Expert Commentary

FDA labels kratom an opioid. What is it?

Research on the history, pharmacology and toxicology of kratom, a "herbal high" that's new to the U.S.

(Thor Porre / Wikipedia)

It seems that every few months a new drug makes headlines. First bath salts, a synthetic stimulant which can produce paranoia and hallucinations, then K2, a man-made substance that contains compounds resembling the active chemicals in marijuana, and now kratom (Mitragyna speciosa), a botanical substance often sold as an herbal supplement.

The plant was labeled an opioid by the U.S. Food and Drug Administration (FDA) in February 2018. It made this determination based on a 3-D modeling study of its compounds.

In an earlier public health advisory on the substance, issued in November 2017, the FDA cautioned against using the substance, whether recreationally, or medically, to treat conditions like pain, anxiety, depression and opioid use disorder. The agency cited reports of 36 deaths linked to the use of products containing kratom. However, it is not clear whether the substance was the cause of death.

Still, against the backdrop of the nation’s ongoing opioid epidemic, officials have concerns about this lesser-known substance. FDA Commissioner Scott Gottlieb writes, “At a time when we have hit a critical point in the opioid epidemic, the increasing use of kratom as an alternative or adjunct to opioid use is extremely concerning.”

In August 2016, the Drug Enforcement Administration (DEA) issued a notice of intent to temporarily classify the main psychoactive components of kratom as schedule I controlled substances, like heroin and ecstasy. In November 2016, however, the DEA withdrew the notice, awaiting further FDA input and citing public comments against the action.

Local news coverage of the substance reveals some supportive public sentiment, as some perceive kratom as less risky than heroin or prescription opioids. In certain areas, however, law enforcement has seized the substance and penalized smoke shops for selling misbranded kratom products.

For journalists looking to learn more about kratom, we’ve collected the latest research on the history of the substance, its pharmacology and toxicology, addiction potential and more.



Following ‘the Roots’ of Kratom (Mitragyna speciosa): The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive Drug in Western Countries
Cinosi, Eduardo; et al. BioMed Research International, 2015. DOI: 10.1155/2015/968786.

Abstract: “The use of substances to enhance human abilities is a constant and cross-cultural feature in the evolution of humanity. Although much has changed over time, the availability on the Internet, often supported by misleading marketing strategies, has made their use even more likely and risky. This paper will explore the case of Mitragyna speciosa Korth, (kratom), a tropical tree used traditionally to combat fatigue and improve work productivity among farm populations in Southeast Asia, which has recently become popular as a novel psychoactive substance in Western countries. Specifically, it (i) reviews the state of the art on kratom pharmacology and identification; (ii) provides a comprehensive overview of kratom use cross-culturally; (iii) explores the subjective experiences of users; (iv) identifies potential risks and side effects related to its consumption. Finally, it concludes that the use of kratom is not negligible, especially for self-medication, and more clinical, pharmacological, and socioanthropological studies as well as a better international collaboration are needed to tackle this marginally explored phenomenon.”

Traditional and Non-traditional Uses of Mitragynine (Kratom): A Survey of the Literature
Singh, Darshan; Narayanan, Suresh; Vicknasingam, Balasingam. Brain Research Bulletin, 2016. DOI: 10.1016/j.brainresbull.2016.05.004.

Results: “Apart from the differences in the sources of supply, patterns of use and social acceptability of kratom within these two regions, the most interesting finding is its evolution to a recreational drug in both settings and the severity of the adverse effects of kratom use reported in the West. While several cases of toxicity and death have emerged in the West, such reports have been non-existent in South East Asia where kratom has had a longer history of use. We highlight the possible reasons for this as discussed in the literature. More importantly, it should be borne in mind that the individual clinical case-reports emerging from the West that link kratom use to adverse reactions or fatalities frequently pertained to kratom used together with other substances. Therefore, there is a danger of these reports being used to strengthen the case for legal sanction against kratom. This would be unfortunate since the experiences from South East Asia suggest considerable potential for therapeutic use among people who use drugs.”


