7-OH: build the bridge before you close the road.

7-OH in five minutes

Concentrated 7-hydroxymitragynine is a potent opioid that has been sold in gas stations. Federal control is coming and is, in my view, correct. The danger is not the control. The danger is the gap between the day the shelves empty and the day these patients reach a clinician.

The short version

1. 7-OH is not kratom. It is one alkaloid out of more than fifty in Mitragyna speciosa, present in the leaf only in trace amounts. Modern retail "7-OH" is concentrated or semisynthetic; one 2026 analysis found evidence of semisynthetic origin in more than 98% of tested 7-OH–labeled products.³⁰
2. It is a high-potency μ-opioid agonist. Human receptor data place 7-OH at roughly 15 nM binding affinity and ~14 nM functional potency at MOR, an order of magnitude more potent than mitragynine.⁸
3. It causes real dependence and real withdrawal. Published cases describe daily doses in the hundreds of milligrams, hourly redosing, and opioid withdrawal syndromes that conventional scales under-read.^20,21
4. It can depress respiration and naloxone reverses it. Demonstrated in a controlled rat model and reported in a human cardiopulmonary arrest.^14,15
5. Buprenorphine works. In the only published series to date, eight of nine patients using purified 7-OH successfully initiated and stabilized, with no precipitated withdrawal reported.²¹ Nine patients is not a guideline. It is still the best evidence we have.
6. The transition is the hazard. Removing a potent opioid from retail is good policy. Removing it from a physically dependent person with no bridge is how people find fentanyl.

The call: five things, this month

What 7-OH actually is

Most people have never heard the phrase 7-hydroxymitragynine. A great many physicians have not either. That has to change in the next several weeks.

Four different things, routinely confused

Commercial description, and portions of the secondary literature, blur categories that must stay separate if any clinical reasoning is to survive contact with a real patient.

What the chemistry actually shows

Analysis of products marketed as "kratom extracts" found 7-OH concentrations of 22–75 mg/g, with overall alkaloid fingerprints inconsistent with authentic kratom leaf; the investigators concluded such concentrations could only be reached through synthetic processing.²⁹ A separate 2026 quantitative analysis found evidence of semisynthetic origin in more than 98% of 7-OH–labeled products, along with substantial label–content disagreement, oxidation byproducts, and additional opioid-active compounds not declared anywhere on the package.³⁰

A six-month survey of the online market (September 2024 – February 2025) identified 304 semisynthetic 7-OH and mitragynine pseudoindoxyl products, more than 80% of them 7-OH–only, sold predominantly as chewable or sublingual tablets, shots, and gummies.³¹ DEA's own market review documents flavored chewables in bright packaging, prices of roughly $2–4 per tablet, and marketing language explicitly promising "clean and powerful" opioid-receptor activation to people seeking alternatives to prescription opioids.⁴

On the phrase "legal morphine"

The phrase appears in descriptions of 7-OH, including within the scientific literature.³¹ It is not a pharmacologically precise synonym for morphine and I would not use it as a medical label. It does, however, capture the mismatch that developed: potent opioid-active compounds sold over the counter in candy-adjacent dosage forms, without any of the safeguards a patient reasonably associates with an opioid drug.

The argument here is narrow and I want to keep it narrow. It is not that kratom leaf and 7-OH are the same thing; they are not. It is not that everyone who has taken kratom has opioid use disorder; they do not. It is that high-concentration 7-OH products deliver an opioid exposure qualitatively and quantitatively different from botanical kratom, and should not be treated clinically as benign herbal supplements.^29,12

Pharmacology and pharmacodynamics

What follows uses a deliberately strict inclusion standard: demonstrated functional receptor activation, not docking studies or radioligand displacement alone, at potencies plausibly relevant to biology. Applied honestly, that standard produces a receptor map considerably smaller than most kratom diagrams imply, and considerably more interesting.

3.1 The defensible activated-receptor map

3.2 Stop calling 7-OH "a partial μ-agonist"

That description is historically correct in several signaling systems, older human MOR BRET experiments found roughly 47% maximal efficacy.¹⁷ But the comprehensive 2026 human-receptor study found 7-OH producing approximately 86–98% of reference-agonist efficacy in cAMP assays at MOR depending on experimental configuration.⁸ Its intrinsic efficacy is assay- and receptor-reserve-dependent: it behaves as a partial agonist in low-reserve systems and approaches full functional efficacy in others.

This is not pedantry. "Partial agonist" carries a clinical connotation of mildness: a ceiling, a safety margin, a reason to relax. That connotation is precisely what made concentrated 7-OH marketable and precisely what has been misleading clinicians. Whatever 7-OH is doing at the receptor, it is not behaving like a drug with a comfortable ceiling in the people who are dependent on it.

3.3 What should not go on the diagram

Several commonly repeated targets do not meet the functional-activation standard. Including them makes a diagram look authoritative while making it wrong.

3.4 The visual hierarchy I would actually teach

3.5 Why withdrawal from this drug class is clinically distinctive

Three separable reasons, which are frequently collapsed into one and should not be.

