Mitragyna speciose or Kratom is a plant in the coffee family (Rubiaceae) native to Southeast Asia and Thailand [1]. Their leaves have caused opioid-like and stimulant responses upon ingestion. Kratom is also known as Biak, Ketum, Kakuam, or Ithang or Thom.
The principle pharmacologically active compounds present in Kratom are the indole alkaloids, mitragynine, and 7-hydroxymitragynine (7-HMG). These indole alkaloids are responsible for its opioid-like activity. It is known for its affinity for the morphine or mu-opioid receptors. Research has also shown that one of its active components has effects on D2 dopamine, serotonin (5-HT2C and 5-HT7), and alpha-2 adrenergic receptors effects [2].
Recently, my colleagues at U.F. [3] showed in neuroscience studies that pharmaceutical mitragynine, 7-hydroxymitragynine, and morphine affected the brain reward thresholds. The kratom-derived compounds were tested at U.F. in Bruinjzeeel’s intracranial self-stimulation (ICSS) laboratory. This classic ICSS test compares the rewarding/aversive effects of potential drugs of abuse.
Scientists look for a drug of abuse to decrease the brain reward thresholds. Negative or aversive drug doses have the opposite effect. The U.F. group reported that a high dose of 7-hydroxymitragynine (3.2 mg/kg) increased the brain reward thresholds, whereas an intermediate amount of morphine (10 mg/kg) decreased the reward thresholds.
These U.F. findings indicate that mitragynine and 7-hydroxymitragynine are not rewarding in the ICSS procedure. These recent results from U.F. suggest that these specific kratom alkaloids do not have abuse potential.
It isn’t straightforward to reconcile individual users reports with existing science
Like users of cannabis and CBD, users of Kratom have reported all sorts of beneficial effects. It is up to scientists and then random assignment, double-blind FDA quality clinical trials to help us to understand if it is safe and effective, at what dose, in what form or use, and for what disease. Then we can ask if it is equal to or better than existing treatments.
For CBD, the FDA has concluded that it is safe and effective for three rare pediatric epilepsies. More uses are likely to be studied and approved.
Kratom products are available in most States as a supplement without a prescription. The American Kratom Association (AKA) estimates that there are more than 10 million people in the U.S. who regularly use the supplement by either eating its ground leaves in food or brewing them in tea or taking it in a pill form.
Some people use Kratom as an herbal alternative to buying buprenorphine on the street, going for an approved medical treatment for OUD, or to self-treat opioid withdrawal symptoms and cravings. Other consumers of Kratom take it for pain or a Psychiatric complaint or problem.
It reminds me of all the claims made for cannabis. There is likely to be some safe and effective medicine that comes from this plant. But, which and for what is unknown at this time. The FDA (Food and Drug Administration) and DEA (Drug Enforcement Administration) and NIDA (National Institute on Drug Abuse) worry that Kratom is not a prescription pharmaceutical, carries medical risks, unknown benefits, and the risk of physical and psychological dependency.
The Johns Hopkins psychedelic research group surveyed more than 2,700 self-reported users of Kratom. With Kirsten Smith of NIDA, they concluded that the supplement is the psychoactive compound somewhat similar to opioids but which they believe is likely to have a lower rate of harm than prescription opioids [10].
In this report on the findings, published in Drug and Alcohol Dependence, the researchers also caution that self-reporting surveys aren’t always entirely reliable. The implications of these user reports, they conclude, are limited as Kratom is not regulated or approved by the FDA. Also, it is worth noting that this report is a user survey and not the kind of scientific studies necessary to establish safety, efficacy, and benefits compared to other treatments.
What is Kratom?
Kratom (Mitragyna speciosa) is a tree-like plant related to coffee trees that is indigenous to Southeast Asia. Kratom leaves and the teas brewed from them have been used by people in that region for energy, to stave off fatigue, and to manage pain and opioid withdrawal.
Kratom contains a chemical called mitragynine, an opioid-like alkaloid that acts on the brain’s opioid receptors to change mood and behavior. In Asia, people typically use it in small doses, similar to coffee use in the West. Here in the USA, most people take Kratom as a pill, capsule, or extract. But, some chew the leaves or brew the dried or powdered leaves as a tea.
Kratom can cause effects similar to opioid drugs of abuse but also some stimulants. Two compounds in kratom leaves, mitragynine and 7-α-hydroxymitragynine [4], have been the focus of scientific studies.