Pharmacology and toxicology

The Medicinal Chemistry and Neuropharmacology of Kratom: A Preliminary Discussion of a Promising Medicinal Plant and Analysis of its Potential for Abuse
Kruegel, Andrew C.; Grundmann, Oliver. Neuropharmacology, 2017. DOI: 10.1016/j.neuropharm.2017.08.026.

Abstract: “The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant’s active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu-opioid receptors and competitive antagonists at kappa- and delta-opioid receptors. Furthermore, both alkaloids are G protein-biased agonists of the mu-opioid receptor and therefore, may induce less respiratory depression than classical opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex pharmacological profile of raw kratom extracts, although characterization of effects at these other targets remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-hydroxymitragynine used in animal studies can be related to single doses of raw kratom plant commonly consumed by humans, permitting preliminary interpretation of expected behavioral and physiological effects in man based on this preclinical data and comparison to both anecdotal human experience and multiple epidemiological surveys. Kratom exposure alone has not been causally associated with human fatalities to date. However, further research is needed to clarify the complex mechanism of action of the Mitragyna alkaloids and unlock their full therapeutic potential.”

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators
Kruegel, Andrew C; et al. Journal of the American Chemical Society, 2016. DOI: 10.1021/jacs.6b00360.

Abstract: “Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analogue 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles.”

Pharmacologic and Clinical Assessment of Kratom
White, C.M. American Journal of Health-System Pharmacy, 2017. DOI: 10.2146/ajhp161035.

Abstract: “Kratom exerts opioid and α-2 receptor agonistic effects as well as anti-inflammatory and parasympathetic-impeding effects. Human pharmacologic, pharmacokinetic, and clinical data are of low quality precluding any firm conclusions regarding safety and efficacy.”

Evaluating the Hematological and Clinical-Chemistry Parameters of Kratom (Mitragyna speciosa) Users in Malaysia
Singh, Darshan; et al. Journal of Ethnopharmacology, 2018. DOI: 10.1016/j.jep.2017.12.017.

Findings: “In conclusion, our findings indicated that long-term and heavy use of brewed kratom tea/juice for enhancing work efficiency is not harmful or toxic among traditional kratom users in Malaysia. We found no significant alterations in kratom users hematological and clinical-chemistry parameters. Importantly, the degree to which other organ systems are affected by regular kratom consumption in traditional settings merits further investigation.”

The Pharmacology and Toxicology of Kratom: From Traditional Herb to Drug of Abuse
Warner, Marcus L.; Kaufman, Nellie C.; Grundmann, Oliver. International Journal of Legal Medicine, 2016. DOI: 10.1007/s00414-015-1279-y.

Abstract: “Relatively new to the illicit market and used in a manner different from its traditional applications, preparations of kratom are touted by many as a safe and legal psychoactive product that improves mood, relieves pain, and may provide benefits in opiate addiction. Available literature was reviewed for M. speciosa via PubMed, Google Scholar, CINAHL, and EBSCO to summarize its traditional uses, phytochemical composition, pharmacology and toxicology of proposed active constituents, and potential for misuse and abuse.”

Notes from the Field: Kratom (Mitragyna speciosa) Exposures Reported to Poison Centers — United States, 2010–2015
U.S. Centers for Disease Control and Prevention Report, 2016.

Findings: “During the study period, U.S. poison centers received 660 calls about reported exposure to kratom. The number of calls increased tenfold from 26 in 2010 to 263 in 2015. … Medical outcomes associated with kratom exposure were reported as minor (minimal signs or symptoms, which resolved rapidly with no residual disability) for 162 (24.5 percent) exposures, moderate (non-life threatening, with no residual disability, but requiring some form of treatment) for 275 (41.7 percent) exposures, and major (life-threatening signs or symptoms, with some residual disability) for 49 (7.4 percent) exposures. One death was reported in a person who was exposed to the medications paroxetine (an antidepressant) and lamotrigine (an anticonvulsant and mood stabilizer) in addition to kratom. For 173 (26.2 percent) exposure calls, no effects were reported, or poison center staff members were unable to follow up again regarding effects.”