1. Kinetics, not just receptors. Concentrated 7-OH behaves like a short-acting opioid in a population accustomed to dosing it hourly. Interdose withdrawal within a single day is the presenting complaint, not an unusual complication.
2. Mixed pharmacology, but only for whole-plant exposure. Botanical kratom withdrawal plausibly involves loss of α_1A adrenergic tone and loss of 5-HT_1A agonism from active metabolites, on top of opioid withdrawal. That is a credible mechanistic basis for affective and sleep features not reproduced by withdrawal from a pure MOR agonist.^9,27 It does not establish that purified 7-OH is serotonergic, and I want that stated rather than implied.
3. κ involvement is a plausible dysphoria mechanism. Several native alkaloids are genuine KOR agonists, and KOR signaling is strongly associated with dysphoria and anhedonia. Whether this contributes materially at real-world exposures is unproven, but it is a more principled hypothesis for the affective severity patients describe than "these patients are anxious."

Pharmacokinetics, metabolism, and testing

4.1 The metabolic map

The pharmacologically important axis is mitragynine → 7-OH → mitragynine pseudoindoxyl. CYP3A4 forms 7-OH from mitragynine; 7-OH is substantially more opioid-active than its parent; and in human plasma 7-OH can rearrange to MP, an even more potent μ-ligand. Everything else is either an exposure biomarker or a side branch.

MITRAGYNINE (MG)
 │
 ├─ CYP3A4 ─────────────────▶ 7-HYDROXYMITRAGYNINE (7-OH)          [ACTIVE — potent MOR]
 │                                │
 │                                └─ human plasma rearrangement ──▶ MITRAGYNINE PSEUDOINDOXYL (MP)
 │                                                                   [ACTIVE — potent MOR, DOR antagonist]
 ├─ CYP2C19 / 3A4 / 2D6 ────▶ 9-O-DEMETHYLMITRAGYNINE               [weakly active — main urinary marker]
 │                             (= 9-hydroxycorynantheidine)
 ├─ CYP2D6 / 2C19 / 2C18 ───▶ 16-CARBOXYMITRAGYNINE                 [inactive at MOR — exposure marker]
 │
 ├─ CYP2C19 ────────────────▶ 9-O-DEMETHYL-16-CARBOXYMITRAGYNINE    [exposure marker]
 │
 ├─ C17 demethylation /  ───▶ 17-O-demethyl-16,17-dihydro-MG        [uncharacterized]
 │  reduction / oxidation     17-carboxy-16,17-dihydro-MG           [uncharacterized]
 │
 ├─ oxidative pathway ──────▶ 3-DEHYDROMITRAGYNINE (3DM)            [preclinical MOR activity + tox signal]
 │
 └─ phase II ───────────────▶ glucuronides and sulfates of multiple hydroxylated /
                              carboxylated metabolites              [elimination]

SPECIOGYNINE  ──▶ 9-O-desmethylspeciogynine (gambirine)   ──▶ functional 5-HT1A agonism
PAYNANTHEINE  ──▶ 9-O-desmethylpaynantheine (gambireine)  ──▶ functional 5-HT1A agonism

SPECIOCILIATINE · MITRACILIATINE · ISOPAYNANTHEINE
  └─ analogous O-demethylation, ester hydrolysis/oxidation, reduction and phase-II
     conjugation; several metabolites detectable in human urine

CYP assignments are supported by recombinant CYP and human microsomal work. CYP3A4 is dominant in mitragynine metabolism and is the isoform directly demonstrated to generate 7-OH. The 7-OH → MP conversion is strongly demonstrated in human plasma in vitro; its quantitative contribution after direct high-dose 7-OH ingestion in living humans has not been established.^1–4

4.2 Core compounds and clinically important metabolites

4.3 Native alkaloids with measured human pharmacokinetics

A standardized kratom-tea study provides the best comparative human dataset across multiple alkaloids, a reminder that botanical kratom is a polypharmacy exposure, not a single drug.⁵

4.4 The semisynthetic derivatives

4.5 Elimination

Mitragynine and the major native alkaloids are cleared predominantly through metabolism rather than unchanged renal excretion. In chronic human tea users, unchanged mitragynine accounted for approximately 0.14% of dose in urine.¹⁶ The standardized tea study similarly found low unchanged urinary fractions for the 3S alkaloids, with somewhat greater unchanged renal recovery of some 3R diastereomers.⁵

For most metabolites, the entire evidence for "elimination" is their presence in urine, frequently after glucuronidation or sulfation. Human fecal mass-balance, biliary clearance and complete recovery studies are lacking. Percentages for total renal versus fecal elimination beyond what has been measured should not be published, and are not published here. There is no human mass-balance study after direct high-dose purified 7-OH, and no validated human elimination study for directly ingested MP.^4–6

