Kratom, or Mitragyna speciosa, is a tropical tree from Southeast Asia that has drawn attention from traditional healers and modern scientists. People have used its leaves for centuries for effects that range from stimulating to opioid-like. What science has found so far comes from plant studies, chemistry, and pharmacology. Together, they show a mix of possible benefits and risks that is still being mapped. This article walks through the research timeline on kratom, covering its botany, traditional uses, key compounds, how it affects the body, possible medical uses, and the major challenges and open questions.
Kratom’s appeal comes from its alkaloids, which can act like stimulants at some doses and like opioids at others. This split effect has driven close scientific study, especially for pain relief and opioid withdrawal, where common treatments can fall short. As scientists study this long-used plant, they keep finding details that may change how we view natural compounds and medicine. But progress is hard because products vary widely and many studies use different methods, which creates ongoing problems for research.
What Is Kratom and Why Has It Attracted Scientific Interest?
Kratom (Mitragyna speciosa) is more than a common plant. It has a long history and a striking chemical profile that has pulled in researchers. This evergreen tree grows in Southeast Asia and has been part of local medicine for generations. Its leaves have been used in many ways, pushing modern science to look for the reasons behind the reported effects.
Interest is practical as well as scientific. With rising concern about pain care and the opioid crisis, researchers want to know if kratom could point to new treatment paths.
Botanical Profile and Alkaloid Content
Mitragyna speciosa belongs to the coffee family (Rubiaceae). It has big, oval, dark green leaves about 18 cm long and 10 cm wide, and deep yellow flowers. The main reason for scientific interest is its chemistry. The leaves contain many alkaloids and other plant compounds, including saponins, terpenoids, triterpenoids, polyphenols, and flavonoids.
Mitragynine is the main alkaloid and has been studied heavily because of its strong activity in the body. The plant also has related indole alkaloids and stereoisomers that add to the overall effect. Many of these alkaloids have a piperidine ring, a structure also found in compounds that can be toxic in humans and animals. This suggests both possible medical value and possible harm.
Traditional Uses in Southeast Asia
People in Southeast Asia have used kratom leaves for many health needs for a long time. Fresh leaves were often chewed by laborers to improve work output and fight fatigue, much like drinking coffee or tea. Beyond stimulation, kratom has been used for pain, fever, cough, anxiety, high blood pressure, diabetes, diarrhea, and intestinal infections. Some used it to prevent cancer and to increase sexual desire.
Ways of using it varied: chewing fresh leaves, smoking them, or brewing tea. In Thailand, kratom tea became part of a drink called “4×100,” mixed with Coca-Cola, cough syrup, and other items. Kratom also stood in for opium to help with withdrawal, a traditional use that later drew attention for treating modern opioid dependence.
Emergence in Western Medicine and Culture
Kratom’s spread to Western countries is recent, growing over the past decade in the U.S., Europe, and Japan. Many people use it as an alternative for pain relief, to lift mood, and to self-manage opioid withdrawal symptoms. Demand has risen, with nearly two metric tons imported from Southeast Asia each month.
In the West, kratom comes as dried leaves for chewing or tea, plus tablets, capsules, and extracts. This shift from fresh, local use to commercial products brought new issues. The U.S. Drug Enforcement Administration (DEA) labeled kratom a “drug of concern” in the early 2000s. The move from traditional use to wide commercial sales helped drive research to better map kratom’s effects and risks.
Kratom Research Timeline: Key Scientific Milestones
Research on kratom spans more than a century, moving from early plant notes to detailed molecular work. The timeline below shows key moments that shaped what we know about Mitragyna speciosa.
Early Observations and Traditional Use
Traditional use is older than written research. The first reports appeared in 1836, noting kratom as an opium substitute in Malaysia and as a stimulant in Thailand. For generations, people used fresh leaves or tea with few recorded severe toxic effects in local groups. These long-standing uses set the stage for later scientific work.
