and anyone working near addiction medicine:** Concentrated 7-hydroxymitragynine, usually sold as 7-OH or 7-hydroxy, is becoming a larger clinical problem than most health systems appear prepared to manage. DEA has issued notices of intent to temporarily place qualifying concentrated 7-OH products and the related compounds mitragynine pseudoindoxyl, MGM-15, and MGM-16 into Schedule I. The final federal orders had not yet been located as of August 8, 2026, but once issued they may take effect upon publication. Products that patients have purchased openly at smoke shops, gas stations, and online may therefore undergo an abrupt legal and supply transition. I agree with the core public-health goal. Concentrated 7-OH should not be treated as benign kratom leaf. It is a potent opioid-active compound sold in consumer-friendly forms, often with uncertain composition and little meaningful warning. Experimental data demonstrate naloxone-reversible respiratory depression; human reports describe cardiopulmonary arrest, severe dependence, rapid redosing, and medically significant withdrawal; poison-center reports are rising sharply. The implementation risk is the problem. People who are already dependent will not become physiologically independent because a scheduling order appears in the Federal Register. Some will need urgent withdrawal treatment or medication for opioid use disorder. Some who have never entered an illicit opioid market may lose retail access and seek counterfeit pills or fentanyl. That is a predictable path to the emergency department, ICU, or morgue. I am a physician board-certified in Addiction Medicine, Anesthesiology, and Sleep Medicine. I have directly treated a practice-based case series in the teens spanning botanical kratom dependence and mild, moderate, and severe 7-OH use disorder, and I have provided informal consultation on dozens of additional 7-OH withdrawal cases. The patients have crossed age, sex, socioeconomic, and professional lines, including physicians. This is unpublished clinical experience rather than a controlled trial, and the published evidence remains sparse. In an emerging field, however, concentrated direct experience is part of the best available signal, provided it is labeled honestly. My request is simple: start asking now. Do not wait for patients to volunteer the correct chemical name. Do not assume a routine drug screen will identify the problem. Do not tell patients merely to white-knuckle withdrawal. Buprenorphine can be highly effective, including through standard or low-dose initiation strategies, but timing and setting should be individualized and clinician-directed. I am available through EusomniaMD for patient referrals, clinician-to-clinician consultation, lectures, detox-center consultation, and development of practical clinical workflows. **Contact:** bharris@eusomniamd.com **Resource center:** https://www.eusomniamd.com/7-oh-withdrawal This is not a defense of unregulated opioid products. It is a warning that removing the product without building a treatment bridge will leave predictable casualties in the gap. ### Evidence note The public-health claims above are supported principally by [E01-E12](11-evidence-library.md), [E23-E29](11-evidence-library.md), and [E46-E48](11-evidence-library.md). The author's case experience is **practice-based evidence, Grade D**, and should never be presented as a prevalence estimate or validated treatment trial. --- ## What 7-OH Actually Is *Source module: `02-what-7-oh-is.md`* **Kratom, mitragynine, 7-OH, pseudoindoxyl, and the semisynthetic retail market** **Audience:** clinicians, patients, journalists, policymakers, toxicologists **Last reviewed:** August 8, 2026 > **The naming problem is clinical, not cosmetic.** “Kratom” can refer to a leaf, a tea, a mitragynine-rich extract, a concentrated 7-OH tablet, a pseudoindoxyl product, an MGM analogue, or a mixture with uncertain contents. Those are not interchangeable exposures. ### Five categories that should be documented separately | Category | What it is | Typical chemical profile | Main clinical implication | |---|---|---|---| | **Botanical kratom leaf** | Dried or brewed *Mitragyna speciosa* leaf | Dozens of alkaloids, usually dominated by mitragynine; naturally occurring 7-OH is trace/low | Polyalkaloid exposure with opioid and nonopioid pharmacology; long mitragynine terminal phase | | **Mitragynine-rich extract** | Concentrated leaf extract, usually preserving several alkaloids | Higher mitragynine exposure; variable minor alkaloids; 7-OH may be present or form metabolically | Greater dose, longer accumulation, and interaction potential than ordinary leaf | | **Concentrated 7-OH product** | Isolated or chemically enriched 7-hydroxymitragynine in tablets, films, gummies, shots, powder, or other dosage forms | Milligram quantities of 7-OH, often far beyond botanical leaf exposure | Potent opioid-dominant exposure, rapid reinforcement, dependence, withdrawal, overdose risk | | **Mitragynine pseudoindoxyl product** | A rearrangement product downstream of 7-OH that is also manufactured and sold directly | MP alone or mixed with 7-OH/MG/other compounds | Potent opioid-active exposure; detection does not always distinguish direct ingestion from downstream formation | | **Emerging analogues and mixtures** | Semisynthetic derivatives such as MGM-15 and MGM-16, plus unlabeled combinations | Product-specific and often poorly characterized | Human PK, toxicity, withdrawal, and testing windows are largely unknown | ### Botanical kratom *Kratom* is the common name for the leaves of *Mitragyna speciosa*, a Southeast Asian tree. The plant contains more than 50 identified alkaloids. Mitragynine is usually the dominant alkaloid; other relevant parents include speciogynine, paynantheine, speciociliatine, mitraciliatine, isopaynantheine, corynantheidine, several oxindoles, and N-oxide derivatives. Traditional leaf exposure is chemically complex. It can produce stimulant-like, analgesic, sedating, and opioid-like effects depending on dose, preparation, individual metabolism, and co-exposures. That complexity matters, but it should not be projected indiscriminately onto a purified 7-OH tablet. Botanical kratom and isolated 7-OH share a chemical family; they are not the same drug experience. ### Mitragynine **Mitragynine (MG)** is the major botanical alkaloid and the main precursor to several active metabolites. It has lower human mu-opioid receptor potency than 7-OH and a comparatively long terminal phase in controlled botanical studies. Human CYP3A4 converts a portion of mitragynine to 7-OH, while CYP2C19, CYP2D6, CYP2C18, and other pathways contribute to additional metabolites. ([E16-E21](11-evidence-library.md)) Mitragynine also contributes to botanical kratom's nonopioid pharmacology. It is a low-potency partial agonist at alpha-1A adrenergic receptors and a low-potency competitive antagonist, not an agonist, at alpha-2A receptors in contemporary human-receptor assays. It is therefore inaccurate to describe mitragynine as simply “an alpha-2 agonist like clonidine.” ([E14](11-evidence-library.md#e14)) ### 7-hydroxymitragynine **7-hydroxymitragynine (7-OH, 7-HMG)** occupies three categories at once: 1. It occurs naturally in very small amounts in botanical kratom. 2. It is an active metabolite formed from mitragynine, principally through CYP3A4. 3. It is manufactured or enriched for direct sale as a semisynthetic retail opioid. The molecule is the same regardless of whether it was present in leaf, formed in the body, or produced in a laboratory. The exposure is not. A consumer taking a concentrated tablet receives a very different dose and concentration-time profile from a person drinking leaf tea in which 7-OH is sparse and continues to form gradually from mitragynine. Recent product analyses found 7-OH concentrations and alkaloid fingerprints inconsistent with authentic leaf material, supporting semisynthetic production. Other studies found disagreement between labels and measured contents, oxidation products, and undeclared opioid-active compounds. ([E09](11-evidence-library.md#e09), [E10](11-evidence-library.md#e10)) ### Mitragynine pseudoindoxyl **Mitragynine pseudoindoxyl (MP)** is a potent opioid-active rearrangement product downstream of 7-OH. Experimental work demonstrates rapid conversion of 7-OH to MP in human plasma ex vivo, but the fraction converted in living humans, the systemic half-life of MP, and its quantitative contribution to intoxication or withdrawal remain unknown. MP is also manufactured and sold directly, sometimes under kratom- or 7-OH-adjacent branding. This creates a forensic problem. A positive MP result can reflect direct MP ingestion, downstream formation after 7-OH exposure, or both. Until validated analyte-ratio methods exist, laboratory interpretation requires product history and context rather than a single molecule treated as a confession. ### MGM-15 and MGM-16 **MGM-15** is dihydro-7-hydroxymitragynine, a semisynthetic analogue rather than a human metabolite. Commercial products have been analytically confirmed. Published in-vitro work suggests strong human MOR and DOR binding, but there are no controlled human studies defining its bioavailability, half-life, metabolism, dose-response, respiratory risk, withdrawal, or treatment. **MGM-16** is 9-fluoro-dihydro-7-hydroxymitragynine. It is another synthetic or semisynthetic analogue with potent preclinical opioid activity and almost no direct human clinical pharmacology. DEA's July 2026 notice treats MGM-15 and MGM-16 as named compounds, separately from the concentration threshold applied to 7-OH. ([E04](11-evidence-library.md#e04), [E39](11-evidence-library.md#e39)) ### 3-dehydromitragynine and other transformation products **3-dehydromitragynine (3DM or 3DMTG)** is an oxidative mitragynine product identified in biological and commercial-product investigations. It has preclinical opioid activity and nonopioid toxicity signals at high experimental exposures. Recent work also found that 7-OH-containing products can change under simulated physiological conditions, which means the swallowed product may not remain chemically static after manufacture, storage, or ingestion. The clinical significance of 3DM in humans remains uncertain. ([E10](11-evidence-library.md#e10)) ### Why “natural” and “synthetic” are inadequate safety labels “Natural” does not mean safe, and “synthetic” does not by itself tell us the clinical risk. The relevant questions are concentration, route, rate of delivery, active metabolites, contaminants, co-formulated alkaloids, dosing interval, and actual human evidence. A concentrated 7-OH tablet can be chemically identical at the molecular level to 7-OH found in a leaf and still create a radically different risk because the dose, delivery, and surrounding alkaloid matrix are different. Conversely, a product marketed as “kratom extract” may be semisynthetic in everything but typography. ### What to record in a clinical history Document the exact product name, manufacturer, form, labeled milligrams per unit, actual units per day, route, dosing interval, duration, lot number, and co-exposures. Ask for a photograph or the package. Record whether the patient wakes in withdrawal, redoses during the night, uses the product to feel normal rather than intoxicated, or has moved from leaf to extracts to 7-OH or MP. Avoid charting only “kratom use.” That phrase may conceal the pharmacologic distance between a cup of leaf tea and a sublingual film taken every one to two hours. ### Detailed chemistry reference The full compound glossary, metabolic map, elimination summary, half-life table, analogue catalogue, and biological-testing matrix are preserved in [Appendix A: Chemistry, Metabolism, and Detection](appendices/appendix-a-chemistry-metabolism-detection.md). The core website should link to that appendix rather than reproducing its tables on every page. ### Evidence note Primary support: [E09-E22](11-evidence-library.md), [E37-E40](11-evidence-library.md), and Appendix A. Direct human data for MGM-15, MGM-16, and directly ingested MP remain **Grade U: data insufficient**. --- ## Pharmacology and Pharmacodynamics *Source module: `03-pharmacology-pharmacodynamics.md`* **Opioid receptors, signaling efficacy, nonopioid targets, and uncertainty** **Audience:** clinicians, pharmacologists, toxicologists, advanced readers **Last reviewed:** August 8, 2026 > **Bottom line:** The clinically dominant target of concentrated 7-OH is the mu-opioid receptor. Kappa- and delta-opioid effects are real in some human-receptor systems but assay-dependent. The broader serotonergic and adrenergic pharmacology belongs mainly to mitragynine, minor botanical alkaloids, and their metabolites, not automatically to purified 7-OH. ![Kratom-family pharmacology includes opioid and selected nonopioid pathways](assets/pharmacology.png) ### How to read receptor data Four terms are often collapsed into one: - **Affinity** asks how strongly a molecule binds. - **Potency** asks what concentration produces a defined effect in a particular assay. - **Efficacy** asks how large a response the ligand can produce relative to a reference agonist. - **Clinical relevance** asks whether human exposure reaches the needed concentration in the relevant tissue for long enough to matter. A radioligand-binding result is not proof of receptor activation. A molecular-docking paper is not proof of either. Even a functional assay can change with receptor density, coupling proteins, signal readout, species, and reference agonist. GPCR pharmacology is not obliged to fit neatly on a vendor's marketing card. ### Mu-opioid receptor: the dominant pathway 7-OH is a high-potency human mu-opioid receptor agonist. In the 2026 systematic human-receptor study, it bound hMOR with a Ki around 15 nM and produced cAMP signaling at roughly 10-14 nM with high measured efficacy in that system. Earlier lower-reserve BRET and G-protein assays described lower maximal efficacy. The correct synthesis is therefore: > **7-OH is a high-potency MOR agonist with strongly G-protein-biased and assay-dependent intrinsic efficacy. It behaves as a partial agonist in some systems and approaches full functional efficacy in others.** That is more accurate than either “full agonist” or “weak partial agonist” used without qualification. ([E12](11-evidence-library.md#e12)) Mitragynine is less potent at hMOR and is more consistently described as a partial agonist in human systems. Mitragynine pseudoindoxyl, 9-O-demethylmitragynine/9-hydroxycorynantheidine, speciociliatine, several oxindoles, and other minor alkaloids also show MOR activity. Some compounds are agonists, some antagonists, and one, speciophylline, acts as a positive allosteric modulator rather than a direct orthosteric agonist. ### Signaling bias is not proven human safety 7-OH and several related alkaloids preferentially engage G-protein signaling with little beta-arrestin-2 recruitment in some assays. This is often called **G-protein bias**. It is mechanistically interesting and may help explain differences from classical opioids. It does not justify the claim that 7-OH cannot cause respiratory depression, tolerance, or dependence. The same 2026 receptor paper explicitly cautions that the translation from in-vitro bias to in-vivo safety remains incompletely understood, and a rat respiratory study demonstrated naloxone-reversible ventilatory depression. ([E12](11-evidence-library.md#e12), [E23](11-evidence-library.md#e23)) ### Kappa-opioid receptor KOR findings vary by compound and assay. The 2026 human cAMP study found 7-OH to be a moderate-potency KOR agonist, while older human-receptor systems characterized mitragynine and 7-OH as weak, negligible, or antagonistic at KOR. Minor compounds such as mitraciliatine, isopaynantheine, speciociliatine, and mitragynine N-oxide can display clearer KOR agonism or mixed MOR-antagonist/KOR-agonist profiles. The defensible clinical statement is not that 7-OH “is a kappa drug.” It is that **secondary KOR activity is demonstrated in some functional systems, but its contribution to human intoxication, dysphoria, analgesia, or withdrawal is not quantified**. ### Delta-opioid receptor 7-OH is the main kratom-family compound with reproducible DOR activity in the newer human cAMP study, with functional potency in the low-hundreds-of-nanomolar range. MGM-15 and MP also have important delta-receptor pharmacology in preclinical or binding work. Again, the human clinical contribution is unknown. DOR activity may modify analgesia, mood, tolerance, or dependence, but the available evidence does not allow those effects to be assigned quantitatively. ### There is no gamma opioid receptor The established opioid receptors are mu, kappa, delta, and nociceptin/orphanin FQ receptor systems. “Gamma opioid receptor” is not an accepted target for 7-OH or kratom. Greek-letter typography has apparently done enough damage already. ### Serotonergic pathways The best-supported nonopioid receptor pathway in botanical kratom is **5-HT1A activation by metabolites of minor alkaloids**, particularly 9-O-desmethylspeciogynine and 9-O-desmethylpaynantheine. Their parent compounds bind several serotonin receptors, but the metabolites produced functional 5-HT1A agonism in human-receptor assays. Neither the parents nor these metabolites demonstrated 5-HT2B agonism in the cited work. ([E13](11-evidence-library.md#e13)) This is a plausible contributor to the mood and affective effects of full-spectrum botanical kratom. It does **not** establish purified 7-OH as a serotonergic antidepressant. Affective withdrawal symptoms after concentrated 7-OH are clinically real, but the mechanism may reflect opioid adaptation, sleep loss, stress-system activation, co-formulated alkaloids, preexisting illness, or several of those at once. ### Adrenergic pathways Contemporary human-receptor experiments found mitragynine to be: - a low-potency competitive **alpha-2A antagonist**, not a direct alpha-2 agonist; - a low-potency partial **alpha-1A agonist**, with an EC50 around 3 micromolar; - capable of downstream ERK activation through Gq/11-coupled alpha-1 receptors. Neither 7-OH nor 9-hydroxycorynantheidine supported the claim that the major metabolites directly activate alpha-2 receptors. These findings may contribute to stimulant-like or autonomic features of botanical/mitragynine-rich exposure, but clinical concentrations and importance remain uncertain. ([E14](11-evidence-library.md#e14)) ### Targets that should not be labeled as established activated receptors Binding or modeling has been reported at 5-HT2A, 5-HT2B, 5-HT2C, 5-HT7, dopamine receptors, muscarinic receptors, transporters, ion channels, and other targets. The evidence does not justify placing all of them on an “activated receptors” diagram. The website should distinguish: - **Functionally activated at plausible potency:** MOR; KOR/DOR in selected compounds and assays; 5-HT1A for the two O-desmethyl metabolites; alpha-1A for mitragynine. - **Binds or modulates without established activation:** several serotonin and dopamine targets, alpha-2A antagonism, hERG/channel effects, CYP enzymes, and speciophylline's MOR allosteric modulation. - **Unsupported or excluded as a principal mechanism:** CB1-mediated analgesia, direct alpha-2 agonism by mitragynine, and a “gamma opioid receptor.” ### Receptor summary table | Target | Best-supported compounds | Functional interpretation | Clinical confidence | |---|---|---|---| | **MOR** | 7-OH, MG, MP, 9-O-demethyl-MG, several minor alkaloids | Dominant opioid pathway; 7-OH high potency, efficacy assay-dependent | **High** | | **KOR** | 7-OH in some systems; mitraciliatine, isopaynantheine, speciociliatine, MG N-oxide | Secondary, compound- and assay-dependent agonism/antagonism | **Moderate mechanistic, low clinical quantification** | | **DOR** | 7-OH, MP, MGM-15 and selected analogues | Secondary agonism/binding; human contribution unknown | **Moderate mechanistic** | | **5-HT1A** | 9-O-desmethylspeciogynine, 9-O-desmethylpaynantheine | Functional agonism from minor-alkaloid metabolites | **Moderate mechanistic, low human exposure data** | | **alpha-1A** | Mitragynine | Low-potency partial agonism | **Established in vitro, uncertain clinical magnitude** | | **alpha-2A** | Mitragynine | Low-potency competitive antagonism; not activation | **Established in vitro** | | **MOR allosteric site** | Speciophylline | Positive allosteric modulation without intrinsic agonism | **Emerging mechanistic** | ### What remains uncertain Direct receptor occupancy in humans after commercial 7-OH dosing has not been measured. Human brain concentrations, active-metabolite contributions, receptor-residence time, pharmacodynamic hysteresis, tolerance mechanisms, and the relative roles of MOR, KOR, DOR, adrenergic, and serotonergic systems during withdrawal remain unknown. The strongest clinical conclusion remains the simplest: **concentrated 7-OH should be treated as a potent opioid exposure with additional product-dependent uncertainty, not as harmless kratom and not as a perfectly understood classical opioid.** ### Evidence note Primary support: [E12-E16](11-evidence-library.md), [E23](11-evidence-library.md), [E32-E33](11-evidence-library.md), and [Appendix D: Receptor and Target Catalogue](appendices/appendix-d-receptor-target-catalogue.md). Receptor potency values are assay-specific and should not be converted into human dose equivalence. --- ## Pharmacokinetics and Metabolism *Source module: `04-pharmacokinetics-metabolism.md`* **What is known from botanical kratom and mitragynine studies, and what remains unknown after direct commercial 7-OH exposure** **Last reviewed:** August 8, 2026 > ## Critical limitation > > Controlled human pharmacokinetic studies have primarily administered botanical kratom or mitragynine-rich extracts, not the repeated high-dose purified 7-OH products now used by dependent patients. A half-life measured after mitragynine exposure can be distorted by continued metabolic formation of 7-OH. It should not be treated as the intrinsic elimination half-life of directly ingested purified 7-OH. ### Core pathway ```text Mitragynine |-- CYP3A --> 7-hydroxymitragynine (7-OH) | |-- plasma/liver-associated rearrangement --> mitragynine pseudoindoxyl (MP) | '-- oxidative/degradation pathways --> 3-dehydromitragynine and related products | |-- CYP2C19 / CYP2D6 / CYP3A --> 9-O-demethylmitragynine | '-- glucuronide and sulfate conjugates | |-- CYP2D6 / CYP2C19 / CYP2C18 --> 16-carboxymitragynine '-- additional oxidation, hydrolysis, reduction, glucuronidation, and sulfation --> urine ``` Speciogynine and paynantheine also undergo O-demethylation to metabolites with 5-HT1A agonist activity in functional assays. [E13, E16-E20] ### What controlled human studies tell us #### Botanical tea A controlled 2 g kratom-tea study measured mitragynine, 7-OH, and other alkaloids in plasma and urine. In that specific botanical context, 7-OH had a terminal half-life on the order of several hours, while mitragynine exhibited much longer terminal kinetics. Targeted urine remained analytically informative through the study’s 120-hour collection period. That does **not** mean every patient remains positive for five days, nor that direct 7-OH has a five-day biologic effect. [E20] #### Mitragynine-rich extract and repeated dosing Repeated extract studies document accumulation of mitragynine and several parent alkaloids, with dose- and regimen-dependent 7-OH exposure. These data are useful for understanding MG-rich products but cannot be substituted for purified 7-OH PK. [E21, E37] #### CYP3A formation in humans In healthy volunteers, itraconazole reduced 7-OH exposure and increased mitragynine exposure, supporting CYP3A-mediated formation of 7-OH in humans. This also means CYP3A inhibitors or inducers can change the relative MG/7-OH exposure after botanical or MG-rich products. [E19] ### What direct 7-OH data do not yet tell us No adequate controlled human study has established, for high-dose commercial 7-OH: - absolute oral or sublingual bioavailability; - Cmax and Tmax across modern tablets, films, shots, or gummies; - intrinsic distribution and elimination half-life; - accumulation with dosing every one to three hours; - fraction converted to MP in vivo; - effect of hepatic or renal impairment; - nonlinear kinetics at high exposure; - relationship between blood concentration, receptor occupancy, withdrawal onset, and overdose; - a validated interval for safe conventional buprenorphine initiation. Rat PK suggests rapid absorption and low oral bioavailability in that species, but rat findings are not a human dosing guide. [E22] ### Formation-limited kinetics After mitragynine ingestion, 7-OH can continue to appear while MG remains available for metabolism. The terminal slope of measured 7-OH may therefore reflect the rate of **formation** as much as the rate of its own elimination. This is called formation-limited kinetics. It is one reason apparently conflicting half-life estimates across botanical studies should not be averaged into a single authoritative number. Direct purified 7-OH exposure may behave differently because the patient bypasses much of the precursor step. Commercial products can also use sublingual delivery, which may alter first-pass metabolism and onset. [E29] ### Elimination Mitragynine and related alkaloids undergo extensive hepatic metabolism followed by phase-II conjugation and urinary excretion of metabolites. A small unchanged urinary fraction does not mean the kidney is irrelevant; it means much of the urinary signal is metabolite rather than parent compound. [E17] For 7-OH, MP, MGM-15, MGM-16, and 3DM, human mass-balance studies are not available. Their exact renal versus biliary elimination fractions are unknown. ### Practical