4.6 Toxicology testing: what to order and how to read it

What to order

1. Urine LC-MS/MS or LC-HRMS, when the question is simply whether kratom/7-OH-family exposure occurred. Usually the highest-yield test.
2. Blood or plasma LC-MS/MS, when recent exposure, intoxication, quantitative concentration, or pharmacokinetic interpretation matters.
3. Product analysis, when it matters whether the patient ingested botanical kratom, concentrated 7-OH, MP, or another semisynthetic. Keep the tablet.
4. Hair LC-MS/MS, for historical/chronic exposure questions only. Poorly suited to recent exposure.^10,12b–15b

Dedicated mitragynine immunoassays exist commercially and experimentally, but they cross-react with multiple related alkaloids and metabolites and therefore behave as class-exposure screens, not compound-level identification. Confirm by chromatography-mass spectrometry when identity matters.³⁴

Recommended urine analyte panel

Detection matrix

Nine interpretation traps

4.7 What is still genuinely unknown

These gaps are not weaknesses in this resource. They are the current state of the science, and presenting them prominently is the only honest option.

Why this matters at the bedside: the absence of a direct purified-7-OH human PK study means precise withdrawal timing, exact buprenorphine timing, and direct-dose detection windows remain clinical judgments informed by emerging case data, not validated constants. Any resource that gives you a confident number is giving you a number nobody has measured.

Toxicity and overdose

What follows is graded. Some of these claims are strong, and some of the ones I would most like to make are not. I have marked them accordingly, including where the grading works against the argument I am making.

5.1 Evidence-ranked clinical manifestations

5.2 Emergency management

Poison Help: 1-800-222-1222. Poison centers are also a useful real-time source of regional signal on novel product presentations, and reporting these cases contributes to a surveillance record that is currently thin.

Dependence and withdrawal

There is currently no nationally validated, evidence-based 7-OH detoxification guideline. That has to be said plainly and early. We are dealing with a retail drug market that has moved faster than the clinical-guideline machinery can follow. The literature is beginning to catch up. It has not caught up.²¹

6.1 Phenomenology

The syndrome patients describe is recognizably opioid, with three features that repeatedly surprise clinicians who expect heroin withdrawal in different packaging:

• Interdose withdrawal within a single day. Heavy users commonly redose hourly or near-hourly specifically to prevent it. Many patients organize their entire waking day around this, and describe waking at night or in the early morning in withdrawal. This is often the most diagnostically useful thing they will tell you.
• Affective and sleep severity out of proportion to the physical exam. Dysphoria, anhedonia, anxiety and insomnia are frequently the dominant complaints, and they persist after the autonomic and GI symptoms improve.
• Absent illness identity. Many of these patients do not believe they use opioids. They bought a supplement. This is not denial in the clinical sense; it is an accurate report of how the product was sold to them, and it changes how the conversation has to be opened.

6.2 The provisional timeline

• 0–8 hours · Interdose onsetIn heavy or high-frequency users, withdrawal can begin within hours of the last dose: rising anxiety, restlessness, yawning, sweating, chills, muscle tension, craving, and early GI hypermotility.
• 8–16 hours · Active phaseSigns become clearer: insomnia, hot/cold chills, myalgias, abdominal cramping, nausea, tremor, tachycardia, rising distress.
• 16–36 hours · Provisional peak windowVomiting, diarrhea, abdominal spasm, diaphoresis, tremor, tachycardia, marked dysphoria. Many patients are in clear objective withdrawal by this point, though severity may still be underestimated by COWS.
• Days 2–3 · Roughest phaseOften the worst window for both autonomic and psychological symptoms: near-total insomnia, muscle cramping, overwhelming anxiety, agitation, dehydration risk. This is also the highest-risk window for impulsive substitution with illicit opioids.
• Days 3–5 · Autonomic resolutionSevere physical symptoms typically begin to ease. Sleep remains fragmented; fatigue is prominent.
• Day 5–14+ · Protracted phaseThe acute syndrome largely resolves, but protracted insomnia, dysphoria, anhedonia, anergia, anxiety and craving can persist for days to weeks. Relapse risk does not track the physical symptoms.

6.3 The COWS problem

COWS was developed and validated for withdrawal from conventional opioids. Applied to concentrated 7-OH it appears, at least sometimes, to under-read the syndrome. The clearest published illustration: a patient using approximately 360 mg/day, assessed roughly 48 hours after his last 30 mg dose, with nausea, diarrhea, abdominal cramping, restlessness, chills, clamminess and anxiety, and a recorded COWS of 5.²⁰

One case does not establish a scale-performance problem. But the mechanistic account is coherent: COWS weights objective autonomic and somatic signs, while a substantial part of this syndrome is affective, sleep-related, and craving-driven. If some of that burden is mediated through KOR signaling or through loss of non-opioid alkaloid effects in whole-plant users, a scale built around piloerection and rhinorrhea will systematically miss it.

