Greenmeier September 30,2013 - Scientific
Thailand is considering legalizing kratom as a safer alternative for meth addicts, and U.S. researchers are studying its potential to help opiate abusers kick the habit without withdrawal side effects. Is that a good thing?
The leaves of the herb kratom (Mitragyna speciosa), a native of Southeast Asia in the coffee family, are used to relieve pain and improve mood as an opiate substitute and stimulant. The herb is also combined with cough syrup to make a popular beverage in Thailand called “4×100.” Because of its psychoactive properties, however, kratom is illegal in Thailand, Australia, Myanmar (Burma) and Malaysia. The U.S. Drug Enforcement Administration lists kratom as a “drug of concern” because of its abuse potential, stating it has no legitimate medical use. The state of Indiana has banned kratom consumption outright.
Now, looking to control its population’s growing dependence on methamphetamines, Thailand is attempting to legalize kratom, which it had originally banned 70 years ago.
At the same time, researchers are studying kratom’s ability to help wean addicts from much stronger drugs, such as heroin and cocaine. Studies show that a compound found in the plant could even serve as the basis for an alternative to methadone in treating addictions to opioids. The moves are just the latest step in kratom’s strange journey from home-brewed stimulant to illegal painkiller to, possibly, a withdrawal-free treatment for opioid abuse.
With kratom’s legal status under review in Thailand and U.S. researchers delving into the substance’s potential to help drug addicts, Scientific American spoke with Edward Boyer, a professor of emergency medicine and director of medical toxicology at the University of Massachusetts Medical School. Boyer has worked with Chris McCurdy, a University of Mississippi professor of medicinal chemistry and pharmacology, and others for the past several years to better understand whether kratom use should be stigmatized or celebrated.
[An edited transcript of the interview follows.]
How did you become interested in studying kratom?
A few years ago [the National Institutes of Health] wanted me to do a bit of consulting on emerging drugs that people might abuse. I came across kratom while searching online, but didn’t think much of it at first. When I mentioned it to the NIH, they suggested I speak with a researcher at the University of Mississippi who was doing work on kratom. [The researcher, McCurdy,] assured me that kratom was fascinating, and he started to go through the science behind it. I decided I needed to look into it further. Talk about chance favoring the prepared mind. I no sooner hung up the phone when a case of kratom abuse popped up at Massachusetts General Hospital.
How did this Mass General patient come to abuse
He was a [43-year-old] successful software engineer who had been self-medicating for chronic pain [as a result of thoracic outlet syndrome, a group of disorders that occurs when the blood vessels or nerves in the space between the collarbone and the first rib—the thoracic outlet—become compressed, causing pain in the shoulders and neck as well as numbness in the fingers]. He had started with pain pills, then switched to OxyContin, and then moved to Dilaudid, which is a high-potency opioid analgesic. He had gotten to the point where he was injecting himself with 10 milligrams of Dilaudid per day, which is a large dose. His wife found out and demanded that he quit.
He read about kratom online and started making a tea out of it. For the most part, this helped him avoid the opioid withdrawal he had been experiencing. After he started drinking the kratom tea, he also began to notice that he could work longer hours and that he was more attentive to his wife when they would speak. He began experimenting with ways to boost his alertness by adding modafinil [a U.S. Food and Drug Administration–approved stimulant] with his kratom tea. That’s when he started to seize and had to be brought to the hospital. I have no idea how that combination of drugs caused a seizure, but that’s how he ended up at Mass General Hospital. Nobody there had heard of kratom abuse at the time. [Boyer and several colleagues, including McCurdy, published a case study about this incident in the June 2008 issue of the journal Addiction.]
The patient was spending $15,000 annually on kratom, according
to your study, which is quite a lot for tea. What happened when he
left the hospital and stopped using it?
After his stay at Mass General, he went off kratom cold turkey. The fascinating thing is that his only withdrawal symptom was a runny noise. As for his opioid withdrawal, we learned that kratom blunts that process awfully, awfully well.
Where did your kratom research go from there?