testing #### Routine urine drug screens A standard “opiates” immunoassay is designed around morphine-like structures. It generally does **not** specifically detect mitragynine, 7-OH, MP, MGM-15, or MGM-16. A negative routine opioid screen therefore does not contradict a credible 7-OH history. #### Targeted testing Compound-specific testing is possible with LC-MS/MS, LC-HRMS, LC-QTOF-MS, and related methods. Validated assays exist for mitragynine, 7-OH, and several botanical alkaloids/metabolites in plasma, urine, and hair. [E37-E38] Analytical sensitivity is not a clinical detection window. A laboratory can detect a trace concentration after pharmacologic effect has ended, and a less sensitive assay can be negative during clinically important exposure. #### Interpretation rules - **7-OH positive:** can reflect direct 7-OH ingestion or metabolism from mitragynine. - **MP positive:** can reflect direct MP exposure or downstream formation from 7-OH. - **Mitragynine positive with 7-OH negative:** does not exclude a prior 7-OH-containing product, especially if the timing or assay differs. - **Routine opioid screen negative:** does not exclude intoxication, dependence, or withdrawal. - **Qualitative urine result:** should not be used to back-calculate the last dose. - **Hair result:** may support historical exposure but is poor for acute timing. ### Detection matrix | Compound | Targeted plasma/blood | Targeted urine | Hair | Validated clinical window | |---|---:|---:|---:|---| | Mitragynine | Yes | Yes | Yes | No universal window; often longer than 7-OH after botanical exposure | | 7-OH | Yes | Yes | Yes | **Unknown for direct high-dose purified use** | | 9-O-demethylmitragynine | Limited/research | Yes | Limited | Unknown | | 16-carboxymitragynine | Limited/research | Yes | Limited | Unknown | | MP | Method-dependent | Method-dependent | Limited | Unknown; route cannot always be inferred | | 3DM | Research/forensic | Research/forensic | Unknown | Unknown | | MGM-15 | Forensic targeted methods | Forensic targeted methods | Unknown | Unknown | | MGM-16 | In principle with standard/HRMS | In principle with standard/HRMS | Unknown | Unknown | ### Drug-interaction implications Botanical kratom at a low controlled dose modestly increased oral midazolam exposure, consistent with intestinal CYP3A inhibition, while not meaningfully changing dextromethorphan exposure in that study. High-dose products may present different interaction risks. [E35] CYP3A inhibition can also reduce conversion of MG to 7-OH while increasing MG exposure. That does not automatically make the combination safer, because the parent and metabolite have different target profiles and commercial products may already contain 7-OH directly. [E19] ### Full compound catalogue The detailed active-metabolite glossary, analogues, half-life table, elimination pathways, and compound-specific detection notes are preserved in [Appendix A: Chemistry, Metabolism, and Detection](appendices/appendix-a-chemistry-metabolism-detection.md). That appendix is the canonical chemistry reference for the site. --- ## Toxicity and Overdose *Source module: `05-toxicity-overdose.md`* **Evidence-ranked clinical manifestations and practical response** **Last reviewed:** August 8, 2026 > ## Emergency > > If a person is difficult to awaken, breathing slowly or abnormally, blue or gray around the lips, having a seizure, or showing severe confusion after using 7-OH or a kratom-derived product, administer naloxone if available and call 911. Provide rescue breathing or CPR if trained and indicated. Poison Help in the United States is **1-800-222-1222**. ### Evidence hierarchy The strongest evidence supports opioid-like respiratory toxicity, altered consciousness, gastrointestinal effects, autonomic abnormalities, dependence, and withdrawal. Seizures and major neuropsychiatric presentations are reported but are often confounded by coexposures or uncertain product composition. Organ-specific chronic risks from isolated 7-OH remain poorly characterized. | Manifestation | Evidence | Confidence and interpretation | |---|---|---| | **Respiratory depression / apnea** | Controlled animal data, naloxone reversal, human arrest report, poison-center signal | **High concern.** Direct human incidence is unknown, but concentrated 7-OH should be treated as capable of opioid overdose. [E23-E24] | | **Somnolence, unresponsiveness, loss of consciousness** | Poison-center reports and human cases | **High concern**, especially with alcohol, benzodiazepines, other opioids, gabapentinoids, or sedatives. [E01, E06-E08] | | **Nausea, vomiting, constipation, abdominal symptoms** | Poison surveillance, opioid pharmacology, withdrawal cases | **Common and credible.** Vomiting increases aspiration/dehydration risk. [E01, E25] | | **Tachycardia and hypertension** | Poison-center surveillance and clinical reports | **Established signal**, but frequency and mechanism vary by product and coexposure. [E01, E29] | | **Seizure** | Surveillance and case reports | **Reported, but single-agent causality is often uncertain.** Treat as an emergency. [E01, E28] | | **Agitation, confusion, hallucinations, psychosis** | Surveillance and complex cases | **Reported.** Consider withdrawal, coexposure, sleep deprivation, nicotine/stimulants, infection, or primary psychiatric illness. [E01, E28] | | **Arrhythmia / QT effects** | Mitragynine hERG studies, botanical-user ECG studies, individual 7-OH cases | **Plausible but not quantified for isolated 7-OH.** Obtain ECG/electrolytes in significant toxicity or cardiac risk. [E29, E32-E33] | | **Liver injury** | Prospective botanical kratom DILIN series | **Real for broader kratom products**, but isolated 7-OH-specific hepatotoxicity is not established. [E31] | | **Endocrine, thyroid, reproductive toxicity** | Sparse broader kratom case literature | **Data insufficient for isolated 7-OH.** Do not present as characteristic toxicity. | | **Chronic cognitive or neurologic injury** | Inadequate direct data | **Data insufficient.** Acute hypoxia, seizures, or polysubstance exposure can cause secondary injury. | ### Respiratory toxicity In awake rats, intravenous 7-OH reduced respiratory rate, tidal volume, and minute ventilation. Naloxone reversed the depression. Its potency for producing a 50% reduction in minute ventilation was 4.5-fold greater than morphine **in that experimental model**. That ratio cannot be translated into a human tablet-equivalence claim because species, route, formulation, and endpoint differ. [E23] A human report described cardiopulmonary arrest after reported 7-OH use with revival following naloxone. One case does not define incidence, but it confirms that severe opioid-like toxicity is no longer merely hypothetical. [E24] ### Factors that increase overdose risk The clearest modifiable risk is **combined central nervous system depression**. Alcohol, benzodiazepines, fentanyl or other opioids, gabapentin/pregabalin, sedating antihistamines, sleep medications, and other sedatives can add to respiratory impairment. Product mislabeling further complicates dose prediction. [E06-E10] Additional risk factors include opioid-naive use of a high-dose product, rapid redosing, sublingual or other fast-onset formulations, recent abstinence with lost tolerance, switching to an unfamiliar brand, hepatic or respiratory disease, sleep apnea, frailty, pregnancy, and use alone where no one can administer naloxone. ### Public response to suspected overdose 1. Try to wake the person and assess breathing. 2. Call 911. 3. Give naloxone if available. Repeat according to the product instructions and dispatcher guidance if there is no adequate response. 4. Provide rescue breathing or CPR if trained and needed. 5. Place the person on their side once breathing adequately if aspiration is a concern. 6. Stay with them. Do not assume a brief response means the danger is over. 7. Tell responders exactly what products may have been used, including packaging or photographs. Naloxone is appropriate because the dominant dangerous mechanism is opioid receptor activation. It will not correct every coingestant, seizure cause, arrhythmia, or metabolic abnormality, so emergency evaluation remains necessary. [E06-E08, E23-E24] ### Emergency-department and inpatient considerations Management follows opioid/toxicologic principles while accounting for product uncertainty: - airway, breathing, ventilation, oxygenation, and repeated naloxone as clinically indicated; - continuous cardiorespiratory monitoring in significant toxicity; - ECG and electrolytes when there is tachycardia, syncope, chest pain, QT-risk medication use, or severe poisoning; - glucose, renal function, hepatic tests, creatine kinase, and acid-base assessment when prolonged unresponsiveness, seizure, hyperthermia, or immobilization is present; - evaluation for acetaminophen, salicylate, ethanol, fentanyl/other opioids, benzodiazepines, stimulants, nicotine, and other coexposures based on history and presentation; - poison-center or medical-toxicology consultation for severe or unusual cases; - observation duration based on clinical course, formulation, coexposures, response to naloxone, and uncertainty rather than a presumed short half-life; - addiction-medicine engagement before discharge when dependence or recurrent use is evident. A negative routine opioid immunoassay should not dissuade treatment when the clinical syndrome and product history support 7-OH exposure. ### Seizures and severe neuropsychiatric presentations Seizures appear in surveillance data and case literature, but commercial-product variability and polysubstance exposure make direct attribution difficult. The complex 7-OH/nicotine withdrawal case involved high-dose nicotine, precipitated withdrawal, agitation, psychosis, and respiratory compromise. It demonstrates that severe syndromes can occur; it does not establish that uncomplicated 7-OH withdrawal routinely causes psychosis or intubation. [E28] When severe agitation or psychosis occurs, broaden the differential rather than forcing every symptom into an opioid-withdrawal box. Consider stimulant or nicotine toxicity/withdrawal, anticholinergic exposure, serotonin toxicity, sedative withdrawal, sleep deprivation, infection, metabolic disease, or primary psychiatric illness. ### Cardiac effects Mitragynine inhibits hERG current in vitro, and traditional kratom-user studies show more sinus tachycardia and borderline QTc without a clear excess of prolonged QTc. These are not direct isolated-7-OH data. Nevertheless, commercial 7-OH products may contain MG or other active compounds, and severe cases have included supraventricular tachycardia. [E29, E32-E33] Clinicians should be more cautious in patients with congenital long-QT syndrome, Brugada syndrome, structural heart disease, significant electrolyte disturbance, or concurrent QT-prolonging drugs. Direct risk magnitude is unknown. ### Liver injury and organ toxicity Kratom-associated drug-induced liver injury is established at case-series level, commonly with jaundice and hospitalization, but the available cases largely involve botanical or mixed products. The website should say **“liver injury is recognized in the broader kratom literature; isolated commercial 7-OH risk is inadequately characterized.”** [E31] Renal failure, rhabdomyolysis, and compartment injury can occur secondarily after prolonged unconsciousness, seizure, hyperthermia, dehydration, or polysubstance poisoning. They should not be advertised as unique receptor-mediated 7-OH syndromes. ### Product-quality toxicity A patient may be harmed by the intended 7-OH dose, by an unexpectedly high dose, by MP or another analogue, by degradation products, or by an entirely undeclared drug. Analytical studies show enough inconsistency that “the label said 20 mg” should be documented as a claim, not a measurement. [E09-E11, E38] ### Harm-reduction message People who continue to use despite counseling should avoid using alone, avoid mixing depressants, carry naloxone, start lower after any abstinence, avoid rapid redosing, keep products away from children, and seek treatment before supply disruption. This is not endorsement. It is the unromantic work of keeping people alive long enough to change course. --- ## Dependence and Withdrawal *Source module: `06-dependence-withdrawal.md`* **Phenomenology, a provisional clinical timeline, COWS limitations, and practice-based experience** **Last reviewed:** August 8, 2026 > ## Evidence boundary > > There is no validated prospective 7-OH withdrawal time-course study. The timeline below is a **best-available clinical synthesis**, derived from published cases, an early case series, opioid pharmacology, and the author’s unpublished clinical experience. It should help people plan, not pretend that every patient owns the same clock. ### Dependence phenotype Concentrated 7-OH can produce a pattern resembling dependence on a short-acting opioid: - escalating dose or potency; - redosing every one to three hours; - waking overnight or early in the morning in withdrawal; - using primarily to avoid sickness rather than to obtain a desired effect; - rapid return of anxiety, restlessness, chills, sweating, pain, or GI symptoms between doses; - inability to reduce despite repeated attempts; - substantial spending, secrecy, work disruption, or family conflict; - craving and fear of losing access; - substitution between brands, formulations, or other opioids. A published patient using a sublingual 7-OH film progressed to one film every one to two hours within weeks. Another reported roughly 360 mg/day before abrupt cessation. A separate inpatient case reached a COWS score of 14 and was managed with symptom-guided buprenorphine before residential care. [E25, E29, E49] ### Typical symptom domains **Opioid-like symptoms:** yawning, lacrimation/rhinorrhea, piloerection, chills, sweating, restlessness, myalgias, abdominal cramping, nausea, vomiting, diarrhea, tachycardia, hypertension, insomnia, and craving. **Affective and cognitive symptoms:** anxiety, dysphoria, irritability, poor concentration, fatigue, anergia, and low mood. These may outlast the most obvious autonomic and gastrointestinal phase. **Product-specific or mixed symptoms:** tremor, unusual stimulation, severe insomnia, agitation, or symptoms related to nicotine, stimulants, alcohol, benzodiazepines, gabapentinoids, or other undeclared compounds. Botanical kratom and mixed extracts can involve more polypharmacology than purified 7-OH. [E12-E14, E28] ### Provisional withdrawal timeline | Time from last dose | Best-available expectation | Confidence | |---|---|---| | **0-8 hours** | Heavy, high-frequency users may notice interdose withdrawal: craving, anxiety, restlessness, yawning, chills, sweating, pain, or GI discomfort. Some patients may still feel relatively well, particularly after larger or mixed products. | **Practice-based / emerging** | | **8-24 hours** | Clinically significant withdrawal often becomes clearer. Insomnia, myalgias, abdominal symptoms, diarrhea, autonomic activation, and distress may intensify. | **Emerging** | | **16-36 hours** | A reasonable **provisional peak window** for many short-acting 7-OH presentations, but not a validated universal range. Some peak earlier; some remain severe or worsen later. | **Provisional** | | **Days 2-3** | Often the roughest overall period for autonomic, GI, sleep, anxiety, and craving symptoms. One patient evaluated around 48 hours remained substantially symptomatic despite COWS 5; another inpatient case reached COWS 14. | **Emerging** [E25, E49] | | **Days 3-5** | For many patients, vomiting/diarrhea, chills, sweating, and pain begin to ease. Sleep disruption, anxiety, dysphoria, fatigue, and craving may remain prominent. | **Practice-based / indirect** | | **Day 5 through 2+ weeks** | Acute physical withdrawal usually fades, but insomnia, low mood, fatigue, restlessness, cue-triggered craving, and impaired concentration can persist. Duration is highly variable and influenced by coexisting psychiatric illness, sleep debt, polysubstance use, and treatment. | **Practice-based / botanical analogy** | ![Evidence-banded provisional 7-OH withdrawal timeline](assets/withdrawal_timeline_evidence_bands.svg) The infographic is deliberately labeled provisional. Its numbers should not be used as a warranty, a home-detox schedule, or a fixed buprenorphine clock. ### Why COWS can under-read the problem The Clinical Opiate Withdrawal Scale remains useful for documenting objective opioid-withdrawal findings and tracking change. It was not designed around 7-OH products, mixed kratom alkaloids, or semisynthetic analogues. COWS can underweight: - severe insomnia and sleep deprivation; - dysphoria, fatigue, and anergia; - product-specific stimulation or tremor; - disproportionate abdominal distress without dramatic objective signs; - mixed nicotine, stimulant, sedative, or serotonergic symptoms; - the patient’s rapidly fluctuating state after frequent redosing. In the high-dose published case, the patient had nausea, diarrhea, cramping, restlessness, chills, clamminess, and anxiety around 48 hours after the last dose while the recorded COWS was only 5. That does not invalidate COWS. It means the score is one instrument, not the patient. [E25] ### Buprenorphine timing and precipitated withdrawal Buprenorphine can be highly effective, but standard induction should be based on **clear clinical withdrawal**, product history, last use, objective findings, and clinician judgment rather than a single elapsed-time rule. A nine-patient series reported successful standard and low-dose initiations without precipitated withdrawal; a separate complex case involving heavy nicotine use reported precipitated withdrawal after buprenorphine. [E26, E28] The best current public-facing recommendation is: > **Do not self-induce from an internet clock. Seek a qualified clinician. Conventional induction should wait for convincing objective withdrawal; low-dose initiation may be preferable when product composition, timing, tolerance, or prior precipitated withdrawal makes the transition uncertain.** The direct high-dose human PK needed to name a universally safe “earliest hour” does not exist. ### Practice-based clinical experience Brian Harris, MD reports directly treating a practice-based series in the teens involving kratom and concentrated 7-OH dependence, with severity ranging from relatively uncomplicated withdrawal to high-dose, high-frequency use. He has also provided informal consultation on dozens of additional 7-OH withdrawal cases involving people across age, sex, profession, and socioeconomic circumstance, including physicians. [E48] This experience supports the clinical usefulness of asking about actual milligrams, units, interval, nocturnal withdrawal, product form, and coexposures rather than using the word “kratom” as a proxy for severity. It also informs the provisional timeline above. It does **not** establish prevalence, a validated average peak, comparative treatment efficacy, or a generalizable dose-conversion formula. The clinical series is unpublished and has not yet been analyzed as a formal research cohort. ### Who is more likely to need monitored care Higher-risk features include very high or uncertain dose, one-to-three-hour redosing, prior overdose, severe vomiting/diarrhea or dehydration, seizure disorder, significant cardiac disease, pregnancy, extremes of age, severe psychiatric illness, polysubstance use, concurrent sedative dependence, unstable housing/support, prior precipitated withdrawal, or likely transition to illicit opioids if symptoms become intolerable. ### The fentanyl substitution risk No study currently quantifies how many dependent 7-OH users will transition to fentanyl when retail access contracts. The risk is nevertheless plausible and foreseeable. A patient with high opioid tolerance, severe withdrawal, no treatment access, and no established illicit-market experience may encounter counterfeit pills with unpredictable fentanyl content and dose as though entering a casino whose principal payout is respiratory arrest. Every withdrawal plan should therefore include naloxone, direct counseling about counterfeit pills, rapid access to buprenorphine or methadone when indicated, and short follow-up intervals. --- ## Treatment Framework for Clinicians *Source module: `07-treatment-for-clinicians.md`* **A risk-stratified approach to concentrated 7-OH dependence and withdrawal** **Last reviewed:** August 8, 2026 > **Scope:** This is a clinician-facing framework derived from emerging published evidence, established opioid-use-disorder practice, toxicology principles, and the author’s practice-based experience. It is **not** a nationally validated 7-OH guideline. There is no universally validated dose-conversion formula, withdrawal clock, COWS threshold, or buprenorphine induction schedule specific to direct high-dose commercial 7-OH exposure. Published experience is nevertheless clinically useful. A 2026 retrospective series described nine patients using purified 7-OH products; eight successfully initiated and stabilized on buprenorphine, using either standard or low-dose initiation, with no precipitated withdrawal reported in that series. Additional outpatient and inpatient cases describe successful buprenorphine treatment after heavy use, while a 14-patient opioid-treatment-program series supports methadone as another viable option for selected kratom/7-OH use disorder. Other reports show why uncertain product composition, coexposures, and atypical symptom burden can complicate induction. [E25-E29, E49-E51] ### The governing principle Treat the **patient’s exposure, physiology, and clinical state**, not the word *kratom* on a package and not a fixed number of hours on a clock. Commercial products may contain concentrated 7-OH, mitragynine pseudoindoxyl, 3-dehydromitragynine, MGM-15, MGM-16, other alkaloids, or mislabeled quantities. Direct human pharmacokinetics for repeated high-dose purified 7-OH remain inadequately defined. A patient reporting the same labeled daily dose as another patient may therefore have a different effective exposure, product composition, metabolism, and induction risk. [E09-E10, E18-E22, E39] ### Step 1: Identify the exposure Ask specifically about **7-OH, 7-hydroxy, hydroxie, kratom extract tablets, sublingual films, shots, gummies, capsules, powders, MGM-15, MGM-16, and pseudoindoxyl**. Many patients will deny “opioid use” because they purchased the product from a gas station, smoke shop, or website. Document or photograph the package when possible. Record: - product and manufacturer; - labeled milligrams per unit and units per day; - estimated total labeled milligrams per day; - route and redosing interval; - duration of use and escalation over time; - nocturnal or interdose withdrawal; - last dose and time of first symptoms; - prior attempts to stop and any prior precipitated withdrawal; - co-use of kratom leaf, extracts, prescription opioids, counterfeit pills, fentanyl, alcohol, benzodiazepines, gabapentinoids, stimulants, nicotine, and sedating medications. Do not convert the exposure into morphine milligram equivalents. No clinically validated 7-OH-to-MME conversion exists, and receptor potency, intrinsic efficacy, route, product variability, active metabolites, and tolerance make such arithmetic falsely precise. ### Step 2: Assess severity beyond COWS COWS remains useful for documenting familiar objective opioid-withdrawal findings, but it may under-represent the total syndrome. In a published patient taking approximately 360 mg/day, prominent gastrointestinal, autonomic, restlessness, and affective symptoms were present about 48 hours after the last dose despite a recorded COWS of only 5. [E25] Add a structured assessment of: - insomnia and inability to remain still or rest; - anxiety, dysphoria, irritability, and panic-like distress; - craving and perceived likelihood of seeking another opioid; - nausea, diarrhea, abdominal cramping, hydration, and oral intake; - myalgias, tremor, chills, diaphoresis, and temperature dysregulation; - tachycardia, hypertension, chest symptoms, syncope, or arrhythmia; - confusion, psychosis, seizure, or severe agitation; - functional collapse despite modest observable signs. The most important induction question is not simply “How many hours has it been?” It is whether the patient has developed a sufficiently convincing and evolving withdrawal state for the selected transition strategy. ### Step 3: Identify features that change the treatment setting Consider observed, emergency-department, hospital, or medically managed withdrawal rather than routine home initiation when there is: - suspected overdose, respiratory depression, or recurrent sedation; - severe dehydration, persistent vomiting, uncontrolled diarrhea, electrolyte risk, or inability to take oral medication; - seizure, delirium, psychosis, severe agitation, or uncertain polysubstance withdrawal; - clinically significant arrhythmia, chest pain, syncope, marked QTc prolongation, or unstable blood pressure; - pregnancy; - very young or older/frail age; - significant hepatic, renal, respiratory, neurologic, or cardiac disease; - heavy alcohol or benzodiazepine use, or concurrent fentanyl/other opioid dependence; - an unreliable product history with possible MGM-15, MGM-16, pseudoindoxyl, counterfeit opioids, or unknown adulterants; - repeated failed outpatient attempts, prior severe precipitated withdrawal, or inability to adhere to monitoring; - imminent likelihood of substituting fentanyl, counterfeit pills, or another non-prescribed opioid. A history of obstructive sleep apnea, chronic lung disease, sedative use, or sleep-related hypoventilation matters during both intoxication and early stabilization. “Partial agonist” is not