Clinical Outcomes after Kratom Exposures: A Poison Center Case Series
Cumpston, Kirk L.; Wills, Brandon K.; Carter, Michael. American Journal of Emergency Medicine, 2018. DOI: 10.1016/j.ajem.2017.07.051.

Findings: “This series illustrates kratom is being used for recreation, analgesia, treatment of opioid addiction and withdrawal prevention, performance enhancement and as a suicidal agent. There was a combination of opioid effects, seizures, tachycardia, and withdrawal. Elevated bilirubin was seen after chronic use in one patient. None of the patients required intensive care when using kratom alone.”

Mitragynine Concentrations in Two Fatalities
Domingo, Olwen; et al. Forensic Science International, 2017. DOI: 10.1016/j.forsciint.2016.12.020.

Abstract: “Two cases of fatalities are reported of which the recreational use of Mitragyna speciosa (“kratom”) could be confirmed. One of these cases presents with one of the highest postmortem mitragynine concentrations published to date. Our results show that even extremely high mitragynine blood concentrations following the consumption of kratom do not necessarily have to be the direct cause of death in such fatalities as a result of an acute overdose. The two cases are compared with regard to the differences in mitragynine concentrations detected and the role of mitragynine in the death of the subjects. Irrespective of the big differences in mitragynine concentrations in the postmortem blood samples, mitragynine was not the primary cause of death in either of the two cases reported here. Additionally, by rough estimation, a significant difference in ratio of mitragynine to its diastereomers in the blood and urine samples between the two cases could be seen.”


Use and abuse

Abuse Potential and Adverse Cognitive Effects of Mitragynine (Kratom)
Yusoff, Nurul H.M.; et al. Addiction Biology, 2016. DOI: 10.1111/adb.12185.

Abstract: “Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of ‘herbal high’ preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioral effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine.”

Prevalence and Motivations for Kratom Use in a Sample of Substance Users Enrolled in a Residential Treatment Program
Smith, Kirsten E.; Lawson, Thomas. Drug and Alcohol Dependence, 2017. DOI: 10.1016/j.drugalcdep.2017.08.034.

Conclusions: “Among substance users, kratom use may be initiated for a variety of reasons, including as a novel form of harm-reduction or drug substitution, particularly in the context of dependence and withdrawal from other substances.”

Kratom Use and Mental Health: A Systematic Review
Swogger, Marc T.; Walsh, Zach. Drug and Alcohol Dependence, 2018. DOI: 10.1016/j.drugalcdep.2017.10.012.

Results: “Findings indicate kratom’s potential as a harm reduction tool, most notably as a substitute for opioids among people who are addicted. Kratom also enhances mood and relieves anxiety among many users. For many, kratom’s negative mental health effects – primarily withdrawal symptoms – appear to be mild relative to those of opioids. For some users, however, withdrawal is highly uncomfortable and maintaining abstinence becomes difficult.”

A Case Report of Kratom Addiction and Withdrawal
Reig-Galbis, David. Wisconsin Medical Journal, 2016.

Abstract: “Kratom, a relatively unknown herb among physicians in the western world, is advertised on the Internet as an alternative to opioid analgesics, as a potential treatment for opioid withdrawal and as a ‘legal high’ with minimal addiction potential. This report describes a case of kratom addiction in a 37-year-old woman with a severe opioid-like withdrawal syndrome that was managed successfully with symptom-triggered clonidine therapy and scheduled hydroxyzine. A review of other case reports of kratom toxicity, the herb’s addiction potential, and the kratom withdrawal syndrome is discussed. Physicians in the United States should be aware of the growing availability and abuse of kratom and the herb’s potential adverse health effects, with particular attention to kratom’s toxicity, addictive potential, and associated withdrawal syndrome.”