6.4 Clinical experience informing this page

I am an addiction medicine physician. I have directly treated 13 patients for kratom- and 7-OH-related opioid use disorder, ranging from relatively uncomplicated botanical kratom dependence to severe, high-dose compulsive use of concentrated products. I have provided dozens of additional informal consultations to colleagues concerned about their own patients' use. In 2025 I served as faculty for the California Society of Addiction Medicine Addiction Medicine Board Exam Preparation Course, lecturing on the neurobiology of addiction including emerging compounds of concern, kratom among them.

That experience is why I am raising this now, before emergency departments begin seeing more of it, rather than afterward.

Treatment: a framework for clinicians

7.1 The evidence, honestly stated

The best published evidence supports treating the opioid component of 7-OH dependence seriously and pragmatically with standard opioid use disorder tools.

• The nine-patient retrospective series (2026) examined patients using purified 7-OH products. Six underwent low-dose buprenorphine initiation and three standard initiation. Eight of nine successfully initiated and stabilized, no precipitated withdrawal or other adverse events were reported, and eight reported symptomatic improvement at a median six-week follow-up.²¹
• A high-dose case report describes successful management with buprenorphine/naloxone plus symptomatic medication after ~360 mg/day chronic use.²⁰
• A conference case report describes successful low-dose initiation in a patient in his twenties using 30–50 mg/day of concentrated 7-OH for two years, titrated to 12 mg daily and discharged stable on day 5.³⁸
• A co-exposure case describes combined 7-OH and nicotine-pouch withdrawal successfully managed with buprenorphine-based treatment.^23b

For an emerging substance this is encouraging. It is also, in total, roughly a dozen published patients. Nine patients are nine patients, not a treatment guideline.

7.2 Five-step intake and triage

Step 1 · Define the exposure

Ask what the patient actually bought. Do not expect them to volunteer the phrase "seven-hydroxymitragynine."

Record product form (pressed tablet, chewable, liquid shot, gummy, sublingual film, powder), labeled milligrams, actual units per day, redosing interval, route, duration in months or years, and daily cost. Where possible, photograph or keep the package. Remember that the label may not reflect content.³⁰

Step 2 · Determine dependence severity

Assess interdose withdrawal onset and severity, failed self-cessation attempts, functional impairment, compulsive use pattern, and DSM-5 criteria for opioid use disorder. Name the diagnosis explicitly. A patient who understands they have opioid use disorder can accept opioid use disorder treatment; a patient who believes they have a supplement habit cannot.

Step 3 · Risk-stratify

Step 4 · Match the treatment setting

Options span outpatient structured taper with clinical support; outpatient buprenorphine/naloxone induction; low-dose (micro-) initiation, outpatient or inpatient; and medically managed inpatient withdrawal. See 7.5 for why the default should be the least intensive setting that is safe.

Step 5 · Prevent substitution, then plan safety

Establish the plan before retail access changes. Explicit counseling about counterfeit pills and fentanyl. Naloxone co-prescribed or dispensed. Tight follow-up interval. Family or caregiver involvement where appropriate. A named contact for the patient if things deteriorate at 2 a.m.

7.3 Buprenorphine: standard versus low-dose initiation

Adjunctive management

Symptomatic support matters more here than in conventional opioid withdrawal, because the affective and sleep burden is prominent and because retention through the first week predicts everything downstream. Reasonable components, individualized: an α₂-agonist such as clonidine or lofexidine where hemodynamics permit; antiemetics; antidiarrheals; NSAIDs or acetaminophen; a muscle relaxant where safe; aggressive attention to hydration and electrolytes; and a deliberate, explicit sleep plan rather than an afterthought. Avoid benzodiazepines and other sedatives where possible, particularly alongside buprenorphine initiation and particularly in patients with any co-exposure history.

7.4 What not to do

7.5 Protecting capacity: the outpatient-first argument

Two failure modes worry me about the coming weeks, and they pull in opposite directions.

The first is capacity collapse. If every 7-OH patient is routed to residential detox, we will exhaust a scarce resource on a population that, by the published experience, largely stabilizes on outpatient buprenorphine. Beds will fill with moderate-risk patients while high-risk patients (the pregnant patient, the patient with a seizure disorder and a benzodiazepine habit, the patient with decompensated cardiac disease) wait. Detox capacity is not fungible and it does not expand on a policy timeline.

The second is substitution. There are not yet data allowing anyone to predict how many dependent 7-OH users will transition to illicit opioids if retail supply disappears, and I will not present that as an established epidemiologic outcome. It is, however, a highly plausible addiction-medicine hazard, it is entirely foreseeable, and the safeguards against it are cheap.

What health systems can do in the next few weeks

• Add 7-OH to intake screening in primary care, psychiatry, pain, obstetrics, and the ED. One line of text.
• Identify who in your system can initiate buprenorphine today, and publish that list internally. In many systems nobody knows.
• Hold rapid-access slots through the scheduling window. A patient in withdrawal who is offered an appointment in three weeks has already made other arrangements.
• Standardize a low-dose initiation protocol now, rather than improvising it at 11 p.m. on the night the order publishes.
• Stock and distribute naloxone at every touchpoint, and say out loud that it is for a product bought at a gas station.
• Brief your EDs and urgent cares on what these presentations look like and who takes the referral. Consider a one-page letter; I am happy to share the one I use.