I had a small grant from the NIH’s National Institute on Drug Abuse to look at individuals who self-treated chronic pain with opioid analgesics they purchased without prescription on the Internet. This was an extremely restricted population, but it nonetheless measures in the hundreds of thousands of people. About the time I started the study, the DEA and the state boards of pharmacy began shutting down online pharmacies, so sources of pain pills for these hundreds of thousands of people in the United States dried up instantaneously. A number of them switched to kratom.
How many people are using kratom in the U.S.?
I don’t know that there’s any epidemiology to inform that in an honest way. The typical drug abuse metrics don’t exist. But what I can tell you, based on my experience researching emerging drugs of abuse is that it is not difficult to get online.
How does kratom work?
Its pharmacology and toxicology aren’t well understood. Mitragynine—the isolated natural product in kratom leaves—binds to the same mu-opioid receptor as morphine, which explains why it treats pain. It’s got kappa-opioid receptor activity as well, and it’s also got adrenergic activity as well, so you stay alert throughout the day. This would explain why the guy who overdosed described himself as being more attentive. Some opioid medicinal chemists would suggest that kratom pharmacology might [reduce cravings for opioids] while at the same time providing pain relief. I don’t know how realistic that is in humans who take the drug, but that’s what some medicinal chemists would seem to suggest.
Kratom also has serotonergic activity, too—it binds with serotonin receptors. So if you want to treat depression, if you want to treat opioid pain, if you want to treat sleepiness, this [compound] really puts it all together.
Overdosing and drug mixing aside, is kratom
People are afraid of opioid analgesics because they can lead to respiratory depression [difficulty breathing]. When you overdose on these drugs, your respiratory rate drops to zero. In animal studies where rats were given mitragynine, those rats had no respiratory depression. This opens the possibility of someday developing a pain medication as effective as morphine but without the risk of accidentally overdosing and dying.
What barriers have you run into when trying to study
I tried to get an NIH grant to study kratom specifically. When I went to the National Institute on Drug Abuse, they said they’d never heard of that drug. When I went to the National Center for Complementary and Alternative Medicine, they said this is a drug of abuse, and we don’t fund drug of abuse research. They want drugs that are used therapeutically. [A team led by McCurdy, who confirms that it is difficult to get funding to study kratom, did manage to secure a three-year grant from the NIH Centers of Biomedical Research Excellence to investigate the herb’s opioid-like effects.]
So the study of this type of substance falls to academics or pharma companies. Drug companies are the ones who can isolate a particular compound, do chemistry on it, study and modify the structure, figure out its activity relationships, and then create modified molecules for testing. Then you have eventually file for a new drug application with the FDA in order to conduct clinical trials. Based on my experiences, the likelihood of that happening is reasonably small.
Why wouldn’t large pharmaceutical companies try to make a
blockbuster drug from kratom?
At least one pharma company [Smith, Kline & French, now part of GlaxoSmithKline] was looking at it in the 1960s, but something didn’t work for them. Either it wasn’t a strong enough analgesic or the solubility was bad or they didn’t have a drug delivery system for it. To the state of the art pharmaceutical business thinking in 1960s, this compound was not sufficient to be brought to market. Of course, now that we have a country with many addicted people dying of respiratory depression, having a drug that can effectively treat your pain with no respiratory depression, I think that’s pretty cool. It might be worth a second look for pharma companies.
There are reports that Thailand might legalize kratom to help
that country control its meth problem. Could that work?
They can decriminalize kratom until they’re blue in the face but the reality is that kratom is indigenous to Thailand—it’s readily available and always has been. Yet drug users are still opting for methamphetamines, which are stronger than kratom, not to mention dirt cheap and widely available. I suspect that Thailand is just trying to say that they’re doing something about their meth problem, but that it might not be that effective.