a permission slip for pharmacologic optimism. ### Step 4: Select the transition pathway #### Pathway A: Standard buprenorphine initiation Standard initiation is reasonable when the product history is reasonably clear and the patient demonstrates convincing, progressive opioid withdrawal. Use the clinician’s established buprenorphine protocol, with reassessment after each step and attention to symptoms that may not be captured by COWS. There is **no evidence-based universal minimum interval** after the last 7-OH dose. Many patients using short-acting products may be ready within the general window expected for short-acting opioids, but heavy or atypical users may require longer. Direct high-dose human PK is unknown, products are heterogeneous, and some patients may have concurrent mitragynine or longer-lived active compounds. A rule such as “always safe after 12, 16, or 24 hours” is not supportable. [E20-E22, E25-E29] #### Pathway B: Low-dose buprenorphine initiation Low-dose initiation is a reasonable clinician-supervised option when: - the last exposure is uncertain; - the patient redoses every one to three hours and cannot tolerate abstinence; - there is possible mixed exposure to mitragynine, pseudoindoxyl, MGM analogues, fentanyl, or other opioids; - conventional initiation previously failed or caused precipitated withdrawal; - medical or psychiatric instability makes a severe withdrawal spike particularly hazardous; - the patient is already taking a full agonist under medical supervision and a gradual transition is clinically indicated. The published nine-patient series included six low-dose initiations and supports feasibility, not a single standardized regimen. Local protocols, formulation availability, monitoring capacity, and the patient’s concurrent opioids should determine the schedule. [E26] #### Pathway C: Methadone Methadone can be appropriate when the patient has very high opioid tolerance, cannot stabilize on buprenorphine, prefers methadone, has repeated relapse during prior buprenorphine treatment, or would benefit from the structure of an opioid treatment program. It should be treated as standard evidence-based OUD care, with attention to QTc risk, sedating co-medications, respiratory disease, and uncertain 7-OH product composition. In a 2026 retrospective opioid-treatment-program series of 14 patients, 64% reported both kratom and 7-OH use, 13 remained in treatment at last follow-up, and no adverse events were reported. The mixed exposure and small sample prevent isolated-7-OH conclusions, but the series supports feasibility. [E50-E51] #### Pathway D: Symptomatic treatment without MOUD A limited symptomatic approach may be reasonable for mild, brief exposure without compulsive use, significant craving, repeated failed cessation, or high risk of substitution. It is usually a poor stand-alone strategy for a patient who is repeatedly dosing to prevent withdrawal, awakening in withdrawal, spending substantial time or money obtaining the product, or likely to seek another opioid when symptoms escalate. ### Step 5: Manage the non-opioid burden Adjunctive treatment can be selected from familiar opioid-withdrawal practice, individualized to comorbidity and setting. Relevant categories include alpha-2 adrenergic agonists for autonomic symptoms, antiemetics, antidiarrheals when appropriate, nonopioid analgesics, hydration/electrolyte replacement, muscle-spasm treatment, and carefully selected sleep support. Avoid reflexively stacking sedatives. Benzodiazepines, alcohol, gabapentinoids, sedating antipsychotics, antihistamines, and other CNS depressants can compound respiratory and cognitive risk. Concurrent benzodiazepine or other CNS-depressant use is not, by itself, a reason to categorically withhold buprenorphine or methadone, but it does require explicit risk management, monitoring, and treatment of any separate sedative dependence. Severe agitation, psychosis, or seizure should trigger reassessment for coexposure, withdrawal from another substance, metabolic illness, and need for a higher level of care rather than being presumed to be a routine 7-OH symptom. [E28, E54] ### Step 6: Prevent the predictable failure mode The regulatory transition creates a specific near-term hazard: a patient accustomed to a retail opioid may lose supply before recognizing the severity of dependence. Counsel directly that counterfeit pills and street opioids may contain fentanyl and that attempting to reproduce a familiar 7-OH effect with another opioid is not dose-equivalent, predictable, or safe. Before discharge or outpatient initiation: - provide or prescribe naloxone and train the patient and household; - ask explicitly whether the patient has considered fentanyl, counterfeit pills, or another opioid; - arrange rapid follow-up, not a distant “return as needed” plan; - confirm access to the chosen medication and pharmacy or opioid treatment program; - review safe storage, especially around children; - provide a clear escalation plan for respiratory symptoms, seizure, severe confusion, chest symptoms, dehydration, or inability to remain safe. ### Step 7: Treat the use disorder, not merely the first 72 hours Acute withdrawal relief is not the endpoint. Reassess craving, sleep, mood, pain, financial and occupational consequences, family impact, and the original reason for use. Determine whether maintenance MOUD, a later taper, behavioral treatment, pain treatment, sleep treatment, or psychiatric care is indicated. A rush to discontinue buprenorphine immediately after stabilization may recreate the same cycle of withdrawal and urgent drug-seeking under a different label. Because insomnia, dysphoria, fatigue, anergia, and craving may outlast the gastrointestinal and autonomic syndrome, schedule follow-up through the first several weeks. Persistent symptoms should be evaluated rather than automatically attributed to “post-acute withdrawal”; coexisting depression, anxiety, sleep disorders, pain, other substance use, and medication effects remain common. ### Suggested documentation language > The patient reports repeated use of a concentrated commercial 7-hydroxymitragynine/kratom-derived product with physiologic dependence and withdrawal. Product composition and direct high-dose 7-OH pharmacokinetics are uncertain. Treatment planning is based on the reported exposure, objective withdrawal findings, supplemental symptom assessment, coexposures, medical risk, and established OUD principles. The patient was counseled regarding naloxone, fentanyl/counterfeit-pill risk, and the danger of substituting non-prescribed opioids. ### Evidence confidence **Moderate and emerging:** Buprenorphine can successfully stabilize many patients with problematic purified 7-OH use; methadone is feasible for selected kratom/7-OH use disorder in an opioid treatment program. [E25-E27, E49-E51] **Provisional:** Low-dose initiation may reduce transition difficulty in selected patients, but no 7-OH-specific protocol has been validated. [E26] **Established by broader OUD evidence, extrapolated here:** Methadone and buprenorphine are effective medications for OUD; naloxone reverses opioid respiratory depression; treatment retention matters more than producing a heroic detoxification anecdote. **Data insufficient:** A universal 7-OH-to-buprenorphine interval, dose conversion, COWS threshold, maintenance dose, detoxification duration, or preferred induction method. ### Consultation and referrals Brian Harris, MD, is available through EusomniaMD for patient evaluation, clinician-to-clinician consultation, treatment planning, lectures, and development of withdrawal-management workflows for outpatient practices and detoxification programs. **Contact:** bharris@eusomniamd.com [Return to the Resource Center](index.md) | [Patient and family guide](08-guide-for-patients-families.md) | [Special populations and interactions](09-special-populations-drug-interactions.md) | [Evidence Library](11-evidence-library.md) --- ## Guide for Patients and Families *Source module: `08-guide-for-patients-families.md`* **What to expect, when to seek help, and how treatment works** **Last reviewed:** August 8, 2026 > ## The central message > > Concentrated 7-hydroxymitragynine (7-OH) can cause real opioid dependence. Withdrawal can be severe, but it is treatable. Do not wait until the last tablet is gone to make a plan, and do not replace 7-OH with street opioids or counterfeit pills. That is how a difficult withdrawal becomes an overdose. ### What 7-OH is 7-OH is an opioid-active compound related to kratom. Tiny amounts may occur naturally in kratom leaf, but many modern tablets, gummies, shots, films, powders, and capsules contain concentrated or semisynthetic 7-OH at levels far beyond ordinary botanical exposure. Some products also contain mitragynine pseudoindoxyl or other related compounds, and labels may not match laboratory measurements. [E09-E11] A product being sold at a gas station, smoke shop, or ordinary website does not make it mild, accurately labeled, or safe. ### Signs that dependence has developed Dependence is likely when a person: - needs progressively larger amounts or stronger products; - doses every few hours or wakes during the night in withdrawal; - takes the product mainly to avoid feeling sick; - develops anxiety, sweating, chills, restlessness, pain, abdominal cramping, nausea, diarrhea, or insomnia between doses; - has tried to stop and repeatedly returned because symptoms were intolerable; - spends more time or money obtaining the product than intended; - hides use, misses obligations, or organizes the day around the next dose; - is considering switching to prescription pills, heroin, or fentanyl because access is changing. These are medical warning signs, not a character assessment. ### What withdrawal may feel like 7-OH withdrawal commonly resembles withdrawal from a short-acting opioid. Heavy users may notice symptoms within hours of a missed dose. Symptoms may include restlessness, anxiety, yawning, sweating, chills, gooseflesh, muscle aches, abdominal cramping, nausea, vomiting, diarrhea, tremor, fast heart rate, elevated blood pressure, inability to sleep, low mood, irritability, and intense craving. [E25-E30, E49] The available human evidence is still small. A practical estimate is that clinically important symptoms often become clearer during the first 8-24 hours, many patients experience their roughest physical period during approximately days 1-3, and the most obvious gastrointestinal and autonomic symptoms often begin easing over days 3-5. Sleep disruption, fatigue, low mood, anxiety, and craving may last longer. This is a provisional pattern, not a promise. Product composition, dose, dosing interval, duration, other substances, medical illness, and treatment can move the timeline substantially. ### When to seek urgent or emergency care Call 911 for inability to awaken, slow or abnormal breathing, blue or gray lips, seizure, severe confusion, collapse, chest pain, fainting, or dangerous agitation. Give naloxone if available when opioid overdose is possible. Stay with the person and provide rescue breathing or CPR if trained and indicated. [E23-E24, E52] Seek prompt medical assessment rather than attempting an unsupervised home withdrawal when there is pregnancy, a seizure disorder, significant heart or lung disease, sleep apnea with sedative use, repeated vomiting or diarrhea, dehydration, older or very young age, serious psychiatric symptoms, heavy alcohol or benzodiazepine use, concurrent fentanyl or prescription-opioid dependence, prior severe precipitated withdrawal, or an unreliable/unknown product. ### How treatment works #### Buprenorphine Buprenorphine can relieve withdrawal and craving and can stabilize people with significant 7-OH dependence. Published reports now include individual cases, an inpatient withdrawal report, and a nine-patient series in which both standard and low-dose initiation strategies were used; eight of nine patients successfully initiated and stabilized, with no precipitated withdrawal reported in that series. [E25-E27, E49] Buprenorphine should not be started from a rigid internet countdown. Taking a standard dose before sufficient withdrawal has developed can cause precipitated withdrawal, a sudden worsening caused by rapid displacement of the prior opioid from receptors. A clinician may recommend waiting for convincing withdrawal, using a low-dose initiation, or choosing a monitored setting depending on the product, timing, tolerance, other opioids, and medical risk. #### Methadone Methadone is another evidence-based treatment for opioid use disorder and can be appropriate when buprenorphine is not suitable or has not worked. A 2026 series described 14 patients treated in opioid treatment programs for kratom use disorder; most had used both kratom and 7-OH, 13 remained in treatment at last follow-up, and no adverse events were reported. This is encouraging but still early evidence. [E50] #### Symptom-relief medications Clinicians may use medications for autonomic symptoms, nausea, diarrhea, pain, muscle spasm, sleep, hydration, and electrolytes. These medications can make withdrawal more tolerable, but they do not provide the same protection against craving, relapse, or substitution as medication treatment for a severe opioid-use-disorder pattern. #### Ongoing treatment The goal is not simply to survive the first three days. Treatment should address craving, sleep, mood, pain, the reason 7-OH was started, other substance use, and the risk of returning to 7-OH or moving to a more dangerous opioid. Some patients benefit from ongoing buprenorphine or methadone rather than a rapid taper. Duration is individualized. [E51] ### What not to do Do not attempt to reproduce the effect of 7-OH with counterfeit tablets, street fentanyl, heroin, leftover prescription opioids, or someone else's methadone or buprenorphine. There is no dependable dose conversion. Fentanyl content is unpredictable, tolerance can be misjudged, and a person who previously bought a labeled retail product may have no experience judging an illicit supply. Do not combine 7-OH with alcohol, benzodiazepines, other opioids, gabapentinoids, or other sedatives. The effects on breathing can add together. Do not take naltrexone while physically dependent on 7-OH or another opioid unless a qualified clinician has confirmed an adequate opioid-free interval. Naltrexone can precipitate severe withdrawal. [E53] Do not assume a negative routine “opiates” urine screen means the product is absent. Standard immunoassays often do not detect 7-OH or mitragynine; targeted mass-spectrometry testing is required. [E17, E37-E38] ### How families can help Remain calm, obtain naloxone, learn the overdose signs, and help arrange medical care before the supply crisis becomes an emergency. Ask what the product is called, how many milligrams are listed per unit, how many units are used daily, how often dosing occurs, and whether the person wakes in withdrawal. Photograph packaging and ingredient labels. Do not confiscate a dependent person's entire supply without a treatment plan unless there is an immediate safety emergency; abrupt forced withdrawal can drive secretive use or substitution. During treatment, help with transportation, hydration, medication pickup, child care, and a low-conflict environment. Monitor for severe depression, confusion, seizure, breathing changes, or plans to obtain street opioids. Support is useful. Surveillance, moral prosecution, and amateur pharmacology generally are not. ### Planning before regulation or retail removal People who use 7-OH daily should arrange assessment now rather than stockpiling. Regulation may reduce future harm, but it does not erase existing dependence. A clinician can help determine whether outpatient treatment is reasonable, whether observed care is safer, and whether buprenorphine, methadone, or a limited symptomatic plan fits the severity. ### Getting help Brian Harris, MD, is available through EusomniaMD for evaluation of kratom and 7-OH dependence, clinician consultation, and treatment planning. **Contact:** bharris@eusomniamd.com **Resource center:** https://www.eusomniamd.com/7-oh-withdrawal For treatment-location assistance in the United States, SAMHSA's National Helpline is **1-800-662-HELP (4357)**. For poisoning questions, Poison Help is **1-800-222-1222**. [Return to the Resource Center](index.md) | [Withdrawal timeline](06-dependence-withdrawal.md) | [Treatment framework for clinicians](07-treatment-for-clinicians.md) | [Evidence Library](11-evidence-library.md) --- ## Special Populations and Drug Interactions *Source module: `09-special-populations-drug-interactions.md`* **A risk-focused reference with conspicuous “data insufficient” designations** **Last reviewed:** August 8, 2026 > ## The most honest headline > > Direct human data for concentrated commercial 7-OH are inadequate in pregnancy, lactation, children, older adults, hepatic or renal impairment, seizure disorders, structural heart disease, and most drug-interaction settings. Clinical caution should be based on opioid pharmacology, product uncertainty, broader kratom evidence, and the patient's physiologic reserve, not on invented precision. ### Population-specific considerations | Population or condition | What is supported | What remains unknown | Practical clinical implication | |---|---|---|---| | **Pregnancy** | Maternal and neonatal withdrawal have been reported after prenatal kratom exposure; a systematic review found withdrawal in all six published case reports it included. [E34] | Direct concentrated-7-OH fetal PK, teratogenicity, obstetric risk, and preferred induction strategy are unknown. | Avoid abrupt unsupported cessation. Coordinate addiction medicine and obstetrics. Treat significant opioid dependence with established pregnancy OUD principles rather than improvising a retail-product detox. | | **Lactation** | No dependable direct safety dataset. Opioid-active alkaloids and metabolites could plausibly enter milk. | Milk concentrations, infant exposure, and clinical outcomes for 7-OH/MP/MGM analogues are unknown. | Individual specialist assessment is required. Monitor infants for sedation, poor feeding, respiratory difficulty, or withdrawal if exposure changes. | | **Children and adolescents** | Poison-center reports and candy-like formulations create accidental-ingestion risk. [E01, E05] | Pediatric dose-response, PK, neurodevelopmental effects, and safe exposure do not exist. | Any significant ingestion warrants Poison Help/medical assessment. Store locked and out of sight; “child-resistant” packaging is not child-proof. | | **Older or frail adults** | General opioid physiology predicts greater vulnerability to sedation, falls, delirium, respiratory depression, constipation, dehydration, and polypharmacy. | No geriatric 7-OH trials or validated dosing adjustments. | Lower threshold for monitored care, medication reconciliation, ECG/electrolytes, and evaluation of cognition and falls. | | **Seizure disorder** | Seizures appear in surveillance and case reports, but causal attribution to isolated 7-OH is uncertain and often confounded. [E01, E28] | Incidence, threshold dose, mechanism, and interaction with antiseizure therapy are unknown. | A seizure history raises the threshold for home withdrawal. Avoid dehydration, sleep deprivation, abrupt sedative withdrawal, and unreviewed interacting drugs. | | **Cardiac disease / arrhythmia risk** | Tachycardia and hypertension occur in reports; mitragynine inhibits hERG in vitro; a 7-OH case included supraventricular tachycardia. [E01, E29, E32-E33] | Isolated-7-OH QT risk and arrhythmia incidence are unknown. | Obtain ECG/electrolytes in significant toxicity, syncope, chest symptoms, marked tachycardia, congenital channelopathy, or QT-prolonging polypharmacy. | | **Respiratory disease / sleep apnea** | 7-OH produces opioid respiratory depression in animal models and severe human opioid-like toxicity has been reported. [E23-E24] | Risk by dose, formulation, sleep stage, OSA severity, COPD, obesity hypoventilation, or home PAP use is unknown. | Avoid sedative combinations, provide naloxone, and consider monitored initiation/observation when reserve is limited. | | **Hepatic disease** | Kratom-associated liver injury is established in broader botanical/mixed-product literature. [E31] | Isolated 7-OH hepatotoxicity, hepatic clearance, and dose adjustment are not established. | Review liver tests and products in symptomatic or high-risk patients. Do not label every kratom DILI case as proven 7-OH toxicity. | | **Renal disease** | Metabolites and conjugates are recovered in urine, and dehydration/rhabdomyolysis can secondarily injure kidneys. [E17] | Direct renal clearance fraction and dosing effects in CKD are unknown. | Correct volume/electrolyte problems and use conservative monitored care in advanced disease. | | **Psychiatric illness** | Anxiety, dysphoria, insomnia, craving, agitation, and confusion occur during intoxication or withdrawal; severe reports are frequently confounded. [E01, E25, E28] | A distinct 7-OH-induced depressive, psychotic, or suicidality syndrome is not established. | Assess suicide risk, psychosis, mania, sleep deprivation, other substances, and medication toxicity. Do not dismiss severe distress because COWS is modest. | | **Chronic pain** | Many users begin kratom/7-OH for pain; repeated short-acting dosing can produce tolerance and opioid-induced behavioral cycles. | Comparative analgesic efficacy, hyperalgesia risk, and long-term outcomes are unknown. | Build a parallel pain plan. Removing the opioid without treating the pain is a particularly efficient way to make the opioid reappear. | ### Drug-interaction matrix #### Highest-concern combinations | Combination | Concern | Evidence boundary and response | |---|---|---| | **Alcohol, benzodiazepines, fentanyl/other opioids, gabapentinoids, sedating sleep agents, sedating antihistamines, antipsychotics, muscle relaxants** | Additive sedation, impaired airway protection, and respiratory depression | Strong pharmacologic concern; exact 7-OH interaction magnitude is unknown. Avoid or closely manage combinations, provide naloxone, and do not use “partial agonist” as reassurance. | | **Unprescribed opioids used to self-treat withdrawal** | Overdose, counterfeit fentanyl exposure, unstable tolerance, and treatment delay | No reliable 7-OH-to-other-opioid conversion exists. Counsel explicitly against substitution and provide rapid MOUD access. | | **Naltrexone** | Precipitated opioid withdrawal while physiologically dependent | Documented with kratom; direct 7-OH-specific interval is unknown. Confirm adequate opioid-free status clinically before use. [E53] | #### Metabolic interactions Mitragynine is converted to 7-OH largely through CYP3A-mediated oxidation, with additional pathways involving CYP2C19 and CYP2D6. A controlled human itraconazole study reduced 7-OH exposure while increasing mitragynine exposure after botanical/MG exposure, confirming that CYP3A inhibition changes the parent-metabolite balance. [E19] A low-dose controlled kratom-tea study increased oral midazolam AUC by approximately 39% and Cmax by approximately 50% without materially changing half-life, consistent with intestinal CYP3A inhibition. It did not meaningfully alter dextromethorphan exposure in that study. These data concern a 2 g botanical tea exposure, not high-dose purified 7-OH, and should not be inflated into a universal interaction table. [E35] **Potential CYP3A inhibitors** include azole antifungals, certain macrolides, protease inhibitors, some calcium-channel blockers, and grapefruit products. **Potential inducers** include rifampin, carbamazepine, phenytoin, and St. John's wort. The direction of effect may differ depending on whether the patient is ingesting mitragynine that must be converted to 7-OH or ingesting 7-OH directly. Commercial mixtures make prediction worse. For direct purified 7-OH, the responsible human clearance enzymes, transporter effects, and magnitude of CYP interactions remain incompletely defined. Rat data suggest CYP3A involvement in clearance, but that is not a human prescribing rule. [E22] #### Serotonergic and adrenergic combinations Botanical kratom contains multiple alkaloids, and metabolites of speciogynine and paynantheine activate 5-HT1A receptors in laboratory systems. Mitragynine has low-potency alpha1A agonism and alpha2A antagonism. [E13-E14] This does not prove that purified 7-OH is itself a clinically meaningful serotonergic or stimulant drug. Serotonin toxicity has been reported in a patient using very high-dose kratom with venlafaxine and quetiapine, plausibly involving pharmacokinetic interactions. [E36] The correct conclusion is that mixed botanical/extract products may interact with serotonergic drugs, not that every 7-OH patient has a serotonin syndrome waiting politely in the lobby. #### QT-prolonging medications Because product mixtures may include mitragynine or other compounds and because tachycardia, electrolyte loss, and QT-risk polypharmacy can coexist, review methadone, antipsychotics, antidepressants, antiemetics, macrolides, fluoroquinolones, and other QT-prolonging agents in severe use or withdrawal. Direct isolated-7-OH QT data remain insufficient. ### Buprenorphine or methadone with benzodiazepines Concurrent benzodiazepines increase sedation and overdose risk, but they are not an automatic reason to deny evidence-based OUD medication. FDA advises that buprenorphine and methadone should not be withheld solely because a patient uses benzodiazepines or other CNS depressants; careful medication management is required because untreated opioid addiction may be more dangerous. [E54] Assess whether benzodiazepine dependence itself is present. Abrupt benzodiazepine cessation can cause seizures and delirium. The patient may need a coordinated plan rather than simultaneous uncontrolled withdrawal from two physiologically consequential drug classes. ### Laboratory and monitoring implications A negative routine opioid immunoassay does not exclude 7-OH exposure. Use targeted LC-MS/MS or high-resolution mass spectrometry when analytical confirmation would change care. ECG, electrolytes, renal function, hepatic tests, creatine kinase, pregnancy testing, and coingestant testing should be driven by presentation and risk rather than ordered as a ceremonial toxicology bouquet. ### Evidence summary **Established:** additive risk with other respiratory depressants; CYP3A participates in MG-to-7-OH formation; botanical kratom can inhibit intestinal CYP3A; broader kratom products can cause dependence, neonatal withdrawal, and liver injury. [E19, E31, E34-E36] **Emerging:** cardiac/autonomic and seizure signals in commercial 7-OH users; successful treatment with buprenorphine or methadone in small clinical reports. [E25-E29, E49-E50] **Data insufficient:** quantitative direct-7-OH interaction magnitudes, pregnancy/lactation PK, pediatric or geriatric safety, renal/hepatic dosing, seizure incidence, isolated hepatotoxicity, and organ-specific long-term toxicity. [Return to the Resource Center](index.md) | [Pharmacokinetics and metabolism](04-pharmacokinetics-metabolism.md) | [Treatment framework](07-treatment-for-clinicians.md) | [Evidence Library](11-evidence-library.md) --- ## Public-Health and Legal Tracker *Source module: `10-public-health-legal-tracker.md`* **Federal and selected state developments** **Last verified:** August 8, 2026, 07:54 UTC > ## Status warning > > This is a dated public-health tracker, not legal advice and not a complete 50-state survey. Controlled-substance status, food-and-drug enforcement, retail restrictions, and pending legislation are different legal mechanisms. Verify the primary source on the day a legal conclusion matters. ### Federal status #### Concentrated 7-OH DEA published a **notice of intent** on July 6, 2026 to temporarily place 7-hydroxymitragynine above specified thresholds into Schedule I. The notice states that a temporary order may be published on or after August 5, 2026 and would impose Schedule I controls when issued. As of the verification time above, this resource did **not locate a subsequently published temporary scheduling order** in the Federal Register. Therefore the correct federal wording is **“temporary Schedule I action pending,” not “already federally Schedule I.”