Special populations and drug interactions

9.1 Drug–drug interactions

9.2 Special populations

Public-health and legal tracker

10.1 What is being scheduled, precisely

Legal effect once in force: manufacture, distribution, sale and possession of covered substances become subject to the criminal, civil and administrative provisions of the CSA. Handling outside federally approved research becomes a federal crime. Note also that temporary scheduling is not subject to judicial review, unlike permanent administrative scheduling.⁴⁸

10.2 Dated timeline

• 2016 · DEA's first attemptDEA issued notice of intent to temporarily schedule mitragynine and 7-OH. After extensive stakeholder comment, DEA withdrew the notice and controlled neither compound. Kratom was instead listed as a Drug and Chemical of Concern, which imposes no CSA restriction. This history is relevant: the 2026 action is deliberately narrower, threshold-based, and aimed at concentrated and semisynthetic products rather than the plant.⁴⁸
• Ongoing · FDA positionFDA has taken the position that kratom is an unapproved new dietary ingredient and an unsafe food additive, and therefore cannot be lawfully marketed in the US as a drug, dietary supplement or food additive. FDA has issued warning letters to firms marketing 7-OH products and has seized foods and supplements containing the compound.^48,49
• 29 July 2025 · FDA restricts 7-OHFDA announced steps to restrict 7-OH opioid products, describing them as novel potent opioid products not proven safe or effective for any use.⁴⁹
• October 2025 · California health warningCDPH publicly warned that products containing kratom and 7-OH are illegal to manufacture or sell for human consumption in California under the Sherman Food, Drug and Cosmetic Act, and reported six overdose deaths in Los Angeles County linked to 7-OH beginning April 2025. CDPH specifically recommends naloxone for people who may use 7-OH.¹²
• January 2026 · California clinician and retailer advisoryCDPH issued a more detailed advisory identifying 7-OH as a potent opioid and warning about addiction, withdrawal, overdose and death, with emphasis on combination with alcohol, benzodiazepines and other intoxicants.¹²
• May 2026 · California enforcement escalatesCDPH reported more than $5 million in kratom and 7-OH products seized, alongside retailer enforcement, embargoes, coordination with alcoholic beverage control and tax authorities, and litigation against a manufacturer. California is not a pending ban. It is an active enforcement program.¹²
• 1 July 2026 · DEA files notices of intentDEA filed intent to temporarily place 7-OH and three related substances into Schedule I. HHS had confirmed that synthetic 7-OH and the three related substances have no accepted medical use and a high potential for abuse; HHS advised no objection by letter of 20 January 2026.^3,50
• 6 July 2026 · Federal Register publicationBoth notices published (91 FR 40917 and companion). The statutory 30-day clock begins.
• 17 July 2026 · Congressional Research Service analysisCRS Legal Sidebar LSB11457 published, summarizing the scheduling regime, thresholds, legal effects, and considerations for Congress, including the possibility of legislative action via the END 7-OH Act (H.R. 8000), which would permanently add 7-OH to Schedule I "including its synthetic equivalents" but not 7-OH naturally contained in kratom.⁴⁸
• 5 August 2026 · Earliest possible order dateFrom this date forward, the temporary scheduling order may publish at any time and takes effect immediately on publication.
• 8 August 2026 · Current statusOrder not verified as published. Action pending. This page will be updated when that changes.

10.3 What this means clinically, week by week

10.4 State-level variation

Multiple states regulate kratom and its derivatives differently, some through Kratom Consumer Protection Acts that set alkaloid limits, some through outright prohibition, some not at all.⁴⁸ State law is not preempted into uniformity by temporary federal scheduling, and I have deliberately not published a state-by-state table here, because a stale legal table is worse than none. Verify your own jurisdiction, and verify it again after the order publishes.

Evidence library

11.1 Evidence grades used on this page

11.2 Confidence hierarchy for the central claims

11.3 Key regulatory documents

• DEA. Schedules of Controlled Substances: Temporary Placement of 7-Hydroxymitragynine Above a Specified Threshold in Schedule I. 91 FR 40917, 6 July 2026.
• DEA. Temporary Placement of Mitragynine Pseudoindoxyl, MGM-15, and MGM-16 in Schedule I. Docket DEA-1644, 6 July 2026.
• DEA. Temporary Placement of 7-OH Above a Specified Threshold in Schedule I; Request for Information. 6 July 2026.
• DEA press release. DEA to Temporarily Schedule 7-OH and Related Substances to Protect Public Safety. 1 July 2026.
• Congressional Research Service. Temporary Control of 7-Hydroxymitragynine (7-OH) and Related Substances Under the Controlled Substances Act. LSB11457, 17 July 2026.
• HHS / FDA. HHS, FDA Commend DEA Action Against Dangerous Enhanced 7-OH Products.
• FDA. FDA Takes Steps to Restrict 7-OH Opioid Products Threatening American Consumers. 29 July 2025.
• FDA. Products Containing 7-OH Can Cause Serious Harm. Consumer update.
• California Department of Public Health. Kratom and 7-OH health advisories and enforcement notices, October 2025 – May 2026.