Mitragynine and 7-α-hydroxymitragynine interact with opioid receptors in the brain, producing sedation, pleasure, and decreased pain, especially when users consume large amounts of the plant. Mitragynine also interacts with other receptor systems in the brain to produce stimulant effects. Like CBD, THC studies, or cannabis extracts and principle psychoactive drugs, the hunt is on to find out what Kratom contains that does have medicinal effects and promise.
A 2015 Thailand report suggested that people in Asia have been using Kratom successfully to self treat opioid use disorders for decades. This 2015 report caused some Americans to buy and use Kratom. But, it also renewed interest among researchers in the U.S., even though these products are unregulated and nonstandardized [5].
Although Thailand and Malaysia have criminalized the use, possession, growing, or selling of Kratom due to its abuse potential [6], it remains virtually unregulated in the United States. Self-reports, social media, and word-of-mouth have increased kratom use.
While use is growing in many parts of the world, lack of research, safety, and efficacy studies, as well as the purity and quality of the Kratom on the market, are raising concerns for healthcare providers [21]. Kratom users generally report increased energy, sociability, and alertness instead of sedation.
However, Kratom can also cause uncomfortable and sometimes dangerous side effects [7]. Reported health effects of its use include nausea, itching, sweating, dry mouth, constipation, increased urination, loss of appetite, seizures, hallucinations, dependence, and psychosis.
Recent evidence has confirmed that Kratom has physiological effects similar to opioids, including pain relief and euphoria, which may also explain clinician reports of opioid use disorder-like problems for kratom users. Mitragynine exerts its analgesic properties by acting on the opioid receptors. One of its active metabolites, 7-hydroxymytraginine, is found to be 40 times more potent than mitragynine and ten times more potent than morphine.
Mitragynine (M.G.) and 7-hydroxymitragynine (7-HMG) are major psychoactive constituents of Kratom. While M.G. and 7-HMG share behavioral and analgesic properties with morphine, 7-HMG is self-administered by lab animals like other drugs of abuse.
The reinforcing effects of 7-HMG are opioid mediated in part by brain μ and δ opiate receptors. The results of pretreatment with nalxonaxine (NLXZ), a μ1 opiate receptor antagonist, and naltrindole (NTI), a δ opiate receptor antagonist, on 7-HMG and morphine self-administration, were also examined.
Both NLXZ and NTI reduced 7-HMG self-administration, whereas only NLXZ decreased morphine intake. Concerns exist about Kratom, making opioid use more likely or reinforcing. Prior exposure to 7-HMG increased subsequent morphine intake, whereas previous exposure to M.G. decreased morphine intake [8].
Mitragynine does not have abuse potential and reduces morphine intake. Both of these effects are ideal for candidate pharmacotherapies for OUDs. 7-HMG should be considered a kratom constituent with high abuse potential that may also increase the intake of other opiates [9]. The OTC Kratom is a little of this and a little of that. Sometimes more of this than that and often full of other active chemicals or impurities.
Kratom User reports
Johns Hopkins researcher Garcia-Romeu says [10] he and his team enrolled 2,798 people through social media to complete an online survey on their use of Kratom. They reported their findings on 02/03/2020. Overall, users were mostly white, educated, and middle-aged. Participants were an average age of 40.
About 84% of participants reported having at least some college education. Of these participants, 91% reported taking Kratom to alleviate pain on average a couple of times a day for back, shoulder, and knee pain, 67% for anxiety, and 65% for depression. About 41% of survey responders said they took Kratom to treat opioid withdrawal.
“Both prescription and illicit opioids carry the risk of lethal overdose as evidenced by the more than 47,000 opioid overdose deaths in the U.S. in 2017,” says Garcia-Romeu. These authors believe that Kratom may offer an alternative to opioids that is less risky.
Risk vs. benefit concerns have been raised by many other health experts too. Experts worry that Kratom will add to existing risks and be used in combination with pain medications, anti-anxiety medications, street, and prescription drugs of abuse. Kratom use can cause addiction, hallucinations, seizures, and liver damage.
Use with other drugs of abuse and medications can increase risks. Consumer surveys are valuable and one part of the medicinal chemistry discovery puzzle. Still, these are prone to selection bias and not a replacement for actual scientific study.
Consumer experiences vary and can be unreliable, but some experts think that user data can give us a significant signal and lead us in the right direction when inventing new medications. The data do not prove that Kratom is safe or that there is a lower rate of abuse potential compared to prescription opioids taken for pain or given as MATs for opioid use disorder.