** [E02-E03] The proposed threshold covers: - botanical *Mitragyna speciosa* material containing more than **0.050% 7-OH by dry weight**; - synthetic articles containing more than **0.050%** 7-OH by weight/weight, weight/volume, or volume/volume, or more than **1.00 mg per article**; - processed extracts, concentrates, edibles, pressed pills, and other dosage forms above the same concentration or per-article threshold. [E03] DEA states that ordinary botanical kratom below the threshold is not the target of this temporary action. The molecule's source, however, does not change its intrinsic pharmacology; the threshold is a regulatory distinction designed to separate trace botanical content from enhanced or synthesized products. #### MP, MGM-15, and MGM-16 A separate July 6, 2026 notice announces DEA's intent to temporarily place **mitragynine pseudoindoxyl, MGM-15, and MGM-16** into Schedule I. The notice concerns the named compounds rather than a botanical concentration threshold. This tracker likewise did not locate a final temporary order as of the verification time above. [E04] #### FDA position FDA states that concentrated or enhanced 7-OH products are not approved drugs, lawful dietary ingredients, or authorized food additives, and it has recommended federal scheduling and taken seizure/enforcement action against commercial products. FDA's current public-health focus distinguishes concentrated 7-OH products from natural kratom leaf while warning that products may contain MP and related analogues. [E05, E46-E47] #### What changes when a federal temporary order is published Once effective, covered manufacture, distribution, sale, import/export, research, reverse distribution, and possession become subject to the Controlled Substances Act's Schedule I controls and sanctions. Exact criminal exposure depends on conduct, quantity, intent, prior history, resulting injury, and federal/state jurisdiction. Schedule I does not mean every simple-possession case produces the maximum distribution penalty, but the legal transition is still abrupt and consequential. For patients, the practical message is simple: do not assume that a product remains lawful merely because it was bought openly before the order, and do not wait for law-enforcement clarification to seek treatment for dependence. ### Selected state actions | Jurisdiction | Verified development | Status as of date above | Clinical relevance | |---|---|---|---| | **California** | CDPH states that kratom- and 7-OH-containing foods, dietary supplements, and unapproved drugs are illegal to manufacture or sell for consumption under state food-and-drug law. Enforcement has included retailer notices, embargoes/seizures, and litigation; CDPH reported six Los Angeles County deaths linked to 7-OH and later more than $5 million in products seized. [E06-E08] | **Active food/drug enforcement.** This is not the same as a blanket California controlled-substance schedule listing. | Retail access can contract before federal scheduling; clinicians should screen and create treatment pathways now. | | **Connecticut** | State guidance reports placement of kratom and 7-OH in Schedule I effective March 25, 2026. [E42] | **Effective.** Verify the current state schedule for legal reliance. | Possession/distribution consequences may already differ from federal status. | | **Florida** | Florida Emergency Rule 2ER26-1 was published in June 2026, and the official Florida rule record lists an effective date of July 1, 2026. It places specified 7-OH-related compounds into Schedule I under the rule's concentration and composition terms. Covered compounds include 7-OH, mitragynine pseudoindoxyl, 7-acetoxymitragynine, 9- and 10-hydroxycorynantheidine, MGM-15, and MGM-16. [E43] | **Emergency rule active as verified; duration, replacement, and permanent codification require current rule review.** | Florida already has state criminal exposure even while the federal temporary orders remain pending. | | **New York** | S8925A would prohibit sale of products exceeding 2% of total alkaloids or 1 mg 7-OH per serving. The official record shows passage by Senate and Assembly in June 2026; it is not shown as signed by the governor on the current bill page. [E44] | **Passed both chambers; not yet shown as enacted.** | Proposed civil retail prohibition is not identical to Schedule I control. | | **Texas** | State health authorities issued a public-health advisory concerning kratom and concentrated 7-OH. [E45] | **Health advisory verified; not itself a scheduling action.** | Supports clinician screening, naloxone, and public education without implying criminal status. | Other states and municipalities have adopted or proposed kratom/7-OH restrictions. Because legislative language, thresholds, effective dates, and whether the action is civil, food/drug, age-restriction, or criminal vary substantially, this resource will add jurisdictions only after verifying a primary government source. ### Public-health indicators America's Poison Centers reported **593 7-OH exposure reports during 2025 and 901 during January-June 2026**. Among 7-OH-only reports, 38.8% were classified as serious, 63.8% were treated at a healthcare facility, and 20.5% were hospitalized. These reports cannot provide a population incidence or dependent-user denominator, but they show a rapidly growing clinical signal. [E01] Analytical market research has found hundreds of commercial semisynthetic 7-OH/MP products, high measured 7-OH concentrations inconsistent with authentic leaf, frequent label discrepancies, oxidation byproducts, and evidence of semisynthetic origin in most examined 7-OH-labeled products. [E09-E11] ### Treatment-capacity concern The number of people physiologically dependent on concentrated 7-OH remains unknown. Poison-center reports, adverse-event databases, and seizures do not supply the denominator. Abrupt retail removal can nevertheless create a foreseeable wave of withdrawal, urgent treatment demand, stockpiling, and substitution with illicit opioids. This is not an argument against controlling concentrated 7-OH. It is an argument for pairing regulation with clinician alerts, naloxone distribution, rapid buprenorphine and methadone access, poison-center coordination, retailer disposal guidance, and surveillance for fentanyl substitution and overdose. ### Tracker update protocol At each update, verify: 1. Federal Register documents by exact title, docket, and action type. 2. DEA and FDA public pages for wording changes. 3. State statute, administrative code, health-department notice, or official bill record. 4. Effective date and whether the action is temporary, permanent, civil, administrative, food/drug, age-restricted, or criminal. 5. Thresholds by concentration, serving, article, or named compound. 6. The prior version in [CHANGELOG.md](CHANGELOG.md). Corrections should be dated, preserve the prior claim in the changelog, explain why it changed, and avoid quietly rewriting history. Regulation already supplies enough drama without editorial time travel. [Return to the Resource Center](index.md) | [7-OH in 5 minutes](01-7-oh-in-5-minutes.md) | [Evidence Library](11-evidence-library.md) --- ## Evidence Library *Source module: `11-evidence-library.md`* **Version:** 1.2 **Last reviewed:** August 8, 2026 **Scope:** Primary papers, regulatory documents, surveillance reports, practice-based evidence, and update/correction policy for the EusomniaMD 7-OH Resource Center. > **Evidence labels used throughout this resource** > > - **Grade A - high confidence:** authoritative regulation/surveillance, controlled human data, validated analytical work, or convergent high-quality evidence. > - **Grade B - moderate/emerging:** small human series, well-documented cases, cross-sectional human studies, or strong mechanistic evidence with clinical concordance. > - **Grade C - provisional/indirect:** animal, in-vitro, modeling, confounded case evidence, or extrapolation from botanical kratom/mitragynine to concentrated 7-OH. > - **Grade D - practice-based hypothesis:** unpublished clinical experience or expert synthesis. > - **Grade U - insufficient:** no dependable direct evidence. Grades describe confidence in a specific claim, not the prestige of a journal or the moral worth of its authors. A paper can be excellent and still be indirect for the question at hand. ### Quick registry | ID | Topic | Source | Grade | Main limitation | |---|---|---|---:|---| | **E01** | Surveillance | [America’s Poison Centers. Health Advisory: Serious Illnesses Associated with Kratom and 7-OH Products.](https://poisoncenters.org/news-alerts/13651143) | **A** | Voluntary exposure reports; undercounting, reporting bias, incomplete product verification, and coexposures limit incidence and causality estimates. | | **E02** | Federal regulation | [U.S. Drug Enforcement Administration. DEA to Temporarily Schedule 7-OH and Related Substances to Protect Public Safety.](https://www.dea.gov/press-releases/2026/07/01/dea-temporarily-schedule-7-oh-and-related-substances-protect-public) | **A** | Announcement is not itself the scheduling order; status must be checked against the Federal Register. | | **E03** | Federal regulation | [DEA. Schedules of Controlled Substances: Temporary Placement of 7-Hydroxymitragynine Above a Specified Threshold in Schedule I - Notice of Intent.](https://www.federalregister.gov/documents/2026/07/06/2026-13580/schedules-of-controlled-substance-temporary-placement-of-7-hydroxymitragynine-above-a-specified) | **A** | Notice of intent is not a final temporary order. | | **E04** | Federal regulation | [DEA. Temporary Placement of Mitragynine Pseudoindoxyl, MGM-15, and MGM-16 in Schedule I - Notice of Intent.](https://www.federalregister.gov/documents/2026/07/06/2026-13581/schedules-of-controlled-substances-temporary-placement-of-mitragynine-pseudoindoxyl-mgm-15-and) | **A** | Notice of intent is not a final temporary order. | | **E05** | Federal public health | [U.S. Food and Drug Administration. Hiding in Plain Sight: 7-OH Products.](https://www.fda.gov/news-events/public-health-focus/hiding-plain-sight-7-oh-products) | **A** | Agency synthesis; not a controlled clinical study. | | **E06** | California regulation | [California Department of Public Health. Foods, Dietary Supplements and Medical Drugs containing Kratom and 7-OH are Dangerous and Illegal to Sell or Manufacture for Consumption.](https://www.cdph.ca.gov/Programs/OPA/Pages/NR25-016.aspx) | **A** | This is food/drug enforcement, not a statement that California scheduled every kratom alkaloid under the controlled-substances schedules. | | **E07** | California regulation | [California Department of Public Health. CDPH Warns Retailers and Public About the Dangers of Kratom-derived Products and 7-OH.](https://www.cdph.ca.gov/Programs/OPA/Pages/NR26-005.aspx) | **A** | Agency notice; linked-death attribution may include complex toxicology. | | **E08** | California clinical guidance | [California Department of Public Health. Kratom addiction - healthcare provider advisory.](https://www.cdph.ca.gov/Programs/OPA/Pages/CAHAN/Kratom-addiction.aspx) | **A** | Broadly combines botanical kratom and concentrated 7-OH; individual risks differ by product. | | **E09** | Product chemistry | [Brown PN, Chan M, Zhang X, Brendler T. Elevated 7-Hydroxymitragynine Levels Found in Products Misbranded as Kratom. J AOAC Int.](https://pubmed.ncbi.nlm.nih.gov/41065466/) | **A** | Product sample may not represent the entire market; clinical outcomes were not studied. | | **E10** | Product chemistry | [Avula B, et al. Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditions. Phytochemistry.](https://pubmed.ncbi.nlm.nih.gov/41825819/) | **A** | In-vitro/simulated conditions do not establish human in-vivo conversion or toxicity. | | **E11** | Market emergence | [Hill K, et al. De facto opioids: Characterization of novel 7-hydroxymitragynine and mitragynine pseudoindoxyl product marketing. Drug Alcohol Depend.](https://pubmed.ncbi.nlm.nih.gov/40373645/) | **A** | Online market snapshot; does not estimate sales, users, or clinical incidence. | | **E12** | Pharmacodynamics | [Hemby SE, et al. Multifaceted modulation of human opioid receptors by kratom alkaloids. Front Pharmacol.](https://pubmed.ncbi.nlm.nih.gov/41924140/) | **A** | In-vitro potency and efficacy do not directly establish clinical effect size or exposure. | | **E13** | Pharmacodynamics | [León F, et al. Activity of Mitragyna speciosa alkaloids at serotonin receptors. J Med Chem.](https://pubmed.ncbi.nlm.nih.gov/34467758/) | **B** | Human concentrations and clinical contribution remain unknown; does not prove isolated 7-OH is serotonergic. | | **E14** | Pharmacodynamics | [Chen Y, et al. In Vitro Pharmacology of Mitragynine at alpha-Adrenoceptors. ACS Chem Neurosci.](https://pubmed.ncbi.nlm.nih.gov/41269061/) | **A** | Low-micromolar in-vitro effects; clinical relevance and tissue exposure uncertain. | | **E15** | Pharmacodynamics | [Chakraborty S, et al. Kratom Alkaloids as Probes for Opioid Receptor Function. ACS Chem Neurosci.](https://pubmed.ncbi.nlm.nih.gov/34213886/) | **B** | Preclinical/in-vitro evidence; many compounds lack human exposure data. | | **E16** | Metabolism | [Kruegel AC, et al. 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. ACS Cent Sci.](https://pubmed.ncbi.nlm.nih.gov/31263758/) | **A** | Animal exposure-response; does not define high-dose direct 7-OH human kinetics. | | **E17** | Metabolism/detection | [Basiliere S, Kerrigan S. CYP450-Mediated Metabolism of Mitragynine and Investigation of Metabolites in Human Urine. J Anal Toxicol.](https://pubmed.ncbi.nlm.nih.gov/32008041/) | **A** | Case urine data and in-vitro CYP systems do not define controlled human PK. | | **E18** | Metabolism | [Kamble SH, et al. Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy. ACS Pharmacol Transl Sci.](https://pubmed.ncbi.nlm.nih.gov/33344889/) | **A** | Ex-vivo conversion is not a systemic human conversion fraction or clinical half-life. | | **E19** | Clinical metabolism/DDI | [Jaisi A, et al. Effects of Itraconazole on Pharmacokinetics of Mitragynine and 7-Hydroxymitragynine in Healthy Volunteers. ACS Pharmacol Transl Sci.](https://pubmed.ncbi.nlm.nih.gov/38481700/) | **A** | Low controlled botanical exposure; direct high-dose 7-OH was not administered. | | **E20** | Human pharmacokinetics | [Tanna RS, et al. Clinical Pharmacokinetic Assessment of Kratom in Healthy Adult Participants. Pharmaceutics.](https://pubmed.ncbi.nlm.nih.gov/35335999/) | **A** | Small study using 2 g botanical tea; formation-limited kinetics and assay sensitivity prevent a universal detection window. | | **E21** | Human pharmacokinetics | [Huestis MA, et al. Mitragynine and 7-hydroxy-mitragynine plasma pharmacokinetics after single and 15 multiple oral kratom extract doses. J Anal Toxicol.](https://pubmed.ncbi.nlm.nih.gov/42266029/) | **B** | Not direct purified 7-OH; industry relationships disclosed; generalizability to commercial 7-OH products is limited. | | **E22** | Preclinical pharmacokinetics | [In Vitro and In Vivo Pharmacokinetic Characterization of 7-Hydroxymitragynine in Sprague-Dawley Rats.](https://pubmed.ncbi.nlm.nih.gov/40119246/) | **C** | Rat kinetics cannot define human purified 7-OH half-life, bioavailability, or induction timing. | | **E23** | Respiratory toxicity | [Mitragynine and 7-hydroxymitragynine: Bidirectional effects on breathing in rats.](https://pubmed.ncbi.nlm.nih.gov/41106041/) | **B** | Species, IV route, and endpoint prohibit conversion to a human dose-potency ratio. | | **E24** | Human overdose | [Pullman MK, et al. Cardio-pulmonary arrest in a patient revived with naloxone following reported use of 7-hydroxymitragynine. Clin Toxicol.](https://pubmed.ncbi.nlm.nih.gov/41025553/) | **B** | Single report; product composition, coexposures, and causality cannot be fully resolved. | | **E25** | Withdrawal/treatment | [Lybik N, et al. Management of acute withdrawal from 7-hydroxymitragynine after high-dose chronic use. J Am Pharm Assoc.](https://pubmed.ncbi.nlm.nih.gov/41690384/) | **B** | One patient; no validated timeline or dose-response. | | **E26** | Treatment | [Fenske E, et al. Buprenorphine for the Management of 7-Hydroxymitragynine Use: A Retrospective Case Series. J Addict Med.](https://pubmed.ncbi.nlm.nih.gov/42225057/) | **B** | Small, retrospective, low-barrier telehealth cohort without comparator. | | **E27** | Treatment | [Hendler R, et al. A Case of 7-Hydroxymitragynine Use Disorder Treated With Buprenorphine. J Addict Med.](https://pubmed.ncbi.nlm.nih.gov/41875249/) | **B** | Single case; cannot establish universal induction timing. | | **E28** | Withdrawal complexity | [7-Hydroxymitragynine and Nicotine Pouch Withdrawal Syndrome: A Case Report.](https://pubmed.ncbi.nlm.nih.gov/41487756/) | **C** | Major nicotine and polysubstance confounding; should not define a typical 7-OH course. | | **E29** | Dependence phenotype | [Substance Use Disorder Following Consumption of a Novel Synthetic 7-Hydroxymitragynine Product. J Addict Med.](https://pubmed.ncbi.nlm.nih.gov/41189061/) | **B** | Single patient with prior opioid history and other substance use. | | **E30** | Botanical dependence | [Singh D, et al. Kratom dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend.](https://pubmed.ncbi.nlm.nih.gov/24698080/) | **B** | Traditional brewed kratom population; does not establish purified 7-OH withdrawal kinetics. | | **E31** | Hepatotoxicity | [Ahmad J, et al. Liver injury associated with kratom: U.S. Drug-Induced Liver Injury Network. Drug Alcohol Depend.](https://pubmed.ncbi.nlm.nih.gov/33257199/) | **B** | Predominantly kratom products/mixtures; isolated 7-OH-specific causality not established. | | **E32** | Cardiac pharmacology | [Lu J, et al. Mitragynine inhibits hERG1a/1b channel current.](https://pubmed.ncbi.nlm.nih.gov/31874991/) | **C** | Mitragynine, not purified 7-OH; in-vitro concentration-response does not establish clinical arrhythmia incidence. | | **E33** | Cardiac clinical data | [Leong Bin Abdullah MFI, Singh D. ECG comparisons between regular kratom users and controls.](https://pubmed.ncbi.nlm.nih.gov/32870119/) | **B** | Traditional kratom users; observational design; not purified 7-OH. | | **E34** | Pregnancy | [Wright ME, et al. Outcomes of mothers and newborns to prenatal exposure to kratom: a systematic review.](https://pubmed.ncbi.nlm.nih.gov/33589723/) | **B** | Extremely small case-report literature; no direct concentrated 7-OH data. | | **E35** | Drug interactions | [Tanna RS, et al. Clinical Assessment of the Drug Interaction Potential of Kratom. Clin Pharmacol Ther.](https://pubmed.ncbi.nlm.nih.gov/36924284/) | **A** | Low botanical dose; may not predict high-dose extract or purified 7-OH interactions. | | **E36** | Drug interactions | [Brogdon HD, et al. Potential pharmacokinetic kratom-drug interactions resulting in toxicity.](https://pubmed.ncbi.nlm.nih.gov/35165231/) | **C** | Single case, very high botanical exposure, and multiple drugs; mechanism inferred. | | **E37** | Analytical testing | [Quantification of 11 kratom alkaloids including mitragynine and main metabolites in human plasma using LC-MS/MS.](https://pubmed.ncbi.nlm.nih.gov/39644381/) | **A** | Analytical validity does not provide universal clinical detection windows. | | **E38** | Analytical testing | [Sheehan D, et al. Avoiding False Identification of 7-Hydroxymitragynine in Kratom Products Using Multicriteria LC-MS Confirmation.](https://pubmed.ncbi.nlm.nih.gov/41989479/) | **A** | Product analysis rather than clinical toxicology outcome data. | | **E39** | Emerging analogues | [Gour A, et al. From Kratom to Semi-Synthetic Opioids: The Rise and Risks of MGM-15. Drug Test Anal.](https://pubmed.ncbi.nlm.nih.gov/40936282/) | **B** | No controlled human pharmacokinetics, metabolism, safety, or withdrawal data. | | **E40** | Forensic review | [Papsun DM, et al. 7-Hydroxymitragynine: Not Your Garden Variety Kratom. Am J Forensic Med Pathol.](https://pubmed.ncbi.nlm.nih.gov/42135874/) | **B** | Forensic perspective; not a prospective clinical study. | | **E41** | Medical education | [California Society of Addiction Medicine. 