11.4 References

1. Kruegel AC, Uprety R, Grinnell SG, et al. 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. ACS Cent Sci. 2019;5(6):992–1001. doi:10.1021/acscentsci.9b00141
2. Basiliere S, Kerrigan S. CYP450-Mediated Metabolism of Mitragynine and Investigation of Metabolites in Human Urine. J Anal Toxicol. 2020;44(4):301–313. PMID 32008041
3. Drug Enforcement Administration. Schedules of Controlled Substances: Temporary Placement of Mitragynine Pseudoindoxyl, MGM-15, and MGM-16 in Schedule I. Notice of intent, Docket DEA-1644. Fed Regist. 2026;91(127):40909–40915. 6 July 2026.
4. Kamble SH, León F, King TI, et al. Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy. ACS Pharmacol Transl Sci. 2020;3(6):1063–1068. doi:10.1021/acsptsci.0c00075
5. Tanna RS, Nguyen JT, Hadi DL, et al. Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants. Pharmaceutics. 2022. 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(5):984. PMID 38474495
7. Mixtures Biotransformation: Multilayer Molecular Networking of Kratom Liver Metabolites. J Nat Prod. 2026. doi:10.1021/acs.jnatprod.5c01235
8. Hemby SE, Rangel-Grimaldo M, McIntosh S, et al. Multifaceted modulation of human opioid receptors by kratom alkaloids: binding affinity, functional selectivity, and allosteric activity. Front Pharmacol. 2026;17:1763551. doi:10.3389/fphar.2026.1763551 · PMID 41924140
9. Obeng S, Kamble SH, Reeves ME, et al. Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids; Activity of Mitragyna speciosa ("Kratom") Alkaloids at Serotonin Receptors. 2021. PMID 34467758
10. Helander A, Rylski A. Drug testing for mitragynine and kratom: Analytical challenges and medico-legal considerations. Drug Test Anal. 2023;15. doi:10.1002/dta.3391
11. Basiliere S, Kerrigan S. Identification of metabolites and potential biomarkers of kratom in urine. J Chromatogr B. 2020;1140:121971.
12. California Department of Public Health. Health advisories and enforcement notices regarding kratom and 7-hydroxymitragynine, October 2025 – May 2026, including six Los Angeles County overdose deaths linked to 7-OH and naloxone recommendation.
13. Olsen EO, et al. The Trouble With Kratom: Analytical and Interpretative Issues Involving Mitragynine. J Anal Toxicol. 2019. PMID 31424079
14. Sheehan D, Li Y, Meckler E, Upton R, Zhang M. Avoiding False Identification of 7-Hydroxymitragynine in Kratom Products Using a Multicriteria LC-MS Confirmation. J Am Soc Mass Spectrom. 2026;37(5):1303–1312. doi:10.1021/jasms.6c00088
15. Mitragynine and 7-hydroxymitragynine: Bidirectional effects on breathing in rats. J Pharmacol Exp Ther. 2025. PMID 40475626. Whole-body plethysmography in awake, freely moving Sprague-Dawley rats after IV administration: morphine and 7-OH produced significant reductions in breathing frequency, tidal volume and minute volume, with 7-OH potency for 50% minute-volume reduction 4.5-fold greater than morphine. Naloxone fully reversed depression from both. Mitragynine unexpectedly increased respiratory frequency, and naloxone did not alter that stimulant effect.
16. Postmortem distribution of mitragynine and 7-hydroxymitragynine in 51 cases. J Anal Toxicol. 2025. PMID 39777518
17. Cardiopulmonary arrest following reported 7-hydroxymitragynine use with revival after naloxone. Clin Toxicol. 2026.
18. Meier U, Mercer-Chalmers-Bender K, Scheurer E, Dussy F. Development, validation, and application of an LC-MS/MS method for mitragynine and 7-hydroxymitragynine analysis in hair. Drug Test Anal. 2020;12(2):280–284. doi:10.1002/dta.2746
19. Trakulsrichai S, Sathirakul K, Auparakkitanon S, et al. Pharmacokinetics of mitragynine in man. Drug Des Devel Ther. 2015;9:2421–2429. PMID 25995615
20. Kruegel AC, Gassaway MM, Kapoor A, et al. Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. J Am Chem Soc. 2016;138:6754–6764. doi:10.1021/jacs.6b00360
21. Huestis MA, Brett MA, Bothmer J, Henningfield JE, Swift S. Mitragynine and 7-hydroxymitragynine plasma pharmacokinetics in humans after single and 15 multiple oral kratom extract doses. J Anal Toxicol. 2026;50(6):bkag042. doi:10.1093/jat/bkag042
22. Váradi A, Marrone GF, Palmer TC, et al. Mitragynine/Corynantheidine Pseudoindoxyls as Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2. J Med Chem. 2016;59(18):8381–8397. PMID 27556704
23. Lybik N, Cone B, Skelton S, Elfessi Z. Management of acute withdrawal from 7-hydroxymitragynine after high-dose chronic use: A case report. J Am Pharm Assoc. 2026;66(3). Full text. doi:10.1016/j.japh.2026.103047 · PMID 41690384
24. Yamamoto LT, Horie S, Takayama H, et al. Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa. Gen Pharmacol. 1999;33(1):73–81. PMID 10428019
25. Fenske E, Williams B, Hallock-Koppelman L, Buchheit BM. Buprenorphine for the Management of 7-Hydroxymitragynine (7-OH) Use: A Retrospective Case Series. J Addict Med. June 2026. Retrospective chart review, low-barrier telehealth addiction medicine clinic, April–October 2025. Nine patients using purified 7-OH products; mean age 33.5 years; low-dose initiation in 6, standard initiation in 3; successful initiation and stabilization in 88.9% with no precipitated withdrawal or adverse events; symptom improvement in 8 at median 6-week follow-up. doi:10.1097/ADM.0000000000001723 · PMID 42225057
26. Severe Early-Onset Withdrawal Following Intentional Use of Mitragynine Pseudoindoxyl: A Case Report and Emerging Clinical Considerations. 2026. PMID 41982589
27. Basiliere S, Kerrigan S. Temperature and pH-Dependent Stability of Mitragyna Alkaloids. 2020. PMID 31897484
28. Sharma A, Nair BS, Pemminati S. 7-Hydroxymitragynine and Nicotine Pouch Withdrawal Syndrome: A Case Report. Cureus. 2025. doi:10.7759/cureus.98386 · PMID 41487756