These early records, though not modern experiments, guided researchers to a plant with many effects. Seeing kratom as a natural aid for pain and fatigue in its home region encouraged studies of its active parts and how they work.
Initial Scientific Studies (1940s-1990s)
Formal research began in the early 20th century. In 1921, Ellen Field at the University of Edinburgh likely isolated mitragynine, the main alkaloid, and correctly labeled it an indole alkaloid. This was the first step in tying kratom’s effects to specific chemicals.
In 1932, Khem Singh Grewal at the University of Cambridge ran the first pharmacology studies of mitragynine in animals. These early projects began to explain the actions of kratom’s key compound. At the time, kratom’s use as a stimulant and an opioid substitute, and reports of dependence, were already known from regional use.
Modern Laboratory Research (2000s-2010s)
The early 2000s saw a big increase in kratom studies, driven by rising use in the West and questions about safety and benefit. New lab tools allowed closer study of the plant’s pharmacology. Scientists isolated and described additional alkaloids beyond mitragynine, including 7-hydroxymitragynine, which, though a minor component, showed much stronger activity.
Research focused on how kratom alkaloids interact with opioid receptors. Mitragynine and 7-hydroxymitragynine act as partial agonists at the mu-opioid receptor, which helps explain pain relief and opioid-like effects. Studies also looked at α2-adrenergic, adenosine A2a, dopamine D2, and serotonin receptors, showing a wider range of actions. Reports of harmful effects in the West pushed work on safety, drug interactions, and organ toxicity.
Current Research Trends and 2020s Progress
By 2025, kratom research is moving fast, with more focus on clinical trials, standard methods, and long-term effects. Teams now mix chemistry, pharmacology, toxicology, and population studies. A key area is the large variation in alkaloid levels in commercial products, especially 7-hydroxymitragynine, which can vary a lot and change both effects and risks. Scientists are developing standardized products, ideally close to traditional teas, to improve consistency in effect and safety.
Work in the 2020s is pushing for controlled human trials to test safety and benefit for opioid withdrawal and chronic pain. There is also interest in turning kratom alkaloids into new drugs with clear targets. Challenges remain, including the lack of federal regulation in the U.S., which affects funding and oversight. Even with these hurdles, researchers aim for a full understanding of kratom, weighing its possible benefits and known risks to guide policy and safer use.
What Major Compounds in Kratom Have Been Studied?
Kratom’s varied effects come from many bioactive compounds, especially its alkaloids. Two draw the most attention for their strong actions: mitragynine and 7-hydroxymitragynine. The plant also carries several minor alkaloids that shape the overall effect, keeping chemists and pharmacologists busy.
Knowing these compounds helps explain how kratom acts in the body and helps weigh its possible medical uses and risks. The mix of alkaloids can create complex and sometimes unpredictable responses, which is why scientists continue to closely study each one.
Mitragynine and 7-Hydroxymitragynine
Mitragynine is the main compound in kratom. It is an indole alkaloid and a partial agonist at the mu-opioid receptor. Its binding to this receptor is much weaker than morphine, and it has much lower efficacy (EC50=339 nM for mitragynine vs. EC50=3 nM for morphine). This helps explain why kratom’s opioid-like effects can be milder than standard opioids. Some studies suggest purified mitragynine has little to no abuse potential and can reduce or stop heroin or morphine self-administration in rodents, hinting at a role in treating opioid addiction.
7-Hydroxymitragynine is present at much lower levels, sometimes not detected in fresh leaves, but it is far more active pharmacologically. It is a more potent and more efficacious partial agonist at the mu-opioid receptor, around 10 times more potent than mitragynine (in vitro EC50=35 nM). This compound can form after harvest and drying, and also by metabolism of mitragynine in the gut and liver. Its presence in kratom products is a major concern because purified 7-hydroxymitragynine shows abuse potential, unlike mitragynine. Wide variation in 7-hydroxymitragynine among U.S. products likely raises harm compared with traditional preparations.