2025 Addiction Medicine Board Exam Preparation Course.](https://cme.csam-asam.org/content/2025-addiction-medicine-board-exam-preparation-course) | **A** | Public program does not independently document every slide or a specific 7-OH segment. | | **E42** | State regulation | [Connecticut Department of Consumer Protection. Information About Kratom: Schedule I controlled-substance update.](https://portal.ct.gov/dcp/knowledge-base/articles/drug-control/patients/kratom-update-october-2025) | **A** | State guidance summarizes the rule; verify the current regulation and statutory penalties before legal reliance. | | **E43** | State regulation | [Florida Department of Legal Affairs. Emergency Rule 2ER26-1: Addition of 7-OH and Related Compounds to Schedule I.](https://flrules.org/gateway/ChapterHome.asp?Chapter=2ER26-) | **A** | Emergency-rule duration, concentration/composition language, repeal, replacement, and permanent status must be checked in the current Florida Administrative Code. | | **E44** | State legislation | [New York Senate Bill S8925A, 2025-2026 session.](https://www.nysenate.gov/legislation/bills/2025/S8925/amendment/A) | **A** | Passage and delivery are not the same as an effective law; verify signing, chapter number, and effective date. | | **E45** | State advisory | [Texas Department of State Health Services. Serious Illnesses Associated with 7-OH Use.](https://www.dshs.texas.gov/news-alerts/serious-illnesses-associated-7-oh-use) | **A** | Advisory and exposure reports do not themselves schedule 7-OH or establish population incidence. | | **E46** | FDA enforcement | [U.S. Food and Drug Administration. FDA Seizes 7-OH Opioids to Protect American Consumers.](https://www.fda.gov/news-events/press-announcements/fda-seizes-7-oh-opioids-protect-american-consumers) | **A** | An enforcement event does not estimate national market size, exposure prevalence, or clinical incidence. | | **E47** | FDA scheduling recommendation | [FDA Takes Steps to Restrict 7-OH Opioid Products Threatening American Consumers.](https://www.fda.gov/news-events/press-announcements/fda-takes-steps-restrict-7-oh-opioid-products-threatening-american-consumers) | **A** | Policy announcement, not a clinical trial. | | **E48** | Practice-based evidence | Harris B. EusomniaMD practice-based 7-OH/kratom clinical experience and consultation series. | **D** | Author-reported, unpublished, not IRB-reviewed, not systematically adjudicated, and not an incidence or efficacy study. | | **E49** | Withdrawal/treatment | [Wightman RS, Hu D. A Case of 7-OH Mitragynine Use Requiring Inpatient Medically Managed Withdrawal. J Addict Med.](https://pubmed.ncbi.nlm.nih.gov/40758956/) | **B** | Single inpatient case; does not establish a universal timeline or preferred taper. | | **E50** | Treatment | [Sherrick RC. Treatment of Kratom Use Disorder With Methadone in an Opioid Treatment Program. J Addict Med.](https://pubmed.ncbi.nlm.nih.gov/41673921/) | **B** | Fourteen-patient retrospective series; most used mixed kratom and 7-OH, not analytically confirmed isolated 7-OH. | | **E51** | General OUD treatment | [ASAM National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 Focused Update.](https://www.asam.org/quality-care/clinical-guidelines/national-practice-guideline) | **A** | General OUD guidance; 7-OH-specific evidence remains limited. | | **E52** | Overdose response | [CDC. What to Do If You Think Someone Is Overdosing.](https://www.cdc.gov/stop-overdose/response/index.html) | **A** | General opioid-overdose response, not a 7-OH-specific clinical trial. | | **E53** | Antagonist-precipitated withdrawal | [Williams JB, et al. A Case of Precipitated Withdrawal From Naltrexone Treated With Buprenorphine in a Patient With Kratom Use Disorder.](https://pubmed.ncbi.nlm.nih.gov/41486738/) | **B** | Single botanical/mixed kratom case; direct purified-7-OH opioid-free interval remains unknown. | | **E54** | MOUD with benzodiazepines | [FDA. Opioid addiction medications should not be withheld from patients taking benzodiazepines or other CNS depressants.](https://www.fda.gov/drugs/food-and-drug-administration-overdose-prevention-framework/timeline-selected-fda-activities-and-significant-events-addressing-substance-use-and-overdose) | **A** | Requires careful medication management; does not remove additive sedation risk. | ### Detailed evidence records #### E01 - America’s Poison Centers. Health Advisory: Serious Illnesses Associated with Kratom and 7-OH Products. **Category:** Surveillance **Year:** 2026 **Evidence type:** National poison-center surveillance **Grade:** A **What it supports:** 593 7-OH reports in 2025 and 901 from Jan 1 through Jun 30, 2026; among 7-OH-only reports, 38.8% serious, 63.8% treated in a healthcare facility, and 20.5% hospitalized. **Important limitation:** Voluntary exposure reports; undercounting, reporting bias, incomplete product verification, and coexposures limit incidence and causality estimates. **Source:** https://poisoncenters.org/news-alerts/13651143 #### E02 - U.S. Drug Enforcement Administration. DEA to Temporarily Schedule 7-OH and Related Substances to Protect Public Safety. **Category:** Federal regulation **Year:** 2026 **Evidence type:** Official agency announcement **Grade:** A **What it supports:** DEA filed notices of intent for concentrated 7-OH and for MP, MGM-15, and MGM-16. The announcement states controls apply once temporary orders take effect. **Important limitation:** Announcement is not itself the scheduling order; status must be checked against the Federal Register. **Source:** https://www.dea.gov/press-releases/2026/07/01/dea-temporarily-schedule-7-oh-and-related-substances-protect-public #### E03 - DEA. Schedules of Controlled Substances: Temporary Placement of 7-Hydroxymitragynine Above a Specified Threshold in Schedule I - Notice of Intent. **Category:** Federal regulation **Year:** 2026 **Evidence type:** Official Federal Register notice **Grade:** A **What it supports:** Proposes temporary Schedule I control above specified thresholds; excludes botanical material below threshold; an order may issue on or after Aug 5, 2026 and becomes effective when published. **Important limitation:** Notice of intent is not a final temporary order. **Source:** https://www.federalregister.gov/documents/2026/07/06/2026-13580/schedules-of-controlled-substance-temporary-placement-of-7-hydroxymitragynine-above-a-specified #### E04 - DEA. Temporary Placement of Mitragynine Pseudoindoxyl, MGM-15, and MGM-16 in Schedule I - Notice of Intent. **Category:** Federal regulation **Year:** 2026 **Evidence type:** Official Federal Register notice **Grade:** A **What it supports:** Proposes temporary Schedule I control of MP, MGM-15, and MGM-16. **Important limitation:** Notice of intent is not a final temporary order. **Source:** https://www.federalregister.gov/documents/2026/07/06/2026-13581/schedules-of-controlled-substances-temporary-placement-of-mitragynine-pseudoindoxyl-mgm-15-and #### E05 - U.S. Food and Drug Administration. Hiding in Plain Sight: 7-OH Products. **Category:** Federal public health **Year:** 2025-2026 **Evidence type:** Official agency public-health page **Grade:** A **What it supports:** Distinguishes concentrated/enhanced 7-OH products from botanical kratom and describes opioid-related risks and regulatory concerns. **Important limitation:** Agency synthesis; not a controlled clinical study. **Source:** https://www.fda.gov/news-events/public-health-focus/hiding-plain-sight-7-oh-products #### E06 - California Department of Public Health. Foods, Dietary Supplements and Medical Drugs containing Kratom and 7-OH are Dangerous and Illegal to Sell or Manufacture for Consumption. **Category:** California regulation **Year:** 2025 **Evidence type:** Official state notice **Grade:** A **What it supports:** States products containing kratom or 7-OH are illegal to sell/manufacture for consumption under California food/drug law; reports six LA County deaths linked to 7-OH and recommends naloxone. **Important limitation:** This is food/drug enforcement, not a statement that California scheduled every kratom alkaloid under the controlled-substances schedules. **Source:** https://www.cdph.ca.gov/Programs/OPA/Pages/NR25-016.aspx #### E07 - California Department of Public Health. CDPH Warns Retailers and Public About the Dangers of Kratom-derived Products and 7-OH. **Category:** California regulation **Year:** 2026 **Evidence type:** Official state notice **Grade:** A **What it supports:** Reiterates enforcement, product-quality concerns, overdose risk, naloxone, and more than $5 million in seized products. **Important limitation:** Agency notice; linked-death attribution may include complex toxicology. **Source:** https://www.cdph.ca.gov/Programs/OPA/Pages/NR26-005.aspx #### E08 - California Department of Public Health. Kratom addiction - healthcare provider advisory. **Category:** California clinical guidance **Year:** 2026 **Evidence type:** Official state clinician advisory **Grade:** A **What it supports:** Advises clinicians that kratom and 7-OH may cause addiction, withdrawal, overdose, and death; recommends MOUD referral and naloxone. **Important limitation:** Broadly combines botanical kratom and concentrated 7-OH; individual risks differ by product. **Source:** https://www.cdph.ca.gov/Programs/OPA/Pages/CAHAN/Kratom-addiction.aspx #### E09 - Brown PN, Chan M, Zhang X, Brendler T. Elevated 7-Hydroxymitragynine Levels Found in Products Misbranded as Kratom. J AOAC Int. **Category:** Product chemistry **Year:** 2026 **Evidence type:** Analytical product study **Grade:** A **What it supports:** Very high 7-OH concentrations and alkaloid profiles inconsistent with authentic leaf; concentrations were considered achievable only through synthetic processing. **Important limitation:** Product sample may not represent the entire market; clinical outcomes were not studied. **Source:** https://pubmed.ncbi.nlm.nih.gov/41065466/ #### E10 - Avula B, et al. Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditions. Phytochemistry. **Category:** Product chemistry **Year:** 2026 **Evidence type:** Analytical product and stability study **Grade:** A **What it supports:** Found label-content disagreement, oxidation byproducts, evidence of semisynthetic origin in over 98% of tested 7-OH-labeled products, and 7-OH degradation to 3-dehydromitragynine in simulated gastric conditions. **Important limitation:** In-vitro/simulated conditions do not establish human in-vivo conversion or toxicity. **Source:** https://pubmed.ncbi.nlm.nih.gov/41825819/ #### E11 - Hill K, et al. De facto opioids: Characterization of novel 7-hydroxymitragynine and mitragynine pseudoindoxyl product marketing. Drug Alcohol Depend. **Category:** Market emergence **Year:** 2025 **Evidence type:** Systematic online market survey **Grade:** A **What it supports:** Identified 304 semisynthetic 7-OH/MP products in six months, mostly 7-OH-only tablets, shots, or gummies. **Important limitation:** Online market snapshot; does not estimate sales, users, or clinical incidence. **Source:** https://pubmed.ncbi.nlm.nih.gov/40373645/ #### E12 - Hemby SE, et al. Multifaceted modulation of human opioid receptors by kratom alkaloids. Front Pharmacol. **Category:** Pharmacodynamics **Year:** 2026 **Evidence type:** Human-receptor in-vitro pharmacology **Grade:** A **What it supports:** Characterizes MOR, KOR, and DOR binding/function, signaling bias, assay-dependent efficacy, minor alkaloids, and speciophylline as a MOR positive allosteric modulator. **Important limitation:** In-vitro potency and efficacy do not directly establish clinical effect size or exposure. **Source:** https://pubmed.ncbi.nlm.nih.gov/41924140/ #### E13 - León F, et al. Activity of Mitragyna speciosa alkaloids at serotonin receptors. J Med Chem. **Category:** Pharmacodynamics **Year:** 2021 **Evidence type:** In-vitro receptor pharmacology plus animal behavioral work **Grade:** B **What it supports:** Paynantheine/speciogynine bind 5-HT1A/5-HT2B; O-desmethyl metabolites activate 5-HT1A; none activated 5-HT2B. **Important limitation:** Human concentrations and clinical contribution remain unknown; does not prove isolated 7-OH is serotonergic. **Source:** https://pubmed.ncbi.nlm.nih.gov/34467758/ #### E14 - Chen Y, et al. In Vitro Pharmacology of Mitragynine at alpha-Adrenoceptors. ACS Chem Neurosci. **Category:** Pharmacodynamics **Year:** 2025 **Evidence type:** Recombinant human/rat receptor pharmacology **Grade:** A **What it supports:** Mitragynine was a low-potency alpha1A partial agonist and alpha2A antagonist; MG, 7-OH and 9-OH did not activate tested alpha2 receptor pathways. **Important limitation:** Low-micromolar in-vitro effects; clinical relevance and tissue exposure uncertain. **Source:** https://pubmed.ncbi.nlm.nih.gov/41269061/ #### E15 - Chakraborty S, et al. Kratom Alkaloids as Probes for Opioid Receptor Function. ACS Chem Neurosci. **Category:** Pharmacodynamics **Year:** 2021 **Evidence type:** In-vitro and preclinical pharmacology **Grade:** B **What it supports:** Characterizes multiple minor indole/oxindole alkaloids at opioid receptors. **Important limitation:** Preclinical/in-vitro evidence; many compounds lack human exposure data. **Source:** https://pubmed.ncbi.nlm.nih.gov/34213886/ #### E16 - Kruegel AC, et al. 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. ACS Cent Sci. **Category:** Metabolism **Year:** 2019 **Evidence type:** Human liver preparations plus mouse pharmacology **Grade:** A **What it supports:** CYP3A converts mitragynine to 7-OH; in mice, formed 7-OH explained much of opioid-mediated analgesia. **Important limitation:** Animal exposure-response; does not define high-dose direct 7-OH human kinetics. **Source:** https://pubmed.ncbi.nlm.nih.gov/31263758/ #### E17 - Basiliere S, Kerrigan S. CYP450-Mediated Metabolism of Mitragynine and Investigation of Metabolites in Human Urine. J Anal Toxicol. **Category:** Metabolism/detection **Year:** 2020 **Evidence type:** Recombinant CYP and authentic human urine analysis **Grade:** A **What it supports:** Maps O-demethylated, carboxylated, and conjugated metabolites and CYP contributions; 9-O-demethylmitragynine is an important urinary metabolite. **Important limitation:** Case urine data and in-vitro CYP systems do not define controlled human PK. **Source:** https://pubmed.ncbi.nlm.nih.gov/32008041/ #### E18 - Kamble SH, et al. Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy. ACS Pharmacol Transl Sci. **Category:** Metabolism **Year:** 2020 **Evidence type:** Ex-vivo human plasma and receptor pharmacology **Grade:** A **What it supports:** Demonstrates conversion of 7-OH to mitragynine pseudoindoxyl in pooled human plasma and greater opioid potency/efficacy of the product. **Important limitation:** Ex-vivo conversion is not a systemic human conversion fraction or clinical half-life. **Source:** https://pubmed.ncbi.nlm.nih.gov/33344889/ #### E19 - Jaisi A, et al. Effects of Itraconazole on Pharmacokinetics of Mitragynine and 7-Hydroxymitragynine in Healthy Volunteers. ACS Pharmacol Transl Sci. **Category:** Clinical metabolism/DDI **Year:** 2024 **Evidence type:** Controlled human drug-interaction study **Grade:** A **What it supports:** CYP3A inhibition reduced 7-OH formation and increased mitragynine exposure, supporting CYP3A-mediated formation in humans. **Important limitation:** Low controlled botanical exposure; direct high-dose 7-OH was not administered. **Source:** https://pubmed.ncbi.nlm.nih.gov/38481700/ #### E20 - Tanna RS, et al. Clinical Pharmacokinetic Assessment of Kratom in Healthy Adult Participants. Pharmaceutics. **Category:** Human pharmacokinetics **Year:** 2022 **Evidence type:** Controlled human single-dose botanical tea study **Grade:** A **What it supports:** Measured multiple alkaloids in plasma and urine through extended collection; botanical-context 7-OH terminal half-life was several hours and targeted urine remained informative through 120 hours. **Important limitation:** Small study using 2 g botanical tea; formation-limited kinetics and assay sensitivity prevent a universal detection window. **Source:** https://pubmed.ncbi.nlm.nih.gov/35335999/ #### E21 - Huestis MA, et al. Mitragynine and 7-hydroxy-mitragynine plasma pharmacokinetics after single and 15 multiple oral kratom extract doses. J Anal Toxicol. **Category:** Human pharmacokinetics **Year:** 2026 **Evidence type:** Controlled human extract study **Grade:** B **What it supports:** Shows dose/regimen-dependent exposure and accumulation patterns after a mitragynine-rich extract. **Important limitation:** Not direct purified 7-OH; industry relationships disclosed; generalizability to commercial 7-OH products is limited. **Source:** https://pubmed.ncbi.nlm.nih.gov/42266029/ #### E22 - In Vitro and In Vivo Pharmacokinetic Characterization of 7-Hydroxymitragynine in Sprague-Dawley Rats. **Category:** Preclinical pharmacokinetics **Year:** 2025 **Evidence type:** Rat PK study **Grade:** C **What it supports:** Oral 7-OH was rapidly absorbed with low oral bioavailability in rats; systemic MP exposure was limited in that model. **Important limitation:** Rat kinetics cannot define human purified 7-OH half-life, bioavailability, or induction timing. **Source:** https://pubmed.ncbi.nlm.nih.gov/40119246/ #### E23 - Mitragynine and 7-hydroxymitragynine: Bidirectional effects on breathing in rats. **Category:** Respiratory toxicity **Year:** 2025-2026 **Evidence type:** Controlled rat respiratory study **Grade:** B **What it supports:** IV 7-OH reduced respiratory frequency, tidal volume, and minute ventilation; naloxone reversed depression; potency for 50% minute-volume reduction was 4.5-fold morphine in this model. **Important limitation:** Species, IV route, and endpoint prohibit conversion to a human dose-potency ratio. **Source:** https://pubmed.ncbi.nlm.nih.gov/41106041/ #### E24 - Pullman MK, et al. Cardio-pulmonary arrest in a patient revived with naloxone following reported use of 7-hydroxymitragynine. Clin Toxicol. **Category:** Human overdose **Year:** 2026 **Evidence type:** Human case report **Grade:** B **What it supports:** Documents cardiopulmonary arrest after reported 7-OH use with naloxone-associated revival. **Important limitation:** Single report; product composition, coexposures, and causality cannot be fully resolved. **Source:** https://pubmed.ncbi.nlm.nih.gov/41025553/ #### E25 - Lybik N, et al. Management of acute withdrawal from 7-hydroxymitragynine after high-dose chronic use. J Am Pharm Assoc. **Category:** Withdrawal/treatment **Year:** 2026 **Evidence type:** Human case report **Grade:** B **What it supports:** High-dose use around 360 mg/day; prominent GI/autonomic/affective symptoms about 48 hours after last dose despite COWS 5; treated with buprenorphine/naloxone and adjuncts. **Important limitation:** One patient; no validated timeline or dose-response. **Source:** https://pubmed.ncbi.nlm.nih.gov/41690384/ #### E26 - Fenske E, et al. Buprenorphine for the Management of 7-Hydroxymitragynine Use: A Retrospective Case Series. J Addict Med. **Category:** Treatment **Year:** 2026 **Evidence type:** Nine-patient retrospective case series **Grade:** B **What it supports:** Six low-dose and three standard initiations; 8/9 initiated and stabilized, no precipitated withdrawal/adverse events reported, and most reported improvement at follow-up. **Important limitation:** Small, retrospective, low-barrier telehealth cohort without comparator. **Source:** https://pubmed.ncbi.nlm.nih.gov/42225057/ #### E27 - Hendler R, et al. A Case of 7-Hydroxymitragynine Use Disorder Treated With Buprenorphine. J Addict Med. **Category:** Treatment **Year:** 2026 **Evidence type:** Human case report **Grade:** B **What it supports:** Describes severe 7-OH use disorder and transition to buprenorphine using a staged clinical approach. **Important limitation:** Single case; cannot establish universal induction timing. **Source:** https://pubmed.ncbi.nlm.nih.gov/41875249/ #### E28 - 7-Hydroxymitragynine and Nicotine Pouch Withdrawal Syndrome: A Case Report. **Category:** Withdrawal complexity **Year:** 2025 **Evidence type:** Human case report **Grade:** C **What it supports:** Severe overlapping 7-OH/nicotine withdrawal with precipitated withdrawal after buprenorphine, agitation, psychosis, and respiratory compromise. **Important limitation:** Major nicotine and polysubstance confounding; should not define a typical 7-OH course. **Source:** https://pubmed.ncbi.nlm.nih.gov/41487756/ #### E29 - Substance Use Disorder Following Consumption of a Novel Synthetic 7-Hydroxymitragynine Product. J Addict Med. **Category:** Dependence phenotype **Year:** 2025 **Evidence type:** Human case report with product/blood confirmation **Grade:** B **What it supports:** Rapid tolerance and one sublingual film every 1-2 hours; severe SUD, supraventricular tachycardia, urinary retention; buprenorphine induction. **Important limitation:** Single patient with prior opioid history and other substance use. **Source:** https://pubmed.ncbi.nlm.nih.gov/41189061/ #### E30 - Singh D, et al. Kratom dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend. **Category:** Botanical dependence **Year:** 2014 **Evidence type:** Cross-sectional study of regular traditional kratom users **Grade:** B **What it supports:** Documents dependence, physical and psychological withdrawal, and dose/frequency associations in regular users. **Important limitation:** Traditional brewed kratom population; does not establish purified 7-OH withdrawal kinetics. **Source:** https://pubmed.ncbi.nlm.nih.gov/24698080/ #### E31 - Ahmad J, et al. Liver injury associated with kratom: U.S. Drug-Induced Liver Injury Network. Drug Alcohol Depend. **Category:** Hepatotoxicity **Year:** 2021 **Evidence type:** Prospective DILIN case series and review **Grade:** B **What it supports:** Eleven cases attributed to kratom, commonly jaundiced and hospitalized, all recovered. **Important limitation:** Predominantly kratom products/mixtures; isolated 7-OH-specific causality not established. **Source:** https://pubmed.ncbi.nlm.nih.gov/33257199/ #### E32 - Lu J, et al. Mitragynine inhibits hERG1a/1b channel current. **Category:** Cardiac pharmacology **Year:** 2020 **Evidence type:** In-vitro cardiac ion-channel study **Grade:** C **What it supports:** Mitragynine inhibited hERG current with IC50 about 333 nM and affected channel complexation. **Important limitation:** Mitragynine, not purified 7-OH; in-vitro concentration-response does not establish clinical arrhythmia incidence. **Source:** https://pubmed.ncbi.nlm.nih.gov/31874991/ #### E33 - Leong Bin Abdullah MFI, Singh D. ECG comparisons between regular kratom users and controls. **Category:** Cardiac clinical data **Year:** 2021 **Evidence type:** Cross-sectional human ECG study **Grade:** B **What it supports:** Higher odds of sinus tachycardia and borderline QTc, but no difference in prolonged QTc. **Important limitation:** Traditional kratom users; observational design; not purified 7-OH. **Source:** https://pubmed.ncbi.nlm.nih.gov/32870119/ #### E34 - Wright ME, et al. Outcomes of mothers and newborns to prenatal exposure to kratom: a systematic review. **Category:** Pregnancy **Year:** 2021 **Evidence type:** Systematic review of six case reports **Grade:** B **What it supports:** Maternal and neonatal withdrawal occurred in the included reports and often required pharmacologic treatment. **Important limitation:** Extremely small case-report literature; no direct concentrated 7-OH data. **Source:** https://pubmed.ncbi.nlm.nih.gov/33589723/ #### E35 - Tanna RS, et al. Clinical Assessment of the Drug Interaction Potential of Kratom. Clin Pharmacol Ther. **Category:** Drug interactions **Year:** 2023 **Evidence type:** Controlled human probe-drug study **Grade:** A **What it supports:** A 2 g kratom tea modestly increased oral midazolam AUC/Cmax without changing half-life, suggesting intestinal CYP3A inhibition; no meaningful dextromethorphan change. **Important limitation:** Low botanical dose; may not predict high-dose extract or purified 7-OH interactions. **Source:** https://pubmed.ncbi.nlm.nih.gov/36924284/ #### E36 - Brogdon HD, et al. Potential pharmacokinetic kratom-drug interactions resulting in toxicity. **Category:** Drug interactions **Year:** 2022 **Evidence type:** Human case report **Grade:** C **What it supports:** High-dose kratom with venlafaxine/quetiapine was associated with serotonin toxicity and ECG abnormalities, plausibly through CYP inhibition. **Important limitation:** Single case, very high botanical exposure, and multiple drugs; mechanism inferred. **Source:** https://pubmed.ncbi.nlm.nih.gov/35165231/ #### E37 - Quantification of 11 kratom alkaloids including mitragynine and main metabolites in human plasma using LC-MS/MS. **Category:** Analytical testing **Year:** 2024 **Evidence type:** Validated analytical method applied to controlled human samples **Grade:** A **What it supports:** Demonstrates compound-specific targeted plasma testing and accumulation of several alkaloids with repeated extract dosing. **Important limitation:** Analytical validity does not provide universal clinical detection windows. **Source:** https://pubmed.ncbi.nlm.nih.gov/39644381/ #### E38 - Sheehan D, et al. Avoiding False Identification of 7-Hydroxymitragynine in Kratom Products Using Multicriteria LC-MS Confirmation. **Category:** Analytical testing **Year:** 2026 **Evidence type:** Analytical method paper **Grade:** A **What it supports:** Shows the need for orthogonal/multicriteria confirmation to avoid false 7-OH identification in complex matrices. **Important limitation:** Product analysis rather than clinical toxicology outcome data. **Source:** https://pubmed.ncbi.nlm.nih.gov/41989479/ #### E39 - Gour A, et al. From Kratom to Semi-Synthetic Opioids: The Rise and Risks of MGM-15. Drug Test Anal. **Category:** Emerging analogues **Year:** 2025 **Evidence type:** Commercial product analysis and receptor binding **Grade:** B **What it supports:** Commercial tablets averaged about 10.9 mg MGM-15; MGM-15 had greater hMOR/hDOR binding affinity than 7-OH. **Important limitation:** No controlled human pharmacokinetics, metabolism, safety, or withdrawal data. **Source:** https://pubmed.ncbi.nlm.nih.gov/40936282/ #### E40 - Papsun DM, et al. 7-Hydroxymitragynine: Not Your Garden Variety Kratom. Am J Forensic Med Pathol. **Category:** Forensic review **Year:** 2026 **Evidence type:** Forensic review/brief report **Grade:** B **What it supports:** Emphasizes the forensic distinction between concentrated 7-OH products and botanical kratom. **Important limitation:** Forensic perspective; not a prospective clinical study. **Source:** https://pubmed.ncbi.nlm.nih.gov/42135874/ #### E41 - California Society of Addiction Medicine. 