29. Philipp AA, Wissenbach DK, Zoerntlein SW, Klein ON, Kanogsunthornrat J, Maurer HH. Studies on the metabolism of mitragynine, the main alkaloid of the herbal drug Kratom, in rat and human urine using LC-linear ion trap MS. J Mass Spectrom. 2009;44(8):1249–1261. doi:10.1002/jms.1607
30. Chakraborty S, et al. Oxidative Metabolism as a Modulator of Kratom's Biological Actions. Mechanistic study describing 3-dehydromitragynine and related oxidative metabolites.
31. Philipp AA, Wissenbach DK, Weber AA, Zapp J, Maurer HH. Metabolism studies of the Kratom alkaloids speciociliatine, mitraciliatine and isopaynantheine in rat and human urine. Anal Bioanal Chem. 2011;399(8):2747–2753 and J Chromatogr B. 2011;879(15–16):1049–1055.
32. In Vitro Pharmacology of Mitragynine at α-Adrenoceptors. ACS Chem Neurosci. Demonstrates α_1A partial agonism (EC₅₀ ~3 μM) and α_2A antagonism rather than agonism. doi:10.1021/acschemneuro.5c00719
33. Gour A, Mukhopadhyay S, Henderson A, et al. From Kratom to Semi-Synthetic Opioids: The Rise and Risks of MGM-15. Drug Test Anal. 2025;17(12):2384–2389. doi:10.1002/dta.3952
34. Brown PN, et al. Analysis of 7-hydroxymitragynine content and alkaloid profiles in products marketed as kratom extracts. J AOAC Int. 2026. Found 7-OH at 22–75 mg/g with profiles inconsistent with authentic kratom leaf.
35. Gour A, et al. Mislabeling and Status of Semisynthetic Kratom-Derived Products in the US Market. Drug Test Anal. 2026. doi:10.1002/dta.70122. Quantitative analysis finding evidence of semisynthetic origin in >98% of 7-OH-labeled products examined, with label–content discordance, oxidation byproducts, and additional opioid-active compounds.
36. Hill K, Boyer EW, Grundmann O, Smith KE. De facto opioids: Characterization of novel 7-hydroxymitragynine and mitragynine pseudoindoxyl product marketing. Drug Alcohol Depend. 2025;272:112701.
37. Krotulski AJ, Denn MT, Brower JO, Papsun DM, Logan BK. Evaluation of Commercially Available Smoke Shop Products Marketed as "7-Hydroxymitragynine" & Related Alkaloids. Center for Forensic Science Research and Education, 2025. See also Vadiei N, Evoy KE, Grundmann O. The Impact of Diverse Kratom Products on Use Patterns, Dependence, and Toxicity. Curr Psychiatry Rep. 2025;27(10):584–592.
38. Matsumoto K, Narita M, Muramatsu N, et al. Orally active opioid μ/δ dual agonist MGM-16, a derivative of the indole alkaloid mitragynine, exhibits potent antiallodynic effect on neuropathic pain in mice. J Pharmacol Exp Ther. 2014;348(3):383–392. doi:10.1124/jpet.113.208108
39. Development of an ELISA for detection of mitragynine and its metabolites in human urine. 2020. PMID 32302607
40. Analytical method validation with development for the detection and quantification of kratom alkaloids using LC-MS/MS. 2026. PMID 41500392
41. Drug-Induced Liver Injury Network (DILIN). Kratom-associated hepatotoxicity: prospective case series with chemical confirmation of Mitragyna content. Mixed hepatocellular/cholestatic pattern, median R ~3.0, latency 2–6 weeks.
42. Kratom-induced acute liver injury: a case study and the importance of herbal supplement regulation. J Hepatol. 2023. doi:10.1016/j.jhep.2023.04.006. See also Fernandes CT, Iqbal U, Tighe SP, Ahmed A. Kratom-Induced Cholestatic Liver Injury and Its Conservative Management. 2019. PMID 30920318
43. Successful Buprenorphine Microinduction in a Patient With Severe Kratom (7-OH) Use Disorder. Poster, 57th American Society of Addiction Medicine Annual Conference.
44. Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids. Toxicol Lett. Mitragynine and corynantheidine potent CYP2D6 inhibitors (IC₅₀ 2.2 and 4.2 μM).
45. Tanna RS, et al. Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom. Clin Pharmacol Ther. 2023. Mitragynine strong competitive CYP2D6 inhibitor, Ki ~1.17 μM.
46. Tanna RS, et al. Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations. J Pharmacol Exp Ther. Predicted 5.69-fold midazolam AUC increase at a 2 g kratom dose.
47. Translating Kratom-Drug Interactions: From Bedside to Bench and Back. Drug Metab Dispos. 2023. Kratom can precipitate interactions via CYP2D6, CYP3A and P-glycoprotein inhibition; suspected in several fatal polyintoxication cases.
48. Inhibitory effects of kratom constituents, mitragynine and 7-hydroxymitragynine, on 4-methylumbelliferone glucuronidation by human UDP-glucuronosyltransferases. 2025.
49. Pharmacokinetic and Pharmacodynamic Consequences of Cytochrome P450 3A Inhibition on Mitragynine Metabolism in Rats. J Pharmacol Exp Ther. 2024.
50. Antenatal Kratom Exposure: Literature Review and Clinical Management Recommendations. Res Rep Neonatol. doi:10.2147/RRN.S419864
51. Davidson L, Rawat M, Stojanovski S, Chandrasekharan P. Natural drugs, not so natural effects: Neonatal abstinence syndrome secondary to "kratom." J Neonatal Perinatal Med. 2019. doi:10.3233/NPM-1863
52. Kratom. Drugs and Lactation Database (LactMed). National Institute of Child Health and Human Development. NCBI Bookshelf NBK617437
53. Congressional Research Service. Temporary Control of 7-Hydroxymitragynine (7-OH) and Related Substances Under the Controlled Substances Act. Legal Sidebar LSB11457, 17 July 2026. congress.gov/crs-product/LSB11457
54. US Food and Drug Administration. FDA Takes Steps to Restrict 7-OH Opioid Products Threatening American Consumers. 29 July 2025; and Products Containing 7-OH Can Cause Serious Harm, consumer update.
55. Drug Enforcement Administration. DEA to Temporarily Schedule 7-OH and Related Substances to Protect Public Safety. Press release, 1 July 2026.
56. A Case of 7-Hydroxymitragynine Use Disorder Treated With Buprenorphine. 2026. PMID 41875249. Severe 7-OH use disorder progressing to a sublingual film every one to two hours, with supraventricular tachycardia and profound urinary retention.