“Notably, there’s been fewer than 100 kratom-related deaths reported in a comparable period, and most of these involved mixing with other drugs or in combination with preexisting health conditions.” Fewer than 3% of responses met the criteria for moderate or severe substance use disorder for abusing Kratom, but about 13% met some criteria for kratom-related substance use disorder.
The Hopkins author, in an interview about these data, said: “This is why we advocate for the FDA to regulate Kratom, which would require testing for impurities and maintaining safe levels of the active chemicals. Otherwise, unregulated products run the risk of unsafe additives and dosing problems.
FDA
Scientific research has taken the Kratom leaf and found exciting and important chemical constituents that are likely to have medicinal benefits based on known pharmacological actions [11]. For what, in what dose, when, and other questions remain. Still, use is increasing in the USA for the self-management of opioid withdrawal, behavioral medicine, and treatment of pain.
Kratom-using patients have shown up for treatment, had emergencies, or complained about dependence, which has been reported by addiction physicians and addiction treatment programs. In a recent 18-month period, the CDC-Centers for Disease Control and Prevention reported 90 kratom overdoses. Like opioid overdoses, most involved a combination of other substances too.
These deaths are alarming and of great concern. FDA, DEA, and NIDA worry that Kratom carries the risk of physical and psychological dependency and, in some people, addiction. According to a recent NPR interview and discussion of Kratom with UCSF’s Dr. Scott Steiger, concerns are mounting. “I have seen that people who use kratom end up having a very hard time stopping the use of it” [12].
His patients report withdrawal symptoms such as nausea, sweats, aches and pains, loose stool, tearing, and dysphoria. There are also questions about Kratom’s toxicity, especially on the heart and liver. The use of Kratom in OUD or opioid withdrawal is not logical when existing treatments for these are very good and FDA approved.
Steiger [13] emphasizes that doctors have evidence-based therapies like buprenorphine and methadone to help people with an opioid use disorder. We have an opioid replacement but also have lofexidine and even clonidine to treat opioid withdrawal. Academic clinical trials of Kratom and comparable efficacy to existing treatments for OUDs and pain is necessary. Self-medicating with Kratom is premature.
While deaths are not common, compared to what we know about the total number of users and use events, there have been multiple reports of deaths in people who had ingested Kratom. Most of the deaths are Kratom plus other substances.
A 2019 paper analyzing data from the National Poison Data System found that between 2011-2017 there were 11 deaths associated with kratom exposure. Nine of the 11 deaths reported in this study involved Kratom plus other drugs and medicines, such as diphenhydramine (an antihistamine), alcohol, caffeine, benzodiazepines, fentanyl, and cocaine.
We see these medications and drugs associated with opioid overdoses as well. The FDA reporting on the risk of deaths due to Kratom notes that many of the kratom-associated deaths result from adulterated products or taking Kratom with other potent substances, including illicit drugs, opioids, benzodiazepines, alcohol, gabapentin, and over-the-counter medications, such as cough syrup.
Also, there have been some reports of Kratom packaged as dietary supplements or dietary ingredients that were laced with other compounds that caused deaths. The FDA warns consumers not to use Kratom. The FDA has recalled dozens of salmonella-tainted Kratom sold online or in convenience stores.
The actual number of deaths caused or exacerbated by Kratom is not known. Experts suggest that medical toxicologists and coroners should form working relationships with laboratories and public health officials to aid in the early identification of Kratom or adulterated kratom products that carry risk to the general population.
McClain Haddow [14], a 2020 spokesperson for the American Kratom Association, “We would like vendors to register their product with the FDA and get a chemical analysis from a certified lab to ensure the only ingredient is the naturally occurring alkaloid in the kratom plant,” Haddow says. “Some manufacturers are spiking products with fentanyl, heroin, or morphine to give users a high.”
The FDA has not tested Kratom, and it hasn’t approved Kratom for any disease or problem [22]. Claims that it cures depression or addictions are testimonials, and these or similar claims can not be used to advertise the product. The FDA found toxic heavy metals in some kratom supplements. These days, the DEA still has concerns [15].
Kratom proponents [16] view Kratom as a safer and less addictive alternative to opioids for the management of pain and opioid addiction. The anti-kratom faction argues that Kratom, itself, is a dangerous and addictive drug that ought to be banned.
I tend to look at this the same way that I looked at hydroxychloroquine for COVID-19. The FDA decides what is and what isn’t a medicine. Given consumer use of Kratom and the recent media attention it is receiving, physicians, scientists, and policymakers must be up to date and knowledgeable about the subject.