2025 Addiction Medicine Board Exam Preparation Course. **Category:** Medical education **Year:** 2025 **Evidence type:** Official course/faculty listing **Grade:** A **What it supports:** Lists Brian Harris, MD as faculty for Basic Science (Neurobiology) and Legal Aspects of Addiction Medicine; bio lists board certifications and no relevant financial relationships for the activity. **Important limitation:** Public program does not independently document every slide or a specific 7-OH segment. **Source:** https://cme.csam-asam.org/content/2025-addiction-medicine-board-exam-preparation-course #### E42 - Connecticut Department of Consumer Protection. Information About Kratom: Schedule I controlled-substance update. **Category:** State regulation **Year:** 2026 **Evidence type:** Official state regulatory guidance **Grade:** A **What it supports:** Connecticut designated Mitragyna speciosa and 7-hydroxymitragynine as Schedule I controlled substances, effective March 25, 2026; final regulatory approval was reported April 2, 2026. **Important limitation:** State guidance summarizes the rule; verify the current regulation and statutory penalties before legal reliance. **Source:** https://portal.ct.gov/dcp/knowledge-base/articles/drug-control/patients/kratom-update-october-2025 #### E43 - Florida Department of Legal Affairs. Emergency Rule 2ER26-1: Addition of 7-OH and Related Compounds to Schedule I. **Category:** State regulation **Year:** 2026 **Evidence type:** Official state emergency controlled-substance rule **Grade:** A **What it supports:** Emergency Rule 2ER26-1, effective July 1, 2026, places specified 7-OH-related compounds into Florida Schedule I, including 7-OH, 9-hydroxycorynantheidine, 10-hydroxycorynantheidine, mitragynine pseudoindoxyl, 7-acetoxymitragynine, MGM-15, and MGM-16, subject to the rule terms. **Important limitation:** Emergency-rule duration, concentration/composition language, repeal, replacement, and permanent status must be checked in the current Florida Administrative Code. **Source:** https://flrules.org/gateway/ChapterHome.asp?Chapter=2ER26- #### E44 - New York Senate Bill S8925A, 2025-2026 session. **Category:** State legislation **Year:** 2026 **Evidence type:** Official state legislative record **Grade:** A **What it supports:** Passed both chambers and was delivered to the governor; would prohibit sale of products exceeding 2% of total alkaloids or 1 mg 7-OH per serving, with civil penalties, effective 90 days after becoming law. **Important limitation:** Passage and delivery are not the same as an effective law; verify signing, chapter number, and effective date. **Source:** https://www.nysenate.gov/legislation/bills/2025/S8925/amendment/A #### E45 - Texas Department of State Health Services. Serious Illnesses Associated with 7-OH Use. **Category:** State advisory **Year:** 2025 **Evidence type:** Official state health advisory and poison-center summary **Grade:** A **What it supports:** Texas warned against concentrated 7-OH; as of Aug. 27, 2025, state poison centers had 192 kratom/7-OH reports, including 19 concentrated 7-OH reports, 11 treated at a healthcare facility; clinicians were advised to use naloxone for respiratory depression. **Important limitation:** Advisory and exposure reports do not themselves schedule 7-OH or establish population incidence. **Source:** https://www.dshs.texas.gov/news-alerts/serious-illnesses-associated-7-oh-use #### E46 - U.S. Food and Drug Administration. FDA Seizes 7-OH Opioids to Protect American Consumers. **Category:** FDA enforcement **Year:** 2025 **Evidence type:** Official federal enforcement announcement **Grade:** A **What it supports:** FDA and DOJ announced seizure of approximately 73,000 units of concentrated 7-OH products valued at roughly $1 million from three Missouri firms. **Important limitation:** An enforcement event does not estimate national market size, exposure prevalence, or clinical incidence. **Source:** https://www.fda.gov/news-events/press-announcements/fda-seizes-7-oh-opioids-protect-american-consumers #### E47 - FDA Takes Steps to Restrict 7-OH Opioid Products Threatening American Consumers. **Category:** FDA scheduling recommendation **Year:** 2025 **Evidence type:** Official federal announcement **Grade:** A **What it supports:** Describes FDA action and recommendation concerning concentrated 7-OH. **Important limitation:** Policy announcement, not a clinical trial. **Source:** https://www.fda.gov/news-events/press-announcements/fda-takes-steps-restrict-7-oh-opioid-products-threatening-american-consumers #### E48 - Harris B. EusomniaMD practice-based 7-OH/kratom clinical experience and consultation series. **Category:** Practice-based evidence **Year:** 2024-2026 **Evidence type:** Unpublished clinical experience **Grade:** D **What it supports:** Direct treatment of a case series in the teens plus informal consultation on dozens of additional 7-OH withdrawal cases across diverse demographic and professional groups. **Important limitation:** Author-reported, unpublished, not IRB-reviewed, not systematically adjudicated, and not an incidence or efficacy study. **Source status:** Internal clinical experience; no public URL #### E49 - Wightman RS, Hu D. A Case of 7-OH Mitragynine Use Requiring Inpatient Medically Managed Withdrawal. **Category:** Withdrawal/treatment **Year:** 2025 **Evidence type:** Inpatient human case report **Grade:** B **What it supports:** A 38-year-old man with escalating kratom-to-7-OH use developed opioid-consistent withdrawal with COWS peaking at 14. He received symptom-guided sublingual buprenorphine 2-8 mg/day, completed a short taper during the medically managed withdrawal stay, and transitioned to residential care. **Important limitation:** One patient with prior OUD; does not validate a universal withdrawal timeline, mandatory taper, or preferred induction method. **Source:** https://pubmed.ncbi.nlm.nih.gov/40758956/ #### E50 - Sherrick RC. Treatment of Kratom Use Disorder With Methadone in an Opioid Treatment Program. **Category:** Treatment **Year:** 2026 **Evidence type:** Fourteen-patient retrospective OTP case series **Grade:** B **What it supports:** Fourteen patients with kratom use disorder received methadone across opioid treatment programs; 64% reported both kratom and 7-OH use, mean first-day dose was 27.5 mg, mean maximum dose 98.6 mg, 13/14 remained in treatment at last follow-up, and no adverse events were reported. **Important limitation:** Mixed kratom/7-OH population, retrospective design, no comparator, no systematic isolated-7-OH confirmation, and dosing should not be converted into a universal protocol. **Source:** https://pubmed.ncbi.nlm.nih.gov/41673921/ #### E51 - ASAM National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 Focused Update. **Category:** General OUD treatment **Year:** 2020 **Evidence type:** National clinical-practice guideline **Grade:** A **What it supports:** Buprenorphine and methadone are evidence-based medications for OUD; treatment setting, medication selection, stabilization, ongoing care, and individualized duration should follow established OUD principles. **Important limitation:** The guideline predates the commercial concentrated-7-OH market and does not supply a 7-OH-specific induction interval, dose conversion, or withdrawal timeline. **Source:** https://www.asam.org/quality-care/clinical-guidelines/national-practice-guideline #### E52 - Centers for Disease Control and Prevention. What to Do If You Think Someone Is Overdosing. **Category:** Overdose response **Year:** 2024-current **Evidence type:** Authoritative public-health guidance **Grade:** A **What it supports:** Recognize inability to awaken, slow/shallow or abnormal breathing, and discoloration; administer naloxone, call 911, support breathing, place the person on their side when appropriate, and remain until emergency help arrives. **Important limitation:** General opioid-overdose response, not a 7-OH-specific trial; coingestants may require additional treatment even after naloxone. **Source:** https://www.cdc.gov/stop-overdose/response/index.html #### E53 - Williams JB, et al. A Case of Precipitated Withdrawal From Naltrexone Treated With Buprenorphine in a Patient With Kratom Use Disorder. **Category:** Antagonist-precipitated withdrawal **Year:** 2026 **Evidence type:** Human case report **Grade:** B **What it supports:** Naltrexone can precipitate severe opioid withdrawal in a patient physiologically dependent on kratom-derived opioid agonists; buprenorphine was used in management. **Important limitation:** Single kratom case; product composition and direct purified-7-OH opioid-free interval are not established. **Source:** https://pubmed.ncbi.nlm.nih.gov/41486738/ #### E54 - U.S. Food and Drug Administration. Buprenorphine and methadone should not be withheld solely because a patient uses benzodiazepines or other CNS depressants. **Category:** MOUD safety policy **Year:** 2017-current FDA safety communication history **Evidence type:** Official federal medication-safety guidance **Grade:** A **What it supports:** Combined CNS depressants increase serious adverse-effect risk, but untreated opioid addiction may be more dangerous; careful medication management is preferred to categorical denial of buprenorphine or methadone. **Important limitation:** Does not make the combination safe or remove the need to assess benzodiazepine dependence, respiratory risk, dosing, monitoring, and alcohol/other sedatives. **Source:** https://www.fda.gov/drugs/food-and-drug-administration-overdose-prevention-framework/timeline-selected-fda-activities-and-significant-events-addressing-substance-use-and-overdose ### How to use this library An evidence identifier supports only the claim described in its record. It should not be used as a generic citation for everything the source mentions. A product-chemistry study can establish measured contents but not clinical incidence. A case report can show possibility but not frequency. A controlled botanical-kratom study cannot silently become a direct purified-7-OH pharmacokinetic study. When several sources support one statement, the public page should cite the smallest set that covers the claim and its important limitations. The canonical chemistry and testing details are maintained in [Appendix A](appendices/appendix-a-chemistry-metabolism-detection.md) rather than replicated here. ### Update and correction policy This library is intended to behave like a living clinical reference rather than a frozen marketing page. Each substantive page carries a last-reviewed date. Regulatory statements are checked against official agency or legislative sources. New evidence is added with an explicit grade and limitation. If a correction changes clinical or legal interpretation, the correction is dated and described in the changelog rather than silently overwritten. Readers may report a suspected factual error, missing source, or conflict of interest to **bharris@eusomniamd.com**. Corrections should identify the exact passage, source, and proposed change. Product manufacturers may submit data, but unpublished promotional claims will not be treated as evidence. ### Known evidence gaps The highest-priority gaps are direct human pharmacokinetics of purified high-dose 7-OH; population prevalence of physiological dependence; validated withdrawal time-course studies; comparative standard versus low-dose buprenorphine initiation; human toxicity incidence with analytically confirmed single-agent exposure; special-population and drug-interaction studies; and prospective outcomes after regulatory supply disruption. [Return to the Resource Center](index.md) | [Publication controls](appendices/appendix-c-source-and-publication-notes.md) | [Change history](CHANGELOG.md) --- ## About the Author and Clinical Experience *Source module: `12-about-author-clinical-experience.md`* **Brian Harris, MD** **Board-certified in Addiction Medicine, Anesthesiology, and Sleep Medicine** **EusomniaMD** **Contact:** bharris@eusomniamd.com ### Clinical focus Brian Harris, MD is a physician whose work spans addiction medicine, sleep medicine, anesthesiology, and the clinical management of patients using emerging opioid-active products. Through EusomniaMD, he evaluates and treats kratom and concentrated 7-hydroxymitragynine dependence and provides clinician-to-clinician consultation, treatment planning, lectures, and workflow development for outpatient practices, detoxification programs, and other treatment settings. ### Practice-based 7-OH experience Dr. Harris reports directly treating a practice-based case series **in the teens** involving kratom and concentrated 7-OH dependence, ranging from relatively uncomplicated use and withdrawal to high-dose, high-frequency compulsive use. He has also provided informal consultation on **dozens of additional patients specifically withdrawing from 7-OH**. The patients represented varied ages, sexes, professions, and socioeconomic circumstances, including physicians and other professionals as well as people with unstable resources. The recurring clinical lesson is that the retail setting does not predict severity. Patients may arrive with substantial opioid tolerance and frequent interdose withdrawal while still believing they have not been using an opioid in the ordinary clinical sense. [E48] This experience contributes to the provisional withdrawal timeline, the emphasis on actual milligrams and dosing interval, the supplemental assessment beyond COWS, and the risk-stratified treatment framework presented in this resource. ### What that experience does and does not establish The practice experience is relevant because the published 7-OH treatment literature remains small. It is reasonable to weigh repeated direct clinical observation when prospective evidence does not yet exist. It is also **unpublished, nonrandomized, not a prevalence sample, and not a validated comparative trial**. It cannot establish a universal withdrawal peak, dose conversion, treatment success rate, or superiority of one induction strategy. Consultation cases are not counted as equivalent to directly treated and longitudinally followed patients. These limits are stated because confidence is improved by exposing its load-bearing beams, not by painting over them. If the cohort is later analyzed for scientific publication, formal data abstraction, clear inclusion criteria, de-identification, and an IRB determination should precede public presentation of aggregate outcomes. ### Medical education The California Society of Addiction Medicine's official 2025 Addiction Medicine Board Exam Preparation Course lists Dr. Harris as faculty for **Basic Science (Neurobiology)** and **Legal Aspects of Addiction Medicine**. The course was designed for physicians preparing for the American Board of Preventive Medicine Addiction Medicine examination and carried continuing medical education credit. CSAM's faculty biography lists his certifications in Addiction Medicine, Anesthesiology, and Sleep Medicine and states that he had no relevant financial relationships for the activity. [E41] Dr. Harris reports that his 2025 teaching included kratom and 7-OH within an update on emerging opioids. The official public course page verifies the faculty roles but does not independently enumerate every slide or confirm the specific 7-OH segment. That narrower teaching-content statement is therefore identified as author-reported unless the final 2025 presentation file or program is separately archived. The uploaded predecessor Basic Sciences deck also shows the board-review structure and the curriculum's receptor, withdrawal, and pharmacokinetic teaching context, but it is a 2024 Waseem Khader version and should not be presented as proof of Dr. Harris's later 7-OH content. ### Services available Dr. Harris is available for: - evaluation and treatment of patients with kratom or concentrated 7-OH dependence; - clinician-to-clinician consultation for difficult withdrawal or transition cases; - development and review of buprenorphine or methadone referral pathways; - consultation with detoxification, residential, outpatient, emergency, and primary-care programs; - lectures and grand rounds on 7-OH pharmacology, toxicity, withdrawal, treatment, product chemistry, and regulatory transition; - review of clinical algorithms, patient handouts, screening tools, and escalation criteria; - collaboration on systematic case documentation and future clinical research. ### Editorial method This resource uses a claim-level evidence hierarchy: - **Grade A:** controlled human, validated analytical, authoritative surveillance, or official regulatory evidence; - **Grade B:** small human series, well-documented cases, or strong mechanistic evidence with clinical concordance; - **Grade C:** animal, in-vitro, modeled, confounded, or indirect evidence; - **Grade D:** practice-based clinical observation or expert synthesis; - **Grade U:** data insufficient. Statements are written to distinguish botanical kratom, mitragynine-rich extracts, isolated 7-OH, MP, MGM analogues, and unknown commercial mixtures. Where the evidence does not support a precise answer, the resource says so. ### Disclosures and boundaries Dr. Harris owns and operates EusomniaMD and may receive professional fees for clinical care, consultation, and speaking. This creates a potential professional interest in referrals and educational engagements. The resource is intended primarily as a public-health and clinical service; fees, when applicable, should be disclosed directly to the requesting party. No manufacturer, retailer, trade organization, law-enforcement agency, or advocacy group funded the preparation of this resource. Product names are used only when necessary to characterize exposure and are not endorsements. This resource is educational. It does not establish a clinician-patient relationship, substitute for individualized medical assessment, or provide legal advice. The EusomniaMD clinical framework is an emerging practice protocol, not a nationally validated 7-OH guideline. ### Contact **Brian Harris, MD** **EusomniaMD** **Email:** bharris@eusomniamd.com **Resource center:** https://www.eusomniamd.com/7-oh-withdrawal [Return to the Resource Center](index.md) | [Treatment framework](07-treatment-for-clinicians.md) | [Evidence Library](11-evidence-library.md) --- ## Appendix A: Chemistry, Metabolism, and Detection *Source module: `appendices/appendix-a-chemistry-metabolism-detection.md`* **Working reference for the EusomniaMD 7-OH Resource Center** **Version:** 1.2 **Last reviewed:** August 8, 2026 **Scope:** Clinician-facing reference on pharmacologically active kratom alkaloids and metabolites, metabolic pathways, emerging semisynthetic analogues, and biological detection. > **Evidence rule used here:** A compound is called an **active metabolite** only when it is both a demonstrated metabolite of a kratom alkaloid and has experimental evidence of pharmacologic activity. Mere detection by mass spectrometry is not enough. Human-confirmed metabolism, ex-vivo human metabolism, preclinical pharmacology, and commercial-product chemistry are labeled separately. > **Critical interpretation rule:** "Detected in urine" does **not** mean "primarily eliminated unchanged in urine," and neither statement establishes a fixed clinical detection window. Likewise, a plasma half-life is not the same thing as duration of receptor occupancy, duration of intoxication, duration of withdrawal risk, or urine-test positivity. --- ### 1. Executive metabolic map ```text BOTANICAL KRATOM / MITRAGYNINE EXPOSURE Mitragynine (MG) | |-- CYP3A4 --> 7-hydroxymitragynine (7-OH; 7-HMG) | | | |-- rearrangement in human plasma ex vivo and liver-associated systems --> | | mitragynine pseudoindoxyl (MP) | | | '-- chemical degradation can yield 3-dehydromitragynine (3DM) | under simulated gastric conditions; clinical in-vivo importance unknown | |-- non-CYP, NADPH-independent oxidation demonstrated in human liver fractions --> | 3-dehydromitragynine (3DM; active/toxic in preclinical systems) | |-- CYP2C19 + CYP2D6 + CYP3A4 --> 9-O-demethylmitragynine | (= 9-hydroxycorynantheidine; 9OH) | | | '-- phase II --> 9OH glucuronide (9G) and sulfate conjugates | |-- CYP2D6 + CYP2C19 + CYP2C18 --> 16-carboxymitragynine | |-- CYP2C19 --> 9-O-demethyl-16-carboxymitragynine | '-- additional O-demethylation, ester hydrolysis, oxidation/reduction, and conjugation --> glucuronide/sulfate metabolites --> urine Speciogynine '-- O-demethylation --> 9-O-desmethylspeciogynine (5-HT1A agonist in functional assays) Paynantheine '-- O-demethylation --> 9-O-desmethylpaynantheine (5-HT1A agonist in functional assays) ``` **Important:** CYP assignments above come from recombinant human CYP experiments and, for the MG to 7-OH step, are supported by a controlled itraconazole interaction study in healthy volunteers. Whole-body metabolism can involve additional enzymes and nonenzymatic chemistry. [1-4] --- ### Master glossary: compounds most relevant to the 7-OH clinical problem This is the compact index for webpage implementation. **Metabolite** means formed biologically from another kratom alkaloid; **botanical alkaloid** means present in *M. speciosa*; **semisynthetic analogue** means deliberately chemically modified from a kratom scaffold. Several compounds occupy more than one category. | Compound | Also called | Category | Why it matters clinically | Human detection / timing status | |---|---|---|---|---| | **Mitragynine** | MG, MTG | Major botanical parent alkaloid | Main botanical exposure and precursor to multiple active metabolites, especially 7-OH | Plasma/urine/hair measurable by targeted MS. Botanical human t1/2 commonly ~40-70 h depending regimen; unchanged urinary recovery is very low. [1-7,29,30] | | **7-hydroxymitragynine** | 7-OH, 7-HMG, 7-OH-MTG | Trace botanical alkaloid; **active human MG metabolite**; semisynthetic retail drug | Potent opioid-active compound driving the current high-concentration product problem | Targeted plasma/urine/hair assays exist. After 2-g botanical tea, median terminal t1/2 ~5.67 h and urine remained analytically informative through the 120-h study collection; **direct purified high-dose human PK is unknown**. [1-7,29,30] | | **9-O-demethylmitragynine** | 9ODM, 9-O-desmethylmitragynine, **9-hydroxycorynantheidine**, 9OH | **Active MG metabolite** | MOR partial agonist; prominent phase-I urinary metabolite and potentially clinically relevant secondary opioid pathway | Identified in human urine by targeted MS; human plasma PK and validated urine window unknown. [3,8-10,33] | | **Mitragynine pseudoindoxyl** | MP | **Active downstream 7-OH/MG product**; directly manufactured semisynthetic drug | Potent opioid-active rearrangement product; may be ingested directly or form downstream from 7-OH | Targeted LC-HRMS/LC-QTOF can identify it. No validated human systemic half-life or urine/blood window; detection does not by itself prove direct ingestion. [2,11-14,18] | | **3-dehydromitragynine** | 3DM, 3DMTG, dehydromitragynine | Oxidative MG product; degradation/product constituent | Preclinical MOR partial agonism plus high-dose non-opioid toxicity signal; found in modern commercial products | Targeted HRMS/UPLC-MS/MS can identify it in research/product matrices; human in-vivo PK and biological window unknown. [34-36,40] | | **9-O-demethylmitragynine glucuronide** | 9G, glucuronyl-9OH | Phase-II 9OH conjugate | Weak MOR affinity reported, but clinically meaningful agonism not established | Detectable with conjugate-aware HRMS methods or after hydrolysis depending assay; timing unknown. [9,13,37] | | **16-carboxymitragynine** | 16-COOH-MG | MG metabolite / hydrolysis product | Important urinary/product marker; pharmacologic activity not established | Identified in human urine by targeted MS; no validated window. [3,9,10] | | **9-O-demethyl-16-carboxymitragynine** | 9ODM-16-COOH-MG | MG metabolite | Useful pathway marker; formed predominantly via CYP2C19 in recombinant studies | Human urine identification reported; no validated window. [3,9,10] | | **9-O-desmethylspeciogynine** | - | **Active speciogynine metabolite** | Functional 5-HT1A agonist in vitro, offering a plausible non-opioid pathway in botanical kratom pharmacology | Targeted metabolomics possible; human concentration-time profile and clinical window unknown. [15-17] | | **9-O-desmethylpaynantheine** | - | **Active paynantheine metabolite** | Functional 5-HT1A agonist in vitro | Targeted metabolomics possible; human concentration-time profile and clinical window unknown. [15-17] | | **MGM-15** | dihydro-7-OH, DH7OH; sometimes ambiguously called DHM | **Semisynthetic 7-OH analogue, not a metabolite** | Higher hMOR/hDOR binding affinity than 7-OH in published in-vitro work; commercial human exposure documented, but no human PK studies | LC-MS/MS/LC-QTOF identification is feasible. No validated human half-life or biological detection window. GC analysis can create an MG identification artifact. [18,19,21] | | **MGM-16** | 9-fluoro-dihydro-7-hydroxymitragynine | **Synthetic/semisynthetic analogue, not a metabolite** | Potent preclinical mu/delta agonist; important because it sits immediately adjacent to MGM-15 in the emerging analogue market/regulatory response | No established clinical human PK or validated biological window. Targeted HRMS would require an appropriate standard. [18,20,22] | | **8-hydroxymitragynine / 11-hydroxymitragynine** | 8-OH-MG / 11-OH-MG | Related hydroxylated compounds | Emerging analytical/commercial relevance, but not established clinically important human metabolites | No validated human PK or testing window. | | **Speciogynine / paynantheine / speciociliatine / mitraciliatine / isopaynantheine** | minor botanical alkaloids | Botanical parent alkaloids | Contribute to the polypharmacology of botanical kratom and can have their own active metabolites/receptor activity | Several have controlled human plasma PK after botanical exposure; compound-specific clinical urine windows are not validated. [5,15-17,25-27] | | **Corynantheidine / corynoxines / speciofolines / rhynchophylline-family oxindoles / N-oxides** | various | Minor botanical alkaloids | Relevant to a complete kratom targetome, but not established principal 7-OH metabolic drivers | Detectable analytically when included in targeted methods; clinical PK/window data are sparse or absent. [25-27] | **Not shown as established human metabolites:** medicinal-chemistry compounds such as 7-hydroxypaynantheine, 7-hydroxyspeciogynine, paynantheine pseudoindoxyl, and speciogynine pseudoindoxyl. They are useful structure-activity probes but should not be presented as routine human metabolites without direct metabolic evidence. [24] --- ### 2. Active metabolites with the strongest evidence The table below includes compounds with **demonstrated pharmacologic activity** after formation from a kratom alkaloid. It deliberately distinguishes human-confirmed metabolites from metabolites demonstrated only in human liver systems or preclinical animals. | Compound | Parent / precursor | Formation pathway | Demonstrated pharmacology | Human metabolic evidence | Human half-life | Biological detectability | What remains unknown | |---|---|---|---|---|---|---|---| | **7-hydroxymitragynine (7-OH, 7-HMG, 7-OH-MTG)** | Mitragynine; also a trace botanical constituent and processing/oxidation product | Predominantly **CYP3A4-mediated oxidation of MG**. Human itraconazole pretreatment reduced 7-OH Cmax by about 56% and AUC0-72 by about 43%, supporting CYP3A4-mediated formation in vivo. | Potent opioid agonist, predominantly MOR; intrinsic efficacy is assay- and receptor-reserve-dependent. | **High.** Directly measured in human plasma after botanical/MG-rich exposure; metabolic formation demonstrated in a controlled human CYP3A interaction study. | **Direct purified 7-OH: unknown.