Article first published online: 28 JUN 2008
Edward W. Boyer, MD, PhD,1 Kavita M. Babu, MD,1 Grace E. Macalino, PhD,2 Wilson Compton, MD, MPH3 1Division of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 2Tufts-New England Medical Center, Boston, Massachusetts 3 National Institute on Drug Abuse, Rockville, Maryland
We examined the use of Kratom (Mitragyna sp.), a dietary supplement with mu-opioid agonist activity, by members of a cybercommunity who self-treat chronic pain with opioid analgesics from Internet pharmacies. Within one year, an increase in the number of mentions on Drugbuyers.com, a Web site that facilitates the online purchase of opioid analgesics, suggested that members began managing opioid withdrawal with Kratom. This study demonstrates the rapidity with which information on psychoactive substances disseminates through online communities and suggests that online surveillance may be important to the generation of effective opioid analgesic abuse prevention strategies. (Am J Addict 2007;16:352–356)
Recent increases in the use of opioid analgesics (e.g., hydrocodone and oxycodone, among others) may represent an expanded pathway to opioid addiction that is driven, in part, by new sources of access to these drugs.1,2 Internet pharmacies, which sell drugs to anyone who can afford to pay, are theorized to increase the availability of opioid analgesic agents as well as the risk of opioid abuse and addiction.1,3 As part of ongoing research examining the relationship between Internet pharmacies and substance abuse, we have identified several ‘‘pharmacy watch’’ Web sites.3,4 One, www.drugbuyers.com, not only facilitates the purchase of pharmaceuticals from Internet pharmacies, but also serves as a resource through which information on the self-treatment of chronic pain is disseminated among members. Much of information exchanged on Drugbuyers relates to sources of opioid analgesics, tolerance to opioids, and management of withdrawal using opioid replacement therapy or herbal products. One such herbal product is Kratom (Mitragyna speciosa Korth), a tree native to southeast Asia and Africa.5 Mitragynine, the most prevalent alkaloid isolated from Kratom, and its congeners possess agonist activity at mu- and delta-opioid receptors and are responsible for the drug’s opioid-like effects.6–8 Additional animal studies suggest that mitragynine, a non-opioid indole alkaloid, may also stimulate post-synaptic alpha-2 adrenergic receptors and=or antagonize stimulation of 5-HT2A receptors.9 Kratom was traditionally used in Thailand and Malaysia by manual laborers to enhance productivity and for its euphoric effects; its indication for treatment of pain and opium withdrawal was described as early as 1897.5,10 Kratom is sold by many Internet vendors, suggesting extensive demand for this product.11 After identifying the use of Kratom by Drugbuyer’s members, we investigated the ways in which Drugbuyer’s members incorporated this herb into existing patterns of opioid analgesic use.
We constructed a dataset of Kratom mentions from postings generated by the 113,000 members of Drugbuyers. com.4 Individuals join Drugbuyer’s because they procure pharmaceuticals from online pharmacies; because members purchase medications to treat chronic conditions, membership on Drugbuyer’s is thought to be stable.4 Among Drugbuyers members, 90% self-treat (e.g., without physician oversight) chronic pain with opioid analgesics. Up to 925 unique individuals visit Drugbuyers at any one time, with an average of 22 minutes spent on the Web site per visit.4 The average age of Drugbuyer’s members is 38 (range: 18–67); 59% are female.4 Members post an average of 0.5–1.0 messages per minute on the Web site’s forums. We used the Drugbuyers.com internal search function to identify each instance where Kratom was mentioned on Web site forums (‘‘mentions’’) over a one-year period. Mentions are contained within threads, or series of messages posted as replies to one another; we identified the initial post on every thread that mentioned Kratom. We abstracted the initial post, removed all identifiers such as Drugbuyer’s boardname, and placed all posts in random order prior to review. Because postings on Drugbuyer’s forums were made anonymously and with no expectation of privacy, our Institutional Review Board concluded that this study was excluded from review. The dataset used in this study was empiric and was intended to provide preliminary information on the reasons for which Drugbuyer’s members used Kratom. We analyzed the study variable using Kappa and descriptive statistics. We used an abstraction form to collect information about Kratom use. By means of simple, dichotomous answers (‘‘agree=disagree’’), examiners assessed the intent underlying Kratom use described in the initial post. Masked versions were coded independently by two examiners trained in the use of the form, working according to an instruction manual, and blinded to results until all data collