What Are Semi-Synthetic 7-Hydroxymitragynine Products and Their Implications for Kratom?
Products derived from the botanical Mitragyna speciosa have evolved beyond simple leaf powders into a wide range of offerings, collectively referred to as “kratom.” Traditional whole-leaf products typically maintain consistent concentrations of kratom’s primary alkaloid, mitragynine, and its metabolite, 7-hydroxymitragynine.
Even among extracts, alkaloid levels often adhere to industry norms, with 7-hydroxymitragynine comprising 1–2% of the total content or remaining below the lower limit of quantification. Notably, 7-hydroxymitragynine, a selective partial mu-opioid receptor (MOR) agonist, exhibits binding affinity 14–22 times greater than morphine. While mitragynine is associated with lower abuse potential and greater safety compared to traditional opioids, 7-hydroxymitragynine has been shown to dose-dependently substitute for morphine.
Recently, some manufacturers have introduced novel semi-synthetic products containing 7-hydroxymitragynine in varying forms, such as sublingual tablets and nasal sprays. These products often deliver 14–25 mg of 7-hydroxymitragynine per labeled dose, with some formulations comprising up to 98% 7-hydroxymitragynine along with other kratom alkaloids.
Alarmingly, certain formulations bypass first-pass metabolism, enhancing bioavailability. 7-Hydroxymitragynine converts into mitragynine up to 45% in human liver microsomes over a two-hour incubation period.
The Branding of 7-Hydroxymitragynine Products as Kratom
The marketing of products containing 7-hydroxymitragynine often creates confusion by equating these semi-synthetic formulations with natural kratom. This branding strategy can mislead kratom-naïve consumers, who may believe these products are as natural, safe, and relatively mild as traditional kratom leaf or plain-leaf powder.
However, the reality is starkly different. High-dose, MOR-binding (mu-opioid receptor) formulations of 7-hydroxymitragynine are fundamentally different from natural kratom products. These substances are often produced without adequate human or animal testing, leaving consumers vulnerable to uncharted risks. Acute toxicity, such as respiratory depression, is a significant concern, given the potent pharmacological activity of these products.
Furthermore, chronic use of such formulations can lead to opioid-like physical dependence or addiction. The severity of dependence associated with these products is potentially much higher than that observed with traditional kratom leaf-based or even standard extract products. Traditional kratom is typically associated with a light mild physical dependence, manageable with gradual tapering or short breaks in use and similar to coffee. In contrast, these synthetic or semi-synthetic products may involve a more intense and challenging withdrawal process, posing a higher risk for users.
By misbranding these products as “kratom,” manufacturers exploit the positive reputation of natural kratom while exposing consumers to significantly greater health risks. This highlights the need for clear labeling, education, and regulation to protect consumers and ensure they can make informed choices about the products they are using.
What impact does 7-hydroxymitragynine have on data related to Kratom-associated deaths and adverse events?
The reliance on mitragynine as a forensic marker for kratom use further complicates matters. Fatalities related to 7-hydroxymitragynine may mistakenly implicate kratom, as mitragynine present in these products often results from incomplete conversion during synthesis. Additionally, current 7-hydroxymitragynine products contain trace mitragynine and unknown chemicals that remain untested for safety. The public health risks associated with these unidentified substances and high-dose 7-hydroxymitragynine are significant until they are properly studied and deemed safe.
The policy ramifications of these semi-synthetic products remain uncertain. Adverse events or fatalities linked to 7-hydroxymitragynine could jeopardize the regulatory future of kratom, which is used by an estimated 10–15 million U.S. adults.
Policymakers must differentiate between traditional kratom products and high-potency 7-hydroxymitragynine products synthesized in unregulated or makeshift laboratories. Equating the two is akin to conflating synthetic cannabinoids with natural cannabis or hemp.
While organic kratom products have not demonstrated widespread harm to public health and remain federally unscheduled, these novel semi-synthetic products present significant risks. Clinicians must screen patients for their use, and policymakers must establish clear distinctions to safeguard public health and support informed regulatory decisions.
What Are the Issues with 7-Hydroxymitragynine Products?
7-Hydroxymitragynine (7-HMG) products are often a point of concern for several reasons, particularly in the context of kratom use and its safety profile. Here’s a breakdown of the main issues:
1. High Potency and Risk of Dependency
7-HMG is a naturally occurring metabolite in kratom, but it is present in very small amounts in the plant. Some manufacturers isolate or enhance the 7-HMG content in their products to create highly potent extracts or enhanced kratom. This can lead to:
- Increased risk of dependency: Its potency makes it more likely to cause tolerance and physical dependence compared to plain leaf kratom.
- Stronger withdrawal symptoms: If dependence develops, withdrawal from 7-HMG products may be more intense.
2. Synthetic Manipulation
Some products claiming high levels of 7-HMG may be synthetically enhanced or adulterated. These synthetic modifications:
- Can lead to unpredictable effects.
- Might be more dangerous than naturally occurring alkaloids.
- Have raised concerns about quality control and consumer safety.
3. Regulatory Scrutiny
The presence of high 7-HMG levels in products can attract negative regulatory attention, as it raises concerns about safety and potential abuse. Regulatory bodies like the FDA often cite 7-HMG as a key reason for their scrutiny of kratom products. The argument is that its opioid receptor activity could mimic that of traditional opioids.
4. Lack of Long-Term Studies
While plain leaf kratom has a long history of traditional use with a relatively well-documented safety profile, concentrated 7-HMG products do not. The lack of long-term safety studies means users and regulators cannot fully assess the risks associated with these products.
5. Deviating from Traditional Use
Traditional kratom use in Southeast Asia involves plain leaf consumption, which has a balanced alkaloid profile. Products with artificially elevated 7-HMG content deviate from this traditional use, potentially altering the risk-benefit profile of kratom and overshadowing its intended purpose as a natural botanical.
Conclusion
While 7-HMG is a natural component of the kratom drying process and contributes minimally to its effects, enhancing or isolating it in products significantly increases the risks of dependency, health issues, and regulatory scrutiny. Plain leaf kratom remains the safer option, aligning with traditional practices and supporting a more balanced and sustainable approach to its use.
Two of the compound peaks were previously unknown. These compounds have now been identified as 7-Hydroxymitragynine N-oxide and rearranged N-acylpyrazinylindoles. These chemicals have not been documented in scientific literature, are absent from kratom leaves, and have never been consumed by humans. Their formation requires chemical oxidation and rearrangement reactions that are not part of the natural biosynthetic pathways of kratom.
AUTHOR CONTRIBUTIONS
- 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.
DECLARATION OF INTERESTS
Kirsten E. Smith, K.E.S. has been a paid scientific advisor to the International Plant and Herbal Alliance and The Global 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.
Thank you for making such an informative blog post about these new, much stronger synthetic. The way its packaged and marketed by those that sell it leaves a bad taste in my mouth. I’ll stick with the tested products that I know what they are.