** After botanical tea exposure, median terminal t1/2 was about **5.67 h** in one controlled study. Dried-leaf and extract studies show highly regimen-dependent terminal estimates because circulating 7-OH is being formed from MG. | Targeted LC-MS/MS, LC-HRMS, LC-QTOF, and CZE-MS/MS can measure 7-OH. In one controlled 2-g botanical tea study, 7-OH was quantifiable in plasma through about **24 h** and in urine through the study's **120-h collection** in completers. This is not a universal five-day window. | PK after direct high-dose commercial 7-OH, bioavailability by tablet/sublingual routes, intrinsic elimination, accumulation during q1-3h use, and validated clinical urine window. [1-7,29] | | **9-O-demethylmitragynine (9ODM; 9-hydroxycorynantheidine; 9OH)** | Mitragynine | O-demethylation. Recombinant human CYP studies implicate **CYP2C19, CYP3A4, and CYP2D6**; human liver S9 work identifies CYP3A as a major contributor. | **MOR partial agonist** activity demonstrated in functional pharmacology. | **Moderate-high.** A major MG metabolite in human liver systems and reported as the **most prevalent phase-I metabolite in urine** among kratom users in Basiliere/Kerrigan. | **Unknown in humans.** | Detectable in human urine with targeted LC-HRMS/LC-QTOF metabolite methods. No validated time-since-last-use window. | Plasma exposure, brain penetration, contribution to intoxication/dependence/withdrawal, and quantitative renal/fecal clearance. [3,8-10,33] | | **Mitragynine pseudoindoxyl (MP)** | Downstream of MG/7-OH; also manufactured and consumed directly | 7-OH undergoes oxidative/rearrangement chemistry to MP. Formation is demonstrated in **human plasma ex vivo** and liver systems; CYP3A-associated and nonenzymatic mechanisms both appear to contribute. | Potent opioid-active compound; strong MOR activity with DOR/KOR antagonism in several established assay systems. | **Moderate.** Formation in pooled human plasma ex vivo is directly demonstrated; MP is also found in commercial/forensic contexts. Controlled in-vivo human formation fraction is unknown. | **Unknown systemically in humans.** The 120-min plasma incubation experiment and 7-OH plasma instability are not systemic half-life measurements. | Targeted LC-HRMS/LC-QTOF can identify MP if chromatographic separation and reference standards are adequate. A positive result may reflect direct MP exposure, downstream formation, or both. | Human oral/sublingual PK, fraction formed from 7-OH in vivo, distribution, elimination, urine window, and whether analyte ratios distinguish direct from metabolic exposure. [2,11-14,18] | | **3-dehydromitragynine (3DM; 3DMTG; dehydromitragynine)** | Mitragynine; also described as a minor natural/product constituent | A **non-CYP, NADPH-independent oxidative pathway** was demonstrated in human liver microsomes/S9 and in mice. Separate 2026 chemistry work found that 7-OH can degrade to 3DM under simulated gastric conditions. | Preclinical MOR binding/partial agonism has been demonstrated; the 2021 study also identified **non-opioid toxicity at high doses in mice**. | **Limited for humans.** Formation is demonstrated in human liver fractions, but a controlled study confirming circulating 3DM as an in-vivo human metabolite has not been established. | **Unknown in humans; direct preclinical systemic half-life not adequately established for clinical use.** | Detectable by targeted high-resolution MS in products/research matrices; 3DM has been reported in recent commercial-product analyses. There is no validated clinical urine/blood window. | Human in-vivo formation, exposure after MG versus direct 7-OH, metabolism, clearance, clinical toxicity, and contribution to withdrawal. [34-36] | | **9-O-desmethylspeciogynine** | Speciogynine | O-demethylation; exact quantitative human enzyme contribution is not well defined. | Functional **5-HT1A agonist** in vitro; also inverse partial agonist activity at 5-HT2B was reported rather than 5-HT2B activation. | **Moderate pharmacology; limited human exposure data.** | **Unknown.** | Can be sought with targeted metabolomic/MS methods; no validated routine clinical assay or window. | Whether human concentrations reach clinically meaningful serotonergic exposure, and whether it contributes to mood/sleep/withdrawal phenomena. [15-17] | | **9-O-desmethylpaynantheine** | Paynantheine | O-demethylation; exact quantitative human enzyme contribution is not well defined. | Functional **5-HT1A agonist** in vitro; inverse partial agonist at 5-HT2B rather than agonist activity. | **Moderate pharmacology; limited human exposure data.** | **Unknown.** | Targeted MS is possible; no validated routine clinical window. | Human systemic exposure and clinical serotonergic contribution. [15-17] | | **9-O-demethylmitragynine glucuronide (9G; glucuronyl-9-hydroxycorynantheidine)** | 9OH / 9-O-demethylmitragynine | Phase-II **glucuronidation** downstream of 9OH. | **Weak MOR binding/affinity** has been reported preclinically. Functional agonist efficacy and clinical significance are not established, so this is best classified as an **interaction-positive conjugated metabolite**, not a proven clinically active opioid. | Phase-II formation is supported by metabolic-networking/earlier metabolite work; quantitative in-vivo human exposure is poorly defined. | **Unknown.** | Amenable to direct conjugate LC-HRMS or indirect detection after enzymatic hydrolysis, depending laboratory method. No validated window. | Whether meaningful concentrations reach systemic circulation/CNS and whether receptor binding has any clinical consequence. [9,10,13,37] | **Bottom line:** the best-established clinically relevant active-metabolite chain is **MG -> 7-OH -> MP**. **MG -> 9OH -> 9G** is a second pathway in which 9OH is clearly pharmacologically active and 9G has only weak receptor-binding evidence. **3DM** is an important oxidative product because it is pharmacologically active and potentially toxic in preclinical systems, but its in-vivo human contribution is not yet known. #### Key caution on 7-OH half-life Published human 7-OH half-lives are mostly measured after people ingest **botanical kratom or mitragynine-rich extract**, where much of the circulating 7-OH is being formed continuously from mitragynine. That means the observed terminal phase can be **formation-limited** rather than representing the intrinsic elimination of directly ingested purified 7-OH. It is therefore scientifically unsafe to take a botanical-kratom 7-OH half-life and use it as a fixed waiting-time rule for buprenorphine induction after high-dose commercial 7-OH use. [4-7] --- ### 3. Other identified mitragynine metabolites These compounds are important for forensic interpretation and for understanding total exposure, but **clinically meaningful pharmacologic activity has not been established for each one**. | Metabolite | Transformation | Human occurrence | Pharmacologic activity | Half-life | Detectability / elimination | |---|---|---|---|---|---| | **16-carboxymitragynine** | Ester hydrolysis / carboxylation pathway; CYP2D6, CYP2C19, CYP2C18 implicated in recombinant systems | Confirmed in human metabolite work | Not established as a clinically meaningful active metabolite | Unknown | Detected in urine by targeted MS; phase II conjugation reported. [3,9,10] | | **9-O-demethyl-16-carboxymitragynine** | Combined O-demethylation plus carboxylation; CYP2C19 prominent in recombinant systems | Confirmed in human metabolite work | Unknown | Unknown | Urinary metabolite/conjugate; targeted MS required. [3,9,10] | | **17-O-demethyl-16,17-dihydromitragynine** | O-demethylation plus reduction of the side-chain unsaturation | Identified in classic rat/human metabolite studies | Unknown | Unknown | Detected as unconjugated and/or conjugated metabolite depending species/sample; targeted MS. [9,10] | | **9,17-O-bisdemethyl-16,17-dihydromitragynine** | Additional O-demethylation plus reduction | Identified in classic metabolite studies | Unknown | Unknown | Urinary metabolite/conjugate reported; no clinical window. [9,10] | | **17-carboxy-16,17-dihydromitragynine** | Reduction plus carboxylation | Identified in classic metabolite studies | Unknown | Unknown | Targeted urine MS; no clinical window. [9,10] | | **9-O-demethyl-17-carboxy-16,17-dihydromitragynine** | O-demethylation plus reduction plus carboxylation | Identified in classic metabolite studies | Unknown | Unknown | Targeted urine MS; no clinical window. [9,10] | | **Glucuronide and sulfate conjugates of O-demethylated/carboxylated metabolites** | Phase II conjugation, mainly glucuronidation and sulfation | Confirmed in human urine | Generally treated as elimination metabolites; receptor activity not established | Unknown | Major urinary route for several phase I products; laboratories may require hydrolysis or direct conjugate measurement depending method. [9,10] | The older metabolic literature identified multiple phase I and phase II MG metabolites in rat and human urine, but the exact unconjugated/conjugated pattern differs by species. For the website, avoid implying that every metabolite identified in the combined rat/human work is quantitatively important in humans. [9,10] --- ### 4. Controlled human pharmacokinetics of major botanical kratom alkaloids The following values are useful orientation numbers, **not** direct-purified-7-OH pharmacokinetics. In a controlled single-dose study of a standardized kratom product in healthy adults, median terminal half-lives were approximately: [5] | Alkaloid | Median terminal half-life | Comment | |---|---:|---| | **Mitragynine** | **45.3 h** | Major parent alkaloid; long terminal phase | | **Speciogynine** | **23.5 h** | Parent botanical alkaloid | | **Paynantheine** | **27.0 h** | Parent botanical alkaloid | | **Speciociliatine** | **12.3 h** | Parent botanical alkaloid | | **Mitraciliatine** | **17.8 h** | Parent botanical alkaloid | | **Isopaynantheine** | **14.4 h** | Parent botanical alkaloid | | **7-OH** | **5.67 h** | Mostly metabolically generated in this botanical-exposure context | A separate controlled dried-leaf study found mean MG half-lives around **43 h after single dosing** and **68 h after repeated dosing**, while mean 7-OH estimates were roughly **5 h single-dose** and **25 h repeated-dose** in that study. [6] A 2026 concentrated-mitragynine-extract study reported extremely variable 7-OH half-life estimates after repeated dosing, including much longer terminal estimates in the highest-dose cohort. The authors specifically cautioned that the high-dose estimates may reflect complex formation/elimination kinetics and possible saturation. This is another reason not to use a single fixed 7-OH half-life clinically. [7] #### Renal elimination Unchanged renal excretion differs substantially across alkaloids. **Mitragynine itself is only minimally recovered unchanged in urine**, while some minor alkaloids have materially higher unchanged urinary fractions. Most overall disposition therefore cannot be summarized as "the kidneys simply clear intact kratom alkaloids." Metabolism plus conjugation are important. [5] --- ### 5. Mitragynine pseudoindoxyl: metabolite and commercial drug **Mitragynine pseudoindoxyl (MP)** deserves its own category because it is simultaneously: 1. a downstream transformation product of 7-OH; 2. a potent opioid-active molecule in experimental pharmacology; and 3. an increasingly relevant semisynthetic/commercial compound in the 7-OH marketplace. [11-14,18] Kamble and colleagues demonstrated that 7-OH rearranged rapidly in human plasma ex vivo, with approximately **53.8% conversion to MP after 120 minutes** under their experimental conditions. MP itself remained comparatively stable during the experiment. Those are **ex-vivo plasma stability data**, not systemic human pharmacokinetics. [11,12] More recent metabolic-networking work supports both liver-associated and nonenzymatic contributions to MP formation. Human in-vivo fractional conversion, oral bioavailability, volume of distribution, systemic half-life, renal/fecal clearance, and clinical detection window have **not been established**. [13] For forensic interpretation, a positive MP result can be difficult to interpret without context because MP may represent **direct use of an MP-containing product, downstream formation after 7-OH exposure, or both**. Product analysis and analyte ratios may eventually help, but no universally validated clinical algorithm currently exists. --- ### 6. Emerging semisynthetic / synthetic analogues #### MGM-15 **Preferred descriptive name:** dihydro-7-hydroxymitragynine **Common labels:** MGM-15; DH7OH; some commercial material has used "DHM" terminology, which is chemically ambiguous. - MGM-15 is a **synthetic/semi-synthetic derivative of 7-OH**, produced by reduction/saturation of the relevant imine/double-bond system in the mitragynine scaffold. [19,20] - In receptor studies it shows strong opioid-receptor activity, including MOR and DOR activity. [19,20] - A 2025 analytical report identified commercial tablets averaging about **10.9 mg MGM-15 per tablet** in the products tested. [19] - The Center for Forensic Science Research and Education (CFSRE) reported first U.S. detection in 2025 and confirmed MGM-15 in drug material and toxicology specimens using **LC-QTOF-MS** with reference material. [21] - **GC-MS is problematic:** MGM-15 can undergo analytical conversion to mitragynine during GC analysis, creating a serious identification pitfall. High-quality LC-MS confirmation is preferable. [21] - **Human pharmacokinetics:** unknown. - **Human metabolism:** unknown. - **Human half-life:** unknown. - **Validated urine/blood detection window:** unknown. - **Clinical withdrawal/overdose literature:** essentially absent compared with 7-OH. #### MGM-16 **Description:** fluorinated dihydro-7-OH analogue. Position numbering varies depending on chemical nomenclature convention; the medicinal-chemistry literature describes it as a fluorinated analogue developed alongside MGM-15. [20,22] - Developed in preclinical medicinal chemistry as a potent dual mu/delta opioid agonist. [20,22] - Demonstrated antiallodynic/analgesic activity in animal models. [20,22] - DEA's 2026 scheduling record discusses MGM-16 as an emerging related compound but reported no established consumer-market/toxicology presence comparable to 7-OH or MGM-15 at the time of the notice. [18] - **Human use studies:** none established. - **Human metabolism:** unknown. - **Human half-life:** unknown. - **Urine/blood detection window:** unknown. - **Routine laboratory availability:** no standard clinical assay. #### 3-dehydromitragynine (3DM / 3DMTG) 3DM belongs in **two categories at once**: it is an oxidative MG product demonstrated in metabolic systems, and it can also occur as a minor natural/commercial-product constituent. The 2021 oxidative-metabolism study demonstrated formation from MG by a **non-CYP, NADPH-independent pathway** in human liver microsomes/S9 and in mice, and characterized MOR partial-agonist activity plus high-dose toxicity in mice through a mechanism not fully explained by opioid receptors. [34] A 2026 study additionally showed degradation of 7-OH to 3DM under **simulated gastric conditions**. That chemistry is relevant to oral products but does not establish the fraction of an oral 7-OH dose converted to 3DM in living humans. [35] - **Controlled human in-vivo confirmation:** not established. - **Human PK / half-life / clearance:** unknown. - **Routine toxicology detection:** not standard; targeted HRMS can identify it with an appropriate standard. - **Validated urine/blood detection window:** unknown. - **Commercial relevance:** reported in contemporary product analyses, including products with complex/mislabeled alkaloid profiles. [36] #### 8-hydroxymitragynine and 11-hydroxymitragynine These names appear in emerging commercial/analytical literature. They should be listed as **related hydroxylated mitragynine compounds**, not as established clinically important human metabolites unless a specific human metabolic study demonstrates that pathway. Human pharmacology, PK, half-life, and detection windows remain poorly characterized. #### Research pseudoindoxyl / hydroxyl analogues Medicinal-chemistry literature includes compounds such as **7-hydroxypaynantheine, 7-hydroxyspeciogynine, paynantheine pseudoindoxyl, and speciogynine pseudoindoxyl**. These are useful for understanding structure-activity relationships but should **not** be presented to patients as established human metabolites or common retail exposures without direct evidence. [24] --- ### 7. Relevant parent botanical alkaloids: glossary Kratom contains dozens of indole and oxindole alkaloids. Modern analytical studies have structurally characterized more than forty, with counts varying by plant chemotype, analytical method, and what authors consider a distinct alkaloid. The following are the most relevant to a clinical 7-OH resource. [25,26] #### Mitragynine (MG) The predominant alkaloid in most kratom leaf products. Opioid-active itself but also functions as a **metabolic precursor to 7-OH**. It has a much longer terminal half-life than 7-OH in botanical exposure studies. Human MG metabolism is extensive; unchanged urinary excretion is low. [1-7] #### 7-hydroxymitragynine (7-OH) Minor naturally occurring alkaloid, human MG metabolite, oxidation/processing product, and now a high-dose commercial drug. Potent opioid pharmacology. Direct high-dose purified human PK remains a major evidence gap. [1-7,18] #### Mitragynine pseudoindoxyl (MP) Potent rearrangement product of 7-OH and also a directly manufactured commercial compound. Human systemic PK remains unknown. [11-14,18] #### Speciogynine Common minor alkaloid. Parent compound has serotonergic receptor binding; its **9-O-desmethyl metabolite** demonstrates functional 5-HT1A agonism. [15-17] #### Paynantheine Common minor alkaloid. Like speciogynine, it has serotonergic receptor interactions, while its **9-O-desmethyl metabolite** shows functional 5-HT1A agonism. [15-17] #### Speciociliatine Stereoisomer/related indole alkaloid with opioid-receptor activity. Human PK has been measured after botanical kratom exposure. [5,25,26] #### Mitraciliatine Minor alkaloid present in some chemotypes; has opioid-receptor activity in modern screening studies. Human PK has been measured after botanical exposure. [5,25,26] #### Isopaynantheine and epiallo-isopaynantheine Minor alkaloids found in botanical kratom. Opioid-receptor activity has been reported for some members of this subgroup, including KOR activity in modern functional screens. Clinical contribution is uncertain. [25-27] #### Corynantheidine Minor alkaloid with opioid-receptor binding/antagonist-like pharmacology reported in preclinical work. It is relevant to the broader kratom targetome but is not a principal 7-OH metabolite. #### Corynoxine A / corynoxine B / corynoxeine Oxindole alkaloids present in some kratom samples. They are pharmacologically interesting but far less clinically characterized than MG or 7-OH. [25,26] #### Speciofoline / isospeciofoline (and related spelling variants) Minor alkaloids identified in modern phytochemical profiling. Clinical activity remains incompletely characterized. [25,26] #### Rhynchophylline / 3-epirhynchophylline and related oxindoles Minor botanical constituents. They are part of the broader kratom alkaloid profile but should not be conflated with 7-OH or its metabolic pathway. [25,26] #### N-oxide alkaloids Mitragynine-N(4)-oxide, speciociliatine-N(4)-oxide, isopaynantheine-N(4)-oxide, and related N-oxides have been identified in botanical material. Their abundance can be affected by storage/oxidation and product processing. Clinical pharmacologic significance is incompletely defined. [25,26] --- ### 8. Biological detection: what can actually be tested #### Routine urine drug screens A routine "opiates" immunoassay is generally designed around morphine-like structures and **does not specifically identify mitragynine, 7-OH, MP, MGM-15, or MGM-16**. A negative routine opioid screen therefore does not exclude kratom-family exposure. Dedicated mitragynine immunoassays have been developed, but they are specialized assays and can cross-react with related alkaloids/metabolites. Confirmation by chromatography-mass spectrometry is preferred when compound-level identification matters. [28] #### Targeted urine testing Validated research/forensic methods include LC-MS/MS, LC-HRMS, LC-QTOF-MS, and capillary electrophoresis-MS/MS. A 2024 urine method reported analytical limits of detection of approximately **0.5 ng/mL for mitragynine** and **2 ng/mL for 7-OH**. These are analytical sensitivity limits, **not** clinical detection windows. [29] Controlled human botanical studies collected and quantified kratom alkaloids in urine for up to **120 hours** after dosing. This supports the proposition that targeted urine testing can remain informative for days in some exposure settings, especially for MG and metabolites. It does **not** establish a universal "five-day window" for every dose, product, metabolizer, or assay. [5] #### Plasma / blood Mitragynine, 7-OH, and several parent botanical alkaloids have been measured with validated LC-MS/MS methods in controlled human studies. The time to last quantifiable concentration varies dramatically by analyte, dose, repeated use, and assay sensitivity. [5-7] In the 2026 concentrated-mitragynine-extract study, 7-OH remained quantifiable much longer in some high-dose/repeated-dose participants than in low-dose participants, again demonstrating why a single blood "window" is not defensible. [7] #### Hair Mitragynine and 7-OH have been measured in hair using targeted LC-MS/MS forensic methods. Hair can support longer-term exposure assessment, but segment location, hair growth, cosmetic treatment, external contamination, and incorporation kinetics complicate interpretation. Hair testing is unsuitable for determining a precise recent last-use time. [30] #### MGM-15 CFSRE has confirmed MGM-15 in toxicology specimens and drug materials using LC-QTOF-MS. No validated population detection window has been published. GC-MS can misidentify the compound because MGM-15 can convert to MG during analysis. [21] #### Mitragynine pseudoindoxyl MP can be measured with targeted modern LC-MS methods and has appeared in commercial/toxicology investigations. No validated blood or urine window exists. Because MP may arise downstream of 7-OH, detection alone may not prove direct MP ingestion. [11-14,18] #### MGM-16 No validated clinical biological detection window exists. As of DEA's July 2026 discussion, confirmed real-world consumer/toxicology exposure was not established to the same degree as 7-OH, MP, or MGM-15. [18] --- ### 9. Practical detection matrix | Analyte | Routine opiate screen? | Targeted LC-MS / HRMS? | Demonstrated biological detection | Defensible timing statement | |---|---|---|---|---| | **Mitragynine** | No specific detection | Yes | Plasma, urine, hair | Long terminal PK after botanical use; urine can remain detectable for days with sensitive targeted methods. No universal cutoff. [5-7,29,30] | | **7-OH** | No specific detection | Yes | Plasma, urine, hair | Detectable after botanical MG exposure and direct-product exposure; controlled botanical studies show hours-to-days depending dose/regimen. No validated window for high-dose purified 7-OH. [5-7,29,30] | | **9-O-demethylmitragynine** | No | Yes | Human urine | Prominent urinary MG metabolite; no validated time window. [3,9,10] | | **16-carboxymitragynine** | No | Yes | Human urine | Useful metabolite marker; no validated time window. [3,9,10] | | **Mitragynine pseudoindoxyl** | No | Yes, method-dependent | Commercial/treatment/toxicology contexts; formation demonstrated ex vivo | No validated window; direct ingestion cannot always be distinguished from downstream formation. [11-14,18] | | **MGM-15** | No | Yes; LC-QTOF confirmation preferred | Toxicology specimens and drug materials reported | No validated window. GC-MS transformation to MG is a known analytical trap. [21] | | **MGM-16** | No | In principle yes with reference standard and appropriate HRMS method | Real-world human biological prevalence not established | Unknown. [18,20,22] | | **Speciogynine / paynantheine and metabolites** | No | Yes | Parent alkaloids in plasma/urine; metabolites characterized | No clinically validated metabolite-specific window. [5,15-17] | --- ### 10. Interpretation traps for clinicians, toxicologists, and the website 1. **A positive 7-OH result does not automatically prove a person swallowed a commercial 7-OH product.** Mitragynine is metabolized to 7-OH. Product history and relative analyte concentrations matter. [1-4] 2. **A positive MP result does not automatically prove direct MP ingestion.** MP can form downstream from 7-OH. [11-14] 3. **A negative routine opioid screen does not rule out 7-OH intoxication or withdrawal.** Standard immunoassay design is the problem, not necessarily the patient's history. [28,29] 4. **Do not infer last-dose timing from a qualitative urine result.** Long MG kinetics, metabolite formation, repeated dosing, renal function, assay cutoff, and product composition make back-calculation unreliable. [5-7] 5. **Do not use ex-vivo plasma stability as a clinical half-life.** The approximately 99-minute 7-OH value from the pseudoindoxyl conversion experiment is a laboratory plasma-incubation observation, not a systemic human PK parameter. [11,12] 6. **Do not treat botanical-kratom 7-OH half-life as purified-7-OH PK.** Formation from MG can distort the apparent terminal phase. [4-7] 7. **Commercial labels are not dependable analytical records.** Multiple recent product surveys found large differences between labeled and measured alkaloids, semisynthetic profiles, undeclared active compounds, and oxidation products. [23,31,32] 8. **GC-MS can create identification artifacts for some emerging analogues.