Conclusions
Kratom leaves and extracts have been used for centuries in Southeast Asia and elsewhere to manage pain and other disorders and, by the mid-twentieth century, to manage opioid withdrawal. Kratom is derived from the plant Mitragyna speciosa, which is indigenous to Southeast Asia. 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. User reports and results of preclinical studies in animals suggest that Kratom and its primary constituent alkaloid, mitragynine, may have useful medicinal activity in alleviating pain, OUD, and managing symptoms of opioid withdrawal.
The U.S. Drug Enforcement Agency (DEA) listed Kratom as a “drug of concern” in 2008 with the intent to temporarily place mitragynine and 7-hydroxymitragynine onto Schedule I of the Controlled Substances Act. Just bringing this subject up caused considerable blowback from the general public, U.S. Congress, and Kratom Alliances.
Their efforts kept Kratom as a dietary or herbal supplement used to treat chronic pain, anxiety, PTSD, and depression [17]. Nothing is proven or approved by the FDA, but it is logical to assume that science and clinical trials will identify constituents to study, in what dose, and for which condition.
Where Kratom fits in terms of the Controlled Substances Act (CSA) was reported using the eight factors of the CSA [18]. FDA quality and controlled clinical trials have yet to be done. Kratom lacks quality control, and many of the purported “kratom” products that are being sold in the U.S are very different in composition. Pharmacological trials and traditional research can resolve the issues regarding the safety and efficacy of Kratom and its mitragynine constituent.
The Mitragyna alkaloids also appear to be the critical potential therapeutic agents as they exert essential effects on crucial brain systems and receptors (including opioid, adrenergic, serotonergic, and dopaminergic receptors). There effect on the brain may explain the complex pharmacological profile of raw kratom extracts.
However, the devil is in the details, and a more detailed study is necessary to indeed characterize the effects of these other agents at their brain targets [19]. We do now know that Kratom chemical compounds, mitragynine, and 7-hydroxymitragynine cause a psychostimulant effect and opioid agonist effects through known brain receptors and systems used by cocaine and opioids.
Although Kratom is reported to have potential benefits in the treatment of opioid use disorder, pain, depression, anxiety, PTSD, and other problems, its actual efficacy for any remains to be proved. Numerous and troubling adverse kratom health effects have been reported.
Extensive clinical trials will help us understand the side-effects, risks, and benefits of Kratom. Trials will need better Kratom, which currently has a wide variability and often manufacturing impurities [20], not unexpected, given that this is an unregulated product. Further study of Kratom is warranted based on self-reports, pharmacological research, evolving science of Kratom’s major psychoactive constituents, and neuropharmacology.
Resources:
1. https://link.springer.com/article/10.1007/s00414-015-1279-y
2. Johnson LE, Balyan L, Magdalany A, et al. The Potential for Kratom as an Antidepressant and Antipsychotic. Yale J Biol Med. 2020;93(2):283-289. Published 2020 Jun 29.
3. https://doi.org/10.1016/j.drugalcdep.2020.108235
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12. https://www.npr.org/sections/health-shots/2020/01/13/789145948/the-kratom-debate-helpful-herb-or-dangerous-drug
13. https://medicine.ucsf.edu/people/scott-steiger
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19. Kruegel AC, Grundmann O. The medicinal chemistry and neuropharmacology of Kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology. 2018;134(Pt A):108-120. doi:10.1016/j.neuropharm.2017.08.026
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About the Author:
Mark S. Gold, M.D., Professor, Washington University School of Medicine – Department of Psychiatry, served as Professor, the Donald Dizney Eminent Scholar, Distinguished Professor and Chair of Psychiatry from 1990-2014. He was the first Faculty from the College of Medicine to be selected as a University-wide Distinguished Alumni Professor and served as the 17th University of Florida’s Distinguished Alumni Professor.
Dr. Gold is also a Distinguished Fellow, American Society of Addiction Medicine; Distinguished Life Fellow, the American Psychiatric Association; Distinguished Fellow, American College of Clinical Pharmacology; Clinical Professor of Psychiatry, Tulane University School of Medicine; Professor( Adjunct), Washington University in St Louis, School of Medicine, Department of Psychiatry; National Council, Washington University in St Louis, Institute for Public Health
Learn more about Mark S. Gold, MD
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Published on September 25, 2020. Published on AddictionHope.com
Reviewed by Jacquelyn Ekern, MS, LPC on September 25, 2020