Clinical Context

The scientific name for kratom is Mitragyna speciosa, and it is well-known in pain management practices as an analgesic with opioid-like properties. The authors of the current study explore the mechanism of action of kratom.

Kratom leaves are typically chewed or used to create an extract for brewing. Kratom can produce stimulation at low doses and has been used to reduce the intensity of opiate withdrawal. The efficacy of the plant may be linked to the alkaloids mitragynine (MG) and 7-hydroxymitragynine (7-MHG), which constitute 60% and 2%, respectively, of kratom's total concentration of alkaloids. MG and 7-MHG both stimulate the μ opioid receptor, with affinity of 7-MHG approximately 5 times greater than MG. Both alkaloids are also weak antagonists of the δ and κ opiate receptors. 7-MHG is also far more sensitive to naloxone compared with MG, and it is associated with tolerance to analgesic effects after repeated use, as well as cross-tolerance to the antinociceptive action of morphine.

Kratom remains legal in most states in the United States, but the US Food and Drug Administration (FDA) has recognized a potential risk for abuse with kratom. The current study uses an animal model to further assess the potential for abuse of kratom.

Study Synopsis and Perspective

One of the 2 major psychoactive constituents in kratom has high abuse potential that may also increase the intake of other opiates, new research shows.

The finding contradicts claims by kratom makers that the substance has no abuse potential and supports the FDA's view that kratom is an opioid.

Derived from the plant Mitragyna speciosa, kratom is receiving increased attention as an alternative to traditional opiates and as a replacement therapy for opiate dependence. MG and 7-HMG are the 2 major psychoactive constituents of kratom. Although MG and 7-HMG share behavioral and analgesic properties with morphine, their reinforcing effects have not been fully established.

Results of a series of experiments with rats show that MG does not have abuse or addiction potential and reduces morphine intake, "desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal," Scott Hemby, PhD, from the Department of Basic Pharmacological Sciences, High Point University, North Carolina, and colleagues report.

In contrast, 7-HMG should be considered a kratom constituent with "high abuse potential that may also increase the intake of other opiates," the investigators note.

The study was published online June 27 in Addiction Biology.

"Intriguing" Data

"The study tells us that the most abundant alkaloid in kratom, MG, does not have abuse liability and actually decreases subsequent opiate intake. The 7-HMG data are intriguing because it does seem to have abuse liability," Dr Hemby told Medscape Medical News.

However, he said, "it's important to remember that 7-HMG is about 2% of the alkaloid compound of the plant, whereas MG is about 60%. That's about a 30-fold difference between those 2 alkaloids. That suggests to me that it probably wouldn't be reinforcing if kratom were taken as a whole plant with all the alkaloids and everything else in it."

One reason this is important to study, he said, is that there has been evidence that levels of 7-HMG are elevated in certain strains of kratom or certain products that are being sold. This could be the result of deliberate adulteration of the product or the way the plant is harvested.

"For instance, if you leave it out in the sun to dry after it's harvested, a fair amount of the MG will be converted into 7-HMG. So it could be the way the plant is harvested and not an intentional adulteration," said Dr Hemby.

It is also concerning, he said, that people are starting to recognize that higher levels of 7-HMG seem to be associated with pleasure or euphoria. "No one has sold 7-HMG on its own, but it's possible that that could happen, and so it's important to know that there is a possibility of abuse of that particular compound," said Dr Hemby.

He emphasized that the current experiments did not assess kratom itself, only the 2 psychoactive compounds of the plant. "My guess is, based on the ratio of MG to 7-HMG, it would not have abuse liability, but we are undertaking studies to look at that," Dr Hemby noted.

The FDA is cracking down on kratom. There are no FDA-approved uses for kratom, and the agency has advised against using kratom or its psychoactive compounds MG and 7-HMG in any form and from any manufacturer.

Kratom has been linked to more than 40 deaths. As previously reported by Medscape Medical News, a recent analysis of kratom by FDA scientists found that its compounds act similar to prescription-strength opioids. The findings led the FDA to label kratom an opioid.

"There is no doubt that kratom is an opioid. What the FDA said was perfectly correct," Dr Hemby told Medscape Medical News.

The study was supported by funding from the High Point University, Fred Wilson School of Pharmacy, with additional funding from the National Institutes of Health. The authors have disclosed no relevant financial relationships.

Addiction Biol. Published online June 27, 2018.^[1]

Clinical Implications

• MG and 7-MHG constitute 60% and 2%, respectively, of kratom's total concentration of alkaloids. MG and 7-MHG both stimulate the μ opioid receptor, with affinity of 7-MHG approximately 5 times greater than MG. Both alkaloids are also weak antagonists of the δ and κ opiate receptors. 7-MHG is also far more sensitive to naloxone compared with MG, and it is associated with tolerance to analgesic effects after repeated use, as well as cross-tolerance to the antinociceptive action of morphine.
• In the current study, MG was not found to have abuse potential among rats. In fact, prior exposure to MG reduced morphine use. In contrast, 7-HMG was readily self-administered and reinforced the use of morphine. The reinforcing effects of 7-HMG appeared to be dependent on μ and δ opiate receptors.
• Implications for the Healthcare Team: The healthcare team should be aware of the potential for abuse of kratom and monitor patients closely for signs of abuse, should they use kratom.

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