Other Minor Alkaloids of Interest
Kratom leaves also contain speciogynine, speciociliatine, paynantheine, corynantheidine, and others. These are found at lower levels but still matter. Some may act as competitive antagonists at mu-opioid receptors, changing the net effect of a whole extract. This mix of agonists and antagonists helps explain kratom’s dose-dependent profile.
Speciociliatine and paynantheine may slow certain liver enzymes and could affect how other drugs are processed. Corynantheidine adds to the overall alkaloid pattern. The effects of whole leaf preparations come from all these compounds acting together, not just mitragynine and 7-hydroxymitragynine. More research on the minor alkaloids may reveal new benefits or risks, which means full analysis of the plant is more useful than focusing only on the two major ones.
How Does Kratom Affect the Body and Brain According to Science?
Researchers have worked to explain how kratom acts in the body and brain. Its effects depend on dose: at low doses it can stimulate; at higher doses it can feel opioid-like. This comes from its alkaloids acting at several receptor systems, leading to many physical and mental effects.
Understanding these mechanisms matters for weighing both possible uses and risks. Studies in cells and animals have provided key clues about how this plant works.
Pharmacological and Neuropharmacological Actions
Mitragynine and 7-hydroxymitragynine drive most of kratom’s actions. They bind to different receptors in the central nervous system (CNS). At lower doses, kratom tends to stimulate, raising alertness and energy. This may involve α2-adrenergic receptors and possibly adenosine A2a and dopamine D2 receptors. These effects match traditional use by laborers.
As the dose goes up, kratom shifts to more sedative and pain-relieving effects that resemble opioids. Multiple active compounds-some agonists, some antagonists-act at different receptors, creating a complex profile still under study. Effects start within minutes and often last a few hours, showing rapid action on neural pathways.
Opioid-Like Effects and Pain Pathways
A key finding is kratom’s action at opioid receptors, especially the mu-opioid receptor. Mitragynine and 7-hydroxymitragynine act as partial agonists there. This explains pain relief and the ability to ease opioid withdrawal symptoms.
Mitragynine binds with lower affinity and efficacy than morphine, while 7-hydroxymitragynine is far more potent. Activation of mu-opioid receptors is central to pain relief and euphoria with classic opioids. Kratom’s pain relief can be blocked by naloxone, an opioid antagonist, which supports this mechanism. These pathways help explain why some people use kratom for pain or to cut back on opioids, but they also support the risk of dependence and withdrawal.
Interactions with Serotonin and Other Receptors
Kratom’s alkaloids also affect other neurotransmitter systems. Mitragynine shows affinity for serotonin 5-HT2C and 5-HT7 receptors. Serotonin is important for mood, anxiety, and perception, which may relate to reported mood-lifting and antidepressant-like effects. The exact activity at these receptors needs more study.
Mitragynine and 7-hydroxymitragynine also show weaker partial competitive antagonism at kappa (κ) and delta (δ) opioid receptors. Together with effects on α2-adrenergic, adenosine A2a, and dopamine D2 receptors, this helps explain stimulation at low doses, anxiety relief for some users, and other reported effects. Mapping all these receptor actions helps predict benefits, side effects, and interactions.
What Are the Potential Benefits Revealed by Kratom Research?
Even with debate and regulatory issues, research points to several possible benefits. These include pain relief, effects on mood, and help with opioid withdrawal and substance use. Evidence is still building and needs stronger clinical trials, but both traditional use and modern studies show promise.
Kratom’s alkaloids act on many pathways, which may explain these effects. This has made kratom a focus for people looking for alternative or added tools for health.
Pain Relief and Analgesic Properties
Pain relief is the most common reported benefit and a main research topic. Traditional use supports it, and modern work is identifying the mechanisms. Mitragynine and 7-hydroxymitragynine act as partial agonists at mu-opioid receptors in the brain and spinal cord, which are central for pain signals. This is similar to opioid painkillers, but with differences in how strongly and how well they bind.