Mitragyna Speciosa: Balancing Potential Medical Benefits and Abuse
Halpenny, Genevieve M. ACS Medicinal Chemistry Letters, 2017. DOI: 10.1021/acsmedchemlett.7b00298.

Abstract:Mitragyna speciosa, also known as kratom, has the potential to meet the need for pain medications that lack the addictiveness and overdose risk of classical opioid analgesics, such as morphine. This need is urgent because opioid addiction and overdose deaths have risen throughout diverse segments of U.S. society. Some opioid addicts have found relief in kratom preparations. The use of kratom as an analgesic has been validated by historical accounts and contemporary pharmacological research. Although kratom is a promising source of analgesic candidates, it is a euphoriant with potential for both abuse and addiction. However, kratom appears to be less addictive and to have milder withdrawal symptoms than opioid drugs. Thus, there is a need to balance the potential medical benefits and abuse of M. speciosa.”

Patterns of Kratom Use and Health Impact in the U.S.— Results from an Online Survey
Grundmann, Oliver. Drug and Alcohol Dependence, 2017. DOI: 10.1016/j.drugalcdep.2017.03.007.

Conclusions: “Kratom shows a dose-dependent opioid-like effect providing self-reported perceived beneficial effects in alleviating pain and relieving mood disorders. Kratom was primarily used for self-treatment of pain, mood disorders, and withdrawal symptoms associated with prescription opioid use.”


False advertising?

Chemical Characterization and In Vitro Cyto- and Genotoxicity of ‘Legal High’ Products Containing Kratom (Mitragyna speciosa)
Oliveira, Ana S.; et al. Forensic Toxicology, 2016. DOI: 10.1007/s11419-015-0305-6.

Abstract: “The obtained results revealed an inconsistency between the information (‘power’) provided in labels and the mitragynine (MG) content. Cytotoxicity tests revealed a concentration-dependent decrease in cell viability in both cellular models, with the SH-SY5Y cells being more sensitive to the Kratom extracts. The resin and the ‘powered extracts’ were the most cytotoxic samples, with IC50 values significantly lower than the leaf extracts and pure MG (P\0.0001 vs. leaf extracts and MG). In addition, significant DNA damage was observed in Caco- 2 cells exposed to these extracts but not to pure MG, which suggests that other substances present in the extracts or interactions involving Kratom components might be responsible for the observed effects.

Suspected Adulteration of Commercial Kratom Products with 7-Hydroxymitragynine
Lyedecker, Alicia G.; et al. Journal of Medical Toxicology, 2016. DOI: 10.1007/s13181-016-0588-y.

Findings: “We have found multiple packaged commercial Kratom products likely to contain artificially elevated concentrations of 7-hydroxymitragynine, the alkaloid responsible for M. speciosa‘s concerning mechanistic and side effect profile. This study describes a unique form of product adulteration, which stresses the importance of increased dietary supplement oversight of Kratom-containing supplements.”

Do You Get What You Paid For? An Examination of Products Advertised as Kratom
Griffin, O.H.; Daniels, J.A.; Gardner E.A. Journal of Psychoactive Drugs, 2016. DOI: 10.1080/02791072.2016.1229876.

Abstract: “Although some novel psychoactive substances (NPS) are newly discovered chemicals, others are traditional or indigenous substances that are introduced to new markets. One of these latter substances is a plant many people refer to as kratom. Indigenous to Southeast Asia and used for a variety of instrumental and recreational purposes, kratom has recently become available to Western drug users. Kratom is somewhat unique in that the plant contains two different psychoactive chemicals, which have both stimulant (mitragynine) and narcotic (7-hydroxymitragynine) properties. Thus, kratom may appeal to different types of drug users for reasons other than curiosity. In the current study, 15 samples of products that were either directly advertised as kratom or were listed in the results of a web search (but were not directly advertised as kratom) were purchased for testing. After laboratory testing, it was determined that all products advertised as kratom contained the active chemical mitragynine, but 7-hydroxymitragynine was not detected in any of the samples. Implications are discussed.”

Photo by Thor Porre used under a Creative Commons license.

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