The rise of novel, semi-synthetic 7-hydroxymitragnine products

Abstract

Products containing the psychoactive botanical, Mitragyna speciosa, have transformed from simple leaf powders into an array of products, falling under the broad umbrella of ‘kratom’. [1, 2] Whole-leaf products contain consistent concentrations of kratom’s major alkaloid, mitragynine, and its metabolite 7-hydroxymitragynine; even among extracts, alkaloid concentrations often remain within self-adopted industry norms, with 7-hydroxymitragynine between 1 and 2% of the total content, or below the lower limit of quantification [3-5]. A highly selective partial mu opioid receptor (MOR) agonist, 7-hydroxymitragynine has binding affinity 14–22 times greater than morphine [6]. Although mitragynine has lower abuse potential and relative safety compared to drugs of abuse, 7-hydroxymitragynine dose-dependently substitutes for morphine [7-11].

However, some manufacturers have begun marketing novel semi-synthetic products with varying routes of administration (e.g. sublingual tablets, nasal sprays) containing 14–25 mg 7-hydroxymitragynine per labeled dose, often with brand names alluding to narcotics. These newly marketed products may contain up to 98% 7-hydroxymitragynine, together with other kratom alkaloids. Concerningly, some product formulations circumvent first-pass metabolism, increasing bioavailability.

To date, 7-hydroxymitragynine product marketing fails to distinguish itself from kratom. Kratom-naïve consumers purchasing 7-hydroxymitragynine products may erroneously believe that they are relatively safe ‘natural’ products similar or identical to kratom products that have been used in the United States for at least two decades. Consumers of these novel products are unwittingly exposing themselves to high-dose, MOR-binding formulations that have never undergone human or animal testing. Apart from toxicity risks from acute exposure, chronic 7-hydroxymitragynine product use could result in opioid-like physical dependence and possibly addiction. Scale and severity may be distinct from kratom leaf-based and extract products, which have not produced widespread severe addiction, but rather mild–moderate physical dependence [12-14].

As forensic laboratories use mitragynine as a surrogate marker for kratom use, 7-hydroxymitragynine-related fatalities would incorrectly implicate kratom, as the presence of mitragynine in these products arises from incomplete conversion of mitragynine into 7-hydroxymitragynine [15]. Currently, 7-hydroxymitragynine products contain trace amounts of mitragynine and ‘new’ chemicals yet to be identified. The safety of these unknown chemicals, and of 7-hydroxymitragynine at high doses, has not been evaluated in living subjects. Accordingly, they pose an eminent public health concern until they have been identified and proven to be safe.

The policy implications of semi-synthetic 7-hydroxymitraynine products are unknown, but adverse events or fatalities resulting from 7-hydroxymitragynine products could pose complications to the regulation of a growing kratom industry. Kratom is now used by 10–15 million US adults. Decisions regarding kratom scheduling and regulation are liable to become confused if policymakers can or will not differentiate between kratom and high-potency 7-hydroxymitragynine products synthesized in unregulated or makeshift laboratories. To be clear: equating 7-hdyroxymitragynine products to kratom is analogous to equating synthetic cannabinoids to unaltered cannabis or hemp. Although not all organic kratom products are equal, they have not emerged as a net detriment to public health, and they remain unscheduled at the federal level. Novel semi-synthetic 7-hydroxymitragynine products pose public health risks due to the unknown chemical constituents and the known pharmacology of 7-hydroxymitragynine. Clinicians must screen patients for their use and policymakers must distinguish between kratom and 7-hydroxymitragynine.

Kirsten E. Smith: Conceptualization; writing—original draft. Edward W. Boyer: Conceptualization; writing—original draft. Oliver Grundmann: Conceptualization; writing—original draft. Christopher R. McCurdy: Conceptualization; writing—original draft. Abhisheak Sharma: Conceptualization; writing—original draft.

K.E.S. has been a paid scientific advisor to the International Plant and Herbal Alliance and The Kratom Coalition. K.E.S., O.G., E.W.B. and C.R.M. have served as expert witnesses in legal cases related to kratom.