R Street Comments on Placement of 7-OH on Schedule I - R Street Institute

R Street Comments on Placement of 7-OH on Schedule I

July 31, 2026

U.S. Department of Health and Human Services

Office of the Assistant Secretary for Health

200 Independence Avenue SW

Washington, DC 20201

Response to HHS-OASH-2026-0232: Temporary Placement of 7-Hydroxymitragynine Above a Specified Threshold in Schedule I

Submitted to the Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services

Re: Docket No. HHS-OASH-2026-0232

Assistant Secretary Brian Christine:

My name is Dr. Jeffrey S. Smith, and I am a Resident Senior Fellow at the R Street Institute, a nonprofit, nonpartisan public policy research organization headquartered in Washington, D.C. R Street supports pragmatic, evidence-based policy solutions that emphasize free markets, limited government, and individual liberty. In that capacity, I have conducted extensive research on substance regulation and the role of informed personal choice in public health. I submit this comment in response to the Office of the Assistant Secretary for Health’s request for information concerning the Drug Enforcement Administration’s proposed threshold for temporarily placing 7-hydroxymitragynine (7-OH) in Schedule I of the Controlled Substances Act.

I. INTRODUCTION AND SUMMARY

The available evidence supports prompt action to reduce harms associated with concentrated and semisynthetic 7-hydroxymitragynine, commonly called 7-OH. It does not support temporary Schedule I placement at the proposed threshold. Those are not contradictory conclusions. 7-OH acts at the mu-opioid receptor, concentrated products have been associated with tolerance, dependence, and withdrawal, and animal studies demonstrate respiratory depression. At the same time, the present record does not identify a human dose or product concentration at which 7-OH suddenly becomes an “imminent hazard to public safety.” It also does not show that Schedule I control would protect public health more effectively than targeted product regulation, premarket review of chemically converted products, and improved surveillance.

The HHS request for information asks two narrow questions. First, it asks whether data support the proposed threshold or an alternative threshold and, specifically, what amount or concentration of 7-OH constitutes an imminent hazard. Second, it asks whether other ways of expressing a threshold would better serve that purpose.[1] The scientific answer to the first question is that current evidence does not establish an imminent-hazard boundary at 0.050% by weight, 1.00 mg per article, or any other single numerical value. The answer to the second question is that neither percentage by weight nor milligrams per “article” are sufficient measures of risk. If HHS develops an interim product classification-framework rather than a criminal scheduling threshold, it should combine milligrams per serving, milligrams per package, concentration, alkaloid ratios, route of administration, manufacturing method, and validated laboratory testing.

The proposed 0.050% threshold equals 0.5 mg of 7-OH per gram of material. That calculation is straightforward, but its biological meaning is not. A concentration is not a dose. A dose is not a complete measure of exposure. Exposure is not the same as demonstrated population risk. Route of administration, speed of absorption, frequency of redosing, co-use with alcohol or sedatives, product composition, and individual vulnerability all influence risk. A scientifically defensible threshold must be derived from evidence connecting a measured exposure to a health outcome. That link has not yet been established for 7-OH in humans.

For those reasons, HHS should advise the Attorney General and the Drug Enforcement Administration not to issue the temporary scheduling order on the present record. HHS should instead lead an expedited, risk-based process that distinguishes botanical kratom from concentrated 7-OH products and from synthetic or semisynthetic derivatives, imposes enforceable safeguards on the products that remain available, and generates the dose-response evidence needed for future decisions.

II. RESPONSE TO QUESTION 1: CURRENT EVIDENCE DOES NOT ESTABLISH THE PROPOSED THRESHOLD OR A SCIENTIFICALLY DEFENSIBLE ALTERNATIVE SCHEDULE I THRESHOLD

The evidence establishes hazard, but not the proposed dividing line. Science distinguishes hazard from risk. Hazard asks whether a substance can cause harm. Risk asks how likely that harm is under specified conditions of use. The evidence supports the conclusion that 7-OH has opioid-related hazards. It does not identify 1.00 mg per article or 0.050% by weight as the point at which those hazards become an imminent threat.

Preclinical studies demonstrate why concentrated 7-OH warrants concern. In one rat self-administration study, 7-OH substituted for morphine, while mitragynine did not, indicating greater reinforcing potential for 7-OH in that model.[2] Another rodent study using intracranial self-stimulation did not find rewarding effects for either mitragynine or 7-OH.[3] These findings are not necessarily incompatible because the experiments measured different aspects of reinforcement, but together they show that the preclinical evidence is not reducible to one simple potency statement. More recent comparative research found that intravenously administered 7-OH reduced breathing frequency and ventilation, while mitragynine increased respiratory frequency. Naloxone reversed the respiratory depression caused by 7-OH.[4] This is an important warning signal, but an intravenous dose in a rat cannot be converted directly into a human oral threshold of 1.00 mg per consumer product.

The human literature is even less suited to deriving the proposed threshold. Recent reports describe clinically meaningful dependence and withdrawal after repeated use of concentrated or rapidly delivered 7-OH. One patient using a sublingual film developed tolerance within days and progressed to using a film every one to two hours before treatment with buprenorphine.[5] Another report described withdrawal after use escalated to 360 mg per day.[6] A retrospective series of nine patients found that eight stabilized after buprenorphine initiation, but the authors did not claim that the series established a population incidence rate or a toxic dose threshold.[7] These observations are clinically important. They support warnings, treatment guidance, and tighter control of high-dose products. They do not establish that a product containing 1.01 mg presents an imminent hazard while one containing 0.99 mg does not.

The Drug Enforcement Administration’s own notice states that no controlled human clinical trials have established safe consumption limits or standardized dosing for concentrated 7-OH products.[8] The absence of a validated safety limit does not mean that low doses are proven safe. It means that a criminal threshold cannot be presented as if it were derived from a known human dose-response curve. Uncertainty can justify precautionary product controls. It does not justify assigning scientific precision to a number that the available studies have not validated.

1. FDA’s assessment supports hazard identification, not numerical threshold derivation

FDA’s own 2025 scientific assessment identifies the central evidentiary gap. FDA found no clinical study in which isolated or purified 7-OH had been administered to humans, described the available human pharmacokinetic evidence as sparse and variable, and noted that much of it came from uncontrolled studies that are difficult to interpret. FDA also concluded that the public health burden could not be quantified because surveillance systems did not estimate the prevalence of 7-OH use and were only beginning to distinguish enhanced 7-OH products from botanical kratom and other kratom-derived products.[9] These are not minor caveats. They are the data elements needed to connect a product’s concentration or quantity to an immine