Studies show mitragynine’s pain relief is reversed by naloxone, an opioid blocker, supporting an opioid-like pathway. Many people in the U.S. use kratom for pain, from short-term aches to long-term conditions. We still need large trials to compare kratom to prescription opioids for both benefit and safety, but early signs suggest it may offer a different way to manage pain.
Mood Effects and Antidepressant-Like Potential
Users also report changes in mood, including better mood, more energy, and less anxiety, especially at lower doses. Early studies point to actions at serotonin receptors (5-HT2C and 5-HT7), as well as dopamine and adrenergic systems, that could explain these effects.
Human trials for depression or anxiety are still limited. Reports and early lab work suggest possible benefit, but product variability and lack of regulation make general claims hard. Research will need to define safe and effective dosing for mood-related uses.
Implications for Opioid Withdrawal and Substance Use Disorders
A major interest area is kratom’s use for opioid withdrawal and substance use disorders. In Southeast Asia, kratom has long helped people avoid opium withdrawal. In the West, many try kratom to ease withdrawal symptoms and cut back on other opioids.
The science points to partial mu-opioid receptor actions by mitragynine and 7-hydroxymitragynine, which can reduce withdrawal discomfort. Early work, including studies led by Christopher R. McCurdy, suggests kratom tea may help manage opioid withdrawal and support tapering. Purified mitragynine has reduced heroin or morphine self-administration in rodents, which may reflect lower cravings. Well-controlled human trials are still needed to judge safety and benefit. Product variability also complicates real-world use.
What Risks and Side Effects Has Kratom Research Identified?
Alongside possible benefits, research has carefully documented risks and side effects. Product variability, self-set dosing, and mixing kratom with other substances make risk assessment harder.
Studies, case reports, and surveys describe harms ranging from mild to severe, including rare deaths, often with other drugs involved. The sections below outline adverse effects, dependence and withdrawal, interactions, and overdose reports.
Adverse Health Effects and Toxicity
Reported side effects include:
- Nausea, vomiting, constipation, stomach upset
- Dry mouth, sweating
- Drowsiness, dizziness, or, at times, irritability and agitation
- With long-term use: skin darkening, frequent urination, insomnia, dehydration, weight loss, and reduced sexual desire
U.S. National Poison Data System reports list agitation (18.6%), tachycardia (16.9%), and vomiting (11.2%). More severe effects include respiratory depression (2.8%), coma (2.3%), and cardiac or respiratory arrest (0.6%).
Animal and cell studies point to organ toxicity risks. Liver, kidneys, lungs, and brain can be affected. Liver findings include sinusoid congestion, bleeding, and fat buildup, which can worsen with repeated exposure. Blood tests have shown higher liver markers (ALT, AST, bilirubin, albumin) and kidney markers (urea, creatinine, GGT). Case reports include liver injury (intrahepatic cholestasis, drug-induced liver injury), kidney problems, heart issues (tachycardia, high blood pressure, coronary atherosclerosis, cardiomyopathy), and neurotoxicity (seizures and neuronal damage).
Risk of Dependence and Withdrawal Symptoms
Kratom can lead to dependence, especially with frequent, high-dose, or long-term use. Tolerance can build, pushing people to take more. Stopping can bring withdrawal symptoms, often milder than opioid withdrawal but still hard to handle.
Reported withdrawal symptoms include:
- Muscle and bone pain, joint pain
- Restlessness, irritability, anxiety
- Insomnia, fatigue, reduced ability to work
- Chest discomfort
- Gastrointestinal upset (diarrhea, nausea)
- Runny nose (rhinorrhea)
Symptoms can last 3 to 10 days. Risk rises when people use kratom to manage opioid withdrawal or pain, especially with concentrated extracts. Varying levels of 7-hydroxymitragynine in products may raise the risk, since this compound shows strong abuse potential when purified.