11.5 Update history

11.6 Corrections policy

If you find an error on this page (a misread study, an overstated claim, a stale legal fact, a citation that does not support the sentence attached to it), please write to bharris@eusomniamd.com. Substantive corrections will be made and logged in the table above with the date and the nature of the change, rather than silently edited. I would rather be corrected in public than be wrong in private, particularly on a page that clinicians may act on.

Disclaimers

This page does not constitute medical advice. It is educational material prepared for clinicians and for the general public. It does not create a physician–patient relationship, does not establish a standard of care, and cannot substitute for individualized evaluation by a qualified clinician who has examined the patient. Clinical decisions (particularly regarding buprenorphine initiation, medication interactions, and level of care) require independent professional judgment applied to the individual case.

This page does not constitute legal advice. The regulatory status described here was verified on the date shown and concerns a pending federal action that may change without notice. Verify current federal and state law before advising any person about legal exposure.

If you are experiencing kratom or 7-OH withdrawal or toxicity, seek help from an addiction medicine professional. Effective medical treatment exists and is available on an outpatient basis for most people. Do not attempt to manage severe opioid withdrawal alone, and do not substitute illicit opioids. Find a buprenorphine prescriber through the SAMHSA buprenorphine practitioner locator or findtreatment.gov, or call the SAMHSA National Helpline at 1-800-662-4357 (free, confidential, 24/7).

Emergency: call 911 for suspected overdose: unresponsiveness, slow or absent breathing, cyanosis. Give naloxone if available. Poison Help: 1-800-222-1222.

Content is provided "as is" without warranty. Neither the author nor EusomniaMD accepts liability for actions taken on the basis of this material. External links are provided for reference and do not imply endorsement.