** MGM-15 is a particularly important example because it can transform to MG during GC analysis. [21] 9. **"Kratom" is chemically too broad for many clinical conclusions.** Botanical leaf, MG-rich extract, purified 7-OH, MP products, MGM-15 products, and mixtures should be documented separately whenever possible. --- ### 11. What is still genuinely unknown The most important unresolved questions for the current public-health crisis are: - Direct human PK of **purified high-dose 7-OH**, including Cmax, Tmax, oral/sublingual bioavailability, distribution, intrinsic elimination half-life, accumulation with frequent redosing, and active-metabolite contribution. - The fraction of direct 7-OH converted to **MP in vivo** in humans. - Human PK, metabolism, elimination, and toxicity of **MGM-15** and **MGM-16**. - Reliable biological detection windows for purified 7-OH, MP, MGM-15, MGM-16, and 3DMTG. - Whether analyte ratios can reliably distinguish botanical kratom use, MG extract use, purified 7-OH use, and direct MP use. - Quantitative contribution of **9-O-demethylmitragynine** to analgesia, intoxication, dependence, or withdrawal in humans. - Whether serotonergic active metabolites of speciogynine/paynantheine contribute materially to the distinctive affective or sleep features reported during botanical kratom withdrawal. - How hepatic impairment, renal impairment, CYP3A inhibition/induction, CYP2D6 phenotype, and polysubstance exposure alter direct 7-OH disposition. - Whether chronic high-frequency 7-OH dosing produces nonlinear kinetics or tissue redistribution that meaningfully changes buprenorphine induction timing. These gaps should be presented prominently. They are not weaknesses in the resource; they are the current state of the science. --- ### 12. Suggested terminology for the EusomniaMD website **Botanical kratom:** Leaf-derived *Mitragyna speciosa* material containing a mixture of naturally occurring alkaloids, usually dominated by mitragynine. **Mitragynine (MG):** Principal kratom alkaloid and metabolic precursor to 7-OH. **7-OH / 7-hydroxymitragynine:** Potent opioid-active alkaloid that exists in trace botanical quantities, is formed metabolically from MG, and is now sold in highly concentrated/semi-synthetic products. **Mitragynine pseudoindoxyl (MP):** Potent rearrangement product downstream of 7-OH that is also sold directly as a semisynthetic opioid-active compound. **MGM-15:** Dihydro-7-OH analogue now documented in commercial drug material and U.S. toxicology specimens; human PK and safety are essentially undefined. **MGM-16:** Fluorinated MGM-15/7-OH analogue from medicinal-chemistry research; potent opioid activity in animals, with human PK and safety undefined. **Active metabolite:** A metabolite with demonstrated pharmacologic activity, not merely a compound detectable after exposure. **Phase I metabolism:** Oxidation, reduction, hydrolysis, or demethylation that changes the parent molecular structure. **Phase II metabolism:** Conjugation, commonly glucuronidation or sulfation, usually increasing water solubility and facilitating elimination. **Detection window:** The interval during which a specified analyte can be detected above a specified assay cutoff in a specified biological matrix. It is assay- and dose-dependent and should not be treated as a universal property of the drug. **Formation-limited kinetics:** A situation in which the measured decline of a metabolite reflects how quickly it is still being produced from a longer-lived precursor, not simply how quickly the metabolite itself is eliminated. --- ### 13. Recommended evidence labels for web pages Use these labels directly beside claims when helpful: - **Human controlled data** - prospective human pharmacokinetic or interaction study. - **Human confirmed metabolite** - directly identified in human plasma, urine, or ex-vivo human biological systems. - **Clinical case evidence** - case report or small case series. - **Preclinical functional evidence** - receptor/cellular/animal pharmacology. - **Forensic/commercial evidence** - confirmed in marketed products, seized material, or toxicology testing. - **Clinical inference** - reasonable extrapolation from pharmacology plus direct clinical experience, but not established by controlled study. - **Unknown** - no adequate evidence currently available. This hierarchy is particularly important for withdrawal timelines and buprenorphine timing, where the current literature does not support false precision. --- ### 14. Author / source provenance for the eventual webpage For the professional biography associated with this resource, the public CSAM record independently confirms that **Brian Harris, MD** served as faculty for the **2025 California Society of Addiction Medicine Addiction Medicine Board Exam Preparation Course** and lists his board certifications in Addiction Medicine, Anesthesiology, and Sleep Medicine. [38] An archived August 2025 **Basic Sciences & Addiction - Addiction Medicine Board Review** deck identifies Brian Harris, MD as the presenter and contains a dedicated board-style kratom neuropharmacology question and explanation focused on mitragynine's opioid-receptor pharmacology. [41] This is useful contemporaneous evidence that kratom pharmacology was part of Dr. Harris's addiction-medicine teaching before the present 7-OH regulatory crisis. I did **not** find searchable text for “7-hydroxymitragynine” in the retrieved copy, so the stronger claim that this specific archived deck explicitly covered 7-OH should remain dependent on locating the relevant slide/version rather than being stated as independently verified. The website should describe prior teaching experience without implying that CSAM endorses the present EusomniaMD resource. --- ### 15. Selected primary and authoritative references 1. Kruegel AC, et al. **7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects.** *ACS Central Science.* 2019;5:992-1001. doi:10.1021/acscentsci.9b00141. 2. Kamble SH, et al. **Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy.** *ACS Pharmacology & Translational Science.* 2020;3:1063-1068. doi:10.1021/acsptsci.0c00075. PMID:33344889. 3. Basiliere S, Kerrigan S. **CYP450-Mediated Metabolism of Mitragynine and Investigation of Metabolites in Human Urine.** *Journal of Analytical Toxicology.* 2020;44:301-313. doi:10.1093/jat/bkz108. 4. Jaisi A, et al. **Effects of Itraconazole on Pharmacokinetics of Mitragynine and 7-Hydroxymitragynine in Healthy Volunteers.** *ACS Pharmacology & Translational Science.* 2024;7:823-833. doi:10.1021/acsptsci.3c00335. PMID:38481700. 5. Tanna RS, et al. **Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants.** *Pharmaceutics.* 2022;14:620. PMID:35335999. 6. Huestis MA, et al. **Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder.** *Molecules.* 2024;29:984. 7. Huestis MA, et al. **Mitragynine and 7-hydroxy-mitragynine plasma pharmacokinetics in humans after single and 15 multiple oral kratom extract doses.** *Journal of Analytical Toxicology.* 2026;50(6):bkag042. doi:10.1093/jat/bkag042. PMID:42266029. (Industry relationships disclosed by the authors.) 8. Matsumoto K, et al. **Partial agonistic effect of 9-hydroxycorynantheidine on mu-opioid receptor in the guinea-pig ileum.** *Life Sciences.* 2006;78:2265-2271. doi:10.1016/j.lfs.2005.09.030. PMID:16266723. 9. Philipp AA, et al. Classic LC-MS/GC-MS studies of **mitragynine phase-I and phase-II metabolites in rat and human urine.** *Journal of Mass Spectrometry.* 2009. 10. Basiliere/Kerrigan and related forensic metabolite studies documenting O-demethylated, carboxylated, glucuronidated, and sulfated MG metabolites in human urine. See ref. 3 and its cited metabolite literature. 11. Kamble SH, et al. Human-plasma ex-vivo conversion of 7-OH to MP. See ref. 2. In pooled human plasma, **53.8 +/- 1.6%** of incubated 7-OH was converted to MP by 120 min under the experiment's conditions; this is not a systemic human conversion fraction. 12. Zhou Y, et al. **Predicted Mode of Binding to and Allosteric Modulation of the Mu-Opioid Receptor by Kratom's Alkaloids with Reported Antinociception In Vivo.** *Biochemistry.* 2021;60:1420-1429. doi:10.1021/acs.biochem.0c00658. PMID:33274929. 13. Crandall WJ, et al. **Mixtures Biotransformation: Multilayer Molecular Networking of Kratom Liver Metabolites.** *Journal of Natural Products.* 2026. doi:10.1021/acs.jnatprod.5c01235. 14. Contemporary forensic/commercial analyses of mitragynine pseudoindoxyl and related semisynthetic kratom-opioid products; interpret biological detection with route and product chemistry in mind. 15. Leon F, et al. **Activity of Mitragyna speciosa (Kratom) Alkaloids at Serotonin Receptors.** *Journal of Medicinal Chemistry.* 2021;64:13510-13523. doi:10.1021/acs.jmedchem.1c00726. 16. Leon et al. supporting information and metabolic experiments for 9-O-desmethylspeciogynine. See ref. 15. 17. Leon et al. supporting information and metabolic experiments for 9-O-desmethylpaynantheine. See ref. 15. 18. U.S. Drug Enforcement Administration. **Schedules of Controlled Substances: Temporary Placement of Mitragynine Pseudoindoxyl, MGM-15, and MGM-16 in Schedule I - Notice of Intent.** *Federal Register.* July 6, 2026; Docket DEA-1644. 19. Gour A, et al. **From Kratom to Semi-Synthetic Opioids: The Rise and Risks of MGM-15.** *Drug Testing and Analysis.* 2025;17:2384-2389. doi:10.1002/dta.3952. PMID:40936282. 20. Matsumoto K, et al. **Orally active opioid mu/delta dual agonist MGM-16, a derivative of the indole alkaloid mitragynine, exhibits potent antiallodynic effect on neuropathic pain in mice.** *Journal of Pharmacology and Experimental Therapeutics.* 2014;348:383-392. PMID:24345467. 21. Center for Forensic Science Research and Education (CFSRE), NPS Discovery. **MGM-15 analytical monograph / public alert.** 2025-2026. Use the specific monograph version cited by the website when discussing analytical artifacts. 22. Medicinal-chemistry studies of MGM-15/MGM-16 and fluorinated 7-OH analogues; see ref. 20 and later structure-activity work. 23. Contemporary 2025-2026 market/product analyses of semisynthetic 7-OH-related alkaloids and label-content discrepancies. 24. Bhowmik S, et al. and related medicinal-chemistry studies of hydroxylated/pseudoindoxyl analogues derived from Mitragyna scaffolds. 25. Flores-Bocanegra L, et al. **The Chemistry of Kratom [Mitragyna speciosa]: Updated Characterization Data and Methods to Elucidate Indole and Oxindole Alkaloids.** *Journal of Natural Products.* 2020. 26. Manwill PK, et al. Modern LC-MS/NMR characterization of kratom alkaloid chemotypes and minor constituents. 2022. 27. Chakraborty S, et al. **Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom.** *ACS Chemical Neuroscience.* 2021;12:2661-2678. doi:10.1021/acschemneuro.1c00149. PMID:34213886. 28. Dedicated **mitragynine immunoassays** have been developed, but they are not equivalent to routine hospital opiate screens and require assay-specific interpretation/cross-reactivity review. 29. Targeted urine methods for MG/7-OH include validated LC-MS/MS and later CZE-MS/MS approaches. A 2015 LC-MS/MS method demonstrated sub-ng/mL analytical sensitivity; analytical LOD is not the same as a clinical cutoff or detection window. 30. 2024 *Journal of Analytical Toxicology* LC-MS/MS hair method for mitragynine and 7-OH; hair establishes historical exposure, not acute timing. 31. Brown et al. 2026 *Journal of AOAC International* analysis of high-7-OH products showing alkaloid concentrations/profiles inconsistent with authentic botanical leaf. 32. 2026 quantitative commercial-product analyses documenting label disagreement, oxidation products, and semisynthetic chemical signatures. 33. **An in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynine.** Human liver S9 study reporting 9ODM formation as a major MG pathway and supporting CYP3A contribution. 2024. 34. Chakraborty S, et al. **Oxidative Metabolism as a Modulator of Kratom's Biological Actions.** *Journal of Medicinal Chemistry.* 2021;64:16553-16572. doi:10.1021/acs.jmedchem.1c01111. Establishes preclinical formation/activity of 7-OH, MP, and 3DM, including non-CYP 3DM formation. 35. Avula B, et al. **Quantitative analysis of 7-hydroxymitragynine in commercial kratom products and its stability under chemical and physiological conditions.** *Phytochemistry.* 2026. PMID: 41825819. Reports degradation of 7-OH to 3DM under simulated gastric conditions; treat this as product/GI chemistry until human in-vivo conversion is quantified. 36. Gour A, et al. **Mislabeling and Status of Semisynthetic Kratom-Derived Products in the US Market.** *Drug Testing and Analysis.* 2026. doi:10.1002/dta.70122. PMID:42448619. Reports frequent label-content disagreement and pharmacologically/toxicologically relevant compounds including 7-OH and 3DM. 37. Metabolic literature identifying **9-O-demethylmitragynine glucuronide (9-hydroxycorynantheidine glucuronide)** and reporting weak MOR affinity; clinical activity is unproven. See refs. 9, 13 and cited pharmacology therein. 38. California Society of Addiction Medicine. **2025 Addiction Medicine Board Exam Preparation Course.** Official CSAM Education Center faculty listing: Brian Harris, MD. 39. Reissig CJ, et al. **A Pilot, Dose-Finding, Pharmacodynamic and Pharmacokinetic Study of Orally Administered Botanical Kratom.** *J Clin Psychopharmacol.* 2026;46:386-398. doi:10.1097/JCP.0000000000002158. PMID:41837407. 40. Gour A, et al. *Drug Testing and Analysis* 2026 commercial-product study; see ref. 36. 41. Harris B. **Basic Sciences & Addiction - Addiction Medicine Board Review.** August 2025 archived presentation deck. Contains a board-style kratom pharmacology item discussing mitragynine as a partial mu-opioid agonist and kappa-opioid antagonist. Internal source archive; distinguish this from formal CSAM endorsement. --- ### 16. Web-publication note For the public-facing resource, prefer wording such as: > "In a controlled study, targeted testing remained informative through the study's 120-hour urine collection period. This should not be interpreted as a universal five-day detection window." rather than: > "7-OH stays in urine for five days." Likewise, prefer: > "Published botanical-kratom studies report 7-OH half-lives ranging from several hours to much longer terminal estimates after repeated high-dose exposure, but direct purified-7-OH human pharmacokinetics have not been adequately characterized." rather than assigning a single half-life to the commercial drug. The scientifically useful message is not that every number is known. It is that **we now know enough to identify the pharmacologically important pathway, and we know exactly where the evidence stops.** --- ## Appendix B: Clinical Assessment Template *Source module: `appendices/appendix-b-clinical-assessment-template.md`* **For clinician adaptation. Not a validated instrument.** **Version:** 1.2 | **Reviewed:** August 8, 2026 ### 1. Exposure characterization - Product/brand and photograph: - Form: tablet / gummy / shot / powder / capsule / film / pouch / other - Label claim per unit: - Units per dose: - Doses per day: - Estimated labeled mg/day: - Shortest redosing interval: - Duration of use: - Route: oral / sublingual / intranasal / inhaled / other - Botanical kratom, extract, 7-OH, MP, MGM-15/16, or unknown mixture: - Source and date purchased: - Recent brand/formulation change: - Prior kratom, prescription opioid, heroin, fentanyl, methadone, or buprenorphine use: ### 2. Dependence and use-disorder phenotype - Interdose withdrawal: - Nocturnal/early-morning withdrawal: - Tolerance/escalation: - Unsuccessful reduction attempts: - Use to avoid withdrawal: - Craving: - Time spent obtaining/using/recovering: - Occupational, financial, family, or medical consequences: - Continued use despite harm: - Prior overdose: - Likelihood of seeking fentanyl/counterfeit pills if supply ends: ### 3. Last exposure and current syndrome - Date/time of last dose: - First symptom and onset time: - Current COWS and serial trend: - GI symptoms and hydration: - Myalgias/restlessness/tremor: - Sweating/chills/piloerection: - Rhinorrhea/lacrimation/yawning: - Heart rate/BP/temperature/oxygen saturation: - Insomnia and hours slept: - Anxiety/dysphoria/irritability: - Craving and ability to remain safe: - Confusion, psychosis, seizure, syncope, chest pain, or respiratory symptoms: ### 4. Coexposures and medication reconciliation - Alcohol: - Benzodiazepines or Z-drugs: - Fentanyl/other opioids: - Nicotine/stimulants: - Gabapentinoids: - Antidepressants/antipsychotics: - QT-prolonging drugs: - CYP3A/2D6/2C19 inhibitors or inducers: - Naltrexone exposure: - OTC/herbal products: ### 5. Medical and social risk - Pregnancy/lactation: - Age/frailty: - Seizure disorder: - Cardiac disease/channelopathy: - Respiratory disease/OSA/hypoventilation: - Hepatic/renal disease: - Severe psychiatric illness/suicide risk: - Concurrent sedative dependence: - Housing, support, phone, transportation, pharmacy access: - Child-safety/storage concerns: ### 6. Suggested disposition screen **Consider emergency/hospital/medically managed care for:** overdose or recurrent sedation; respiratory compromise; seizure; delirium/psychosis; severe agitation; chest pain/syncope/arrhythmia; uncontrolled vomiting/diarrhea/dehydration; pregnancy with significant dependence; severe polysubstance withdrawal; unstable medical illness; unsafe environment; or inability to avoid illicit-opioid substitution. **Consider observed or low-dose transition for:** unclear product/last dose; q1-3h redosing; mixed fentanyl/MP/MGM exposure; previous precipitated withdrawal; inability to tolerate abstinence; or high consequence of a withdrawal spike. **Consider standard initiation for:** credible short-acting exposure with convincing progressive withdrawal, adequate monitoring/support, and no indication for higher care. ### 7. Treatment plan - Chosen pathway: standard buprenorphine / low-dose buprenorphine / methadone referral / symptomatic / inpatient - Rationale: - Objective withdrawal threshold/clinical criteria: - Adjunctive medications: - Naloxone supplied and training completed: - Fentanyl/counterfeit-pill counseling: - Follow-up within: - Escalation instructions: - Maintenance versus taper discussion: - Pain, sleep, mood, and other-SUD plan: ### Suggested note language > Patient reports repeated use of a concentrated commercial 7-hydroxymitragynine/kratom-derived product with physiologic dependence and withdrawal. Product composition and direct high-dose human 7-OH pharmacokinetics are uncertain. Treatment planning is based on reported exposure, objective withdrawal findings, supplemental symptom assessment, coexposures, medical risk, and established OUD principles. The patient was counseled regarding naloxone, counterfeit-pill/fentanyl risk, and the danger of substituting non-prescribed opioids. --- ## Appendix C: Source and Publication Notes *Source module: `appendices/appendix-c-source-and-publication-notes.md`* ### Purpose This appendix prevents the resource from gradually turning provisional clinical synthesis into fake settled science through repetition. Each public claim should retain its evidence class, source ID, population, compound, and last-verified date. ### Compound naming controls Do not use **kratom**, **mitragynine**, **7-OH**, **mitragynine pseudoindoxyl**, **MGM-15**, **MGM-16**, and **commercial kratom-derived product** as interchangeable terms. Use: - **botanical kratom** for minimally processed *Mitragyna speciosa* leaf; - **MG-rich extract** for an extract dominated by mitragynine; - **concentrated 7-OH product** when 7-OH is labeled or analytically demonstrated at enhanced concentration; - **commercial kratom-derived product** when composition is unknown or mixed; - **MP, MGM-15, or MGM-16** only when specifically identified or declared; - **reported 7-OH exposure** when the claim rests on patient history without analytical confirmation. ### Evidence wording controls | Evidence | Preferred wording | Avoid | |---|---|---| | Controlled human | “A controlled human study found…” | “Proves universally…” | | Small series | “In a nine-patient retrospective series…” | “Clinical trials show…” | | Case report | “A published case described…” | “7-OH causes…” without qualification | | Animal/in-vitro | “In rats/in a receptor assay…” | Human dose or incidence conversion | | Practice experience | “In the author's clinical experience…” | “Data show…” | | No direct data | “Data insufficient” | Filling the blank with botanical analogy | ### High-risk recurring errors 1. Calling the July 2026 DEA notice a final federal Schedule I order before an order is published. 2. Presenting California's food/drug enforcement position as a controlled-substance schedule listing. 3. Calling 7-OH a weak partial agonist without noting assay and receptor-reserve dependence. 4. Treating G-protein bias as proof of respiratory safety. 5. Inventing a gamma opioid receptor. 6. Attributing serotonin or stimulant pharmacology of botanical minor alkaloids directly to purified 7-OH. 7. Publishing a universal 7-OH half-life or urine-detection window. 8. Turning the provisional 16-36-hour peak estimate into a validated time-course claim. 9. Using a fixed clock as the sole criterion for buprenorphine initiation. 10. Calling every seizure, psychosis, QT change, or liver injury a proven isolated-7-OH effect. 11. Treating consultation cases as equivalent to directly treated cohort cases. 12. Describing the uploaded 2024 predecessor CSAM deck as the author's 2025 presentation. ### Legal update procedure Record the exact source, action type, publication date, effective date, threshold, and jurisdiction. Search separately for a notice, proposed rule, temporary order, final rule, statute, administrative rule, and health-department enforcement notice. A search failure is not proof of absence; wording should say a later order “was not located in the sources checked as of [timestamp].” ### Correction policy Material corrections require: - a dated changelog entry; - the prior wording and replacement wording; - the source that triggered the correction; - whether the change affects clinical advice, legal status, or only terminology; - prompt correction across all derivative pages, infographics, and decks. ### Author-content provenance The official CSAM 2025 course page verifies Brian Harris, MD as faculty for Basic Science (Neurobiology) and Legal Aspects of Addiction Medicine. His report that the lecture included a dedicated emerging-opioids/7-OH segment is author-reported unless the final 2025 presentation is archived. The currently uploaded PowerPoint parses as a 2024 predecessor deck attributed to Waseem Khader and is useful as curricular context, not proof of the later lecture's exact content. --- ## Appendix D: Receptor and Target Catalogue *Source module: `appendices/appendix-d-receptor-target-catalogue.md`* This appendix preserves the detailed receptor synthesis used for the pharmacodynamics page. The standard is functional activation at plausibly relevant potency, not docking or binding alone. ### Functionally activated receptors with the strongest support | Receptor | Demonstrated activators among characterized kratom alkaloids/metabolites | Interpretation | |---|---|---| | **Mu-opioid receptor (MOR)** | 7-OH, mitragynine, mitragynine pseudoindoxyl, 9-O-demethylmitragynine, speciociliatine, paynantheine, speciogynine, several oxindoles/minor alkaloids | Dominant clinically relevant system. 7-OH is high potency with assay- and receptor-reserve-dependent efficacy. [E12, E15-E16, E18] | | **Kappa-opioid receptor (KOR)** | Compound- and assay-dependent activation by 7-OH, mitragynine, speciociliatine, mitraciliatine, isopaynantheine, and MG-N-oxide | Secondary and inconsistent across assay systems; do not reduce to one universal agonist/antagonist label. [E12, E15] | | **Delta-opioid receptor (DOR)** | Principally 7-OH in recent functional systems; additional activity varies by compound | Functional activation is supported in vitro; clinical contribution remains uncertain. [E12] | | **5-HT1A** | 9-O-desmethylspeciogynine and 9-O-desmethylpaynantheine | Strong functional laboratory signal for metabolites of minor botanical alkaloids; not proof that purified 7-OH is serotonergic. [E13] | | **alpha1A-adrenergic** | Mitragynine | Low-potency partial agonism; possible contribution to botanical autonomic/stimulant features. [E14] | ### Binding or modulation that should not be mislabeled as activation - Mitragynine behaves as an **alpha2A antagonist**, not a direct alpha2 agonist, in current functional work. [E14] - Speciogynine and paynantheine bind several serotonin receptors, but binding is not synonymous with agonism; their O-desmethyl metabolites show 5-HT1A agonism and 5-HT2B inverse-agonist behavior. [E13] - Dopamine-receptor docking or displacement is not proof of functional activation. - CB1 mediation of mitragynine analgesia has not been convincingly demonstrated. - Speciophylline has been described as a positive allosteric modulator of MOR rather than a direct agonist. [E12] - There is no recognized “gamma opioid receptor.” The canonical opioid receptors are MOR, KOR, DOR, and NOP/ORL1; the gamma symbol in an older teaching slide is not a receptor category for kratom pharmacology. ### Preferred 7-OH wording > 7-OH is a high-potency mu-opioid receptor agonist with strongly G-protein-favoring signaling and assay-dependent intrinsic efficacy. It behaves as a partial agonist in some low-reserve systems and approaches full functional efficacy in others. Secondary KOR and DOR activity is assay-dependent, and the human clinical importance of those targets remains uncertain. ---