Interactions with Medications and Other Substances
Kratom can interfere with drug metabolism. In vitro studies show kratom extracts and alkaloids like mitragynine can inhibit cytochrome P450 enzymes (CYP3A4, CYP2D6, CYP1A2), carboxylesterase CES1, and glutathione transferase. These enzymes process many drugs.
Mixing kratom with drugs that use these enzymes can raise drug levels and cause toxicity. Examples include:
- Warfarin (CYP2C9)
- Benzodiazepines (CYP3A)
- Desipramine and dextromethorphan (CYP2D6)
- Clopidogrel, oseltamivir, methylphenidate (CES1)
Kratom can also add to CNS depression from alcohol, benzodiazepines, barbiturates, opioids, antidepressants, and anxiolytics, increasing risk for respiratory depression, coma, and other severe outcomes. Many serious cases and deaths involve kratom taken with other drugs.
Reported Cases of Overdose and Fatality
While studies rarely show deaths from kratom alone, many case reports link kratom to fatalities where other substances were also present. These mixtures can worsen respiratory depression, cause cardiac arrest, and damage organs.
Examples include deaths with cardiorespiratory failure and hypoxic brain injury, kidney failure, lung congestion, and pulmonary edema, often with mitragynine found alongside hydromorphone, zopiclone, citalopram, lamotrigine, or quetiapine. Overdose from kratom alone seems uncommon, but lack of standard dosing and possible contaminants (heavy metals, salmonella) or boosted alkaloid levels in some products raise risks. The FDA has tied more than 35 deaths to salmonella-contaminated kratom. These findings show the need for better quality control and public awareness about mixing kratom with other drugs.
Gaps in Research: What Questions Remain Unanswered?
Even with progress, many gaps remain. Filling them could affect public health, regulation, and safer use. The plant’s complexity and many ways people take it add to these gaps.
Addressing these gaps is important for moving beyond stories and building a strong, evidence-based picture of kratom’s benefits and risks. Below are key areas where research is still thin.
Insufficient Clinical Trials and Human Studies
There are few well-controlled clinical trials. Animal and cell studies give basic insight, but they do not always match what happens in people. Much of what we know in humans comes from self-reports, surveys, and case studies, which lack the control of clinical trials. This makes it hard to set clear efficacy, best dosing, long-term safety, and true rates of side effects across different groups.
Many people report pain relief and help with opioid withdrawal, but without randomized, placebo-controlled trials, the size of the benefit compared with standard treatments is unclear. The dose-response pattern (stimulant at low doses, opioid-like at higher doses) is well reported, but exact dose ranges and clinical use need human data. A lack of standard study products also makes results hard to compare. These missing human data slow policy decisions and drug development based on kratom.
Variability of Kratom Products and Standardization Challenges
A major problem is the wide variation in commercial products, especially in Western markets. Unlike prescription drugs, many kratom products lack clear labels and consistent content. Plant age, growing conditions, harvest season, and post-harvest handling (drying, aging) all change the alkaloid profile. Two products sold as “kratom” may have very different mitragynine and 7-hydroxymitragynine levels, leading to different effects.
Many products come from dried leaves or concentrated extracts, which can differ from freshly prepared leaves. Fresh leaves may have no detectable 7-hydroxymitragynine, but drying and metabolism can create it. Adulteration or enrichment with certain alkaloids adds more risk. Without consistent products, research is hard to reproduce, consumers cannot predict effects, and regulators cannot set strong quality rules. If this variability continues, clear conclusions about safety and benefit will remain hard to reach.
Long-Term Health Effects and Special Populations (e.g., Pregnancy)
Long-term effects are not well studied. Most work looks at short-term or subchronic exposure. We still need data on how years of use affect liver, kidneys, heart, and brain, especially in people with other health issues or those who use kratom for long periods.
Data on special groups are also scarce. Effects during pregnancy and breastfeeding are not well understood. Some case reports describe newborns with symptoms like neonatal abstinence after maternal use, but there are almost no controlled animal or human studies on birth defects or other pregnancy outcomes. We also lack data on adolescents, older adults, and people with specific medical conditions (such as heart disease or psychiatric disorders). This lack of information makes it hard for clinicians to guide patients and raises public health concerns.
What Directions Are Emerging for Future Kratom Research?
As knowledge grows, researchers are setting new goals to close gaps and test new ideas. Future work will mix advanced lab methods with strong clinical trial designs. The aim is to move kratom from a debated herb to a well-understood set of compounds, realizing any medical value while reducing risks.
Focus areas include wide-ranging studies, new drug development from kratom alkaloids, and stronger public health tracking, guided by lessons from past research.
Therapeutic Applications Under Investigation
Future studies will test proposed uses with clinical rigor. A key area is treatment of opioid withdrawal and support for substance use disorders. Teams are planning controlled trials of standardized kratom preparations, looking at efficacy, safety, and dose ranges, and comparing with existing treatments.
Pain management and mood effects will also get more attention. Studies will look at chronic pain conditions, patient groups, and which alkaloid profiles drive benefit. Reported antidepressant and anxiolytic effects need trials that link specific compounds to outcomes. Researchers may also explore traditional claims like effects on diabetes or inflammation, though this work is at an early stage. The aim is to find clear, safe, and effective uses for kratom or its isolated compounds backed by solid clinical evidence.
Innovations in Alkaloid Chemistry and Drug Development
Kratom’s alkaloids are fertile ground for medicinal chemistry. Future work will study both major and minor alkaloids in detail, including speciogynine, speciociliatine, paynantheine, and corynantheidine, and how they interact.
Another path is to design synthetic analogs of kratom alkaloids. By changing parts of molecules like mitragynine, scientists aim to create drugs with better benefit, fewer side effects, and improved safety. Projects may tune opioid receptor signaling (for example, favoring G-protein pathways while limiting beta-arrestin signaling) to avoid problems seen with classic opioids. Researchers also need to see if kratom alkaloids break down into more toxic compounds in the body and how to reduce that risk. Over time, the goal is to identify changes that produce safer, effective medicines inspired by kratom.
Advancing Safety Studies and Public Health Monitoring
Stronger safety research and better monitoring are high priorities. Given the risks and lack of standard products, detailed toxicology work is needed, including long-term animal studies and human trials. These should map liver, heart, nerve, and kidney effects, especially with long-term or high-dose use.
Future work will set clear dose-response curves for both benefits and harms, helping define safe and effective doses. Reducing variability will require standardized products and strict testing methods for quality, consistent alkaloid content, and freedom from contaminants like heavy metals or pathogens. Public health systems should improve tracking of adverse events, interactions, and use patterns. Better reports should measure alkaloid levels to clarify links between dose and outcome. These steps can guide policy and regulation that balance potential benefits with safety.
Key Takeaways from the Kratom Research Timeline
The research timeline shows a complex plant with both helpful and harmful sides. Our view has changed over time, from early reports in traditional settings to detailed receptor studies. Kratom may help with pain and opioid withdrawal, but it also carries risks that call for more research and careful use.
Summary of Scientific Discoveries So Far
Scientists have shown that Mitragyna speciosa, a Southeast Asian tree, contains many alkaloids. Mitragynine is the most abundant, and 7-hydroxymitragynine is a minor but very potent one. Both act as partial agonists at mu-opioid receptors, helping explain pain relief and opioid-like effects. They also affect adrenergic, dopamine, and serotonin systems, which links to stimulation at low doses and possible mood effects.
Traditional preparations used locally for centuries often differ from Western products. Drying, aging, and adulteration can raise levels of potent alkaloids like 7-hydroxymitragynine, which may increase adverse effects. Documented risks include liver, heart, and nerve toxicity, dependence and withdrawal, and dangerous interactions with drugs processed by CYP enzymes. Deaths in case reports usually involve kratom with other substances. Major gaps remain, especially human clinical trials, long-term safety data, and product standardization. Filling these gaps is key for a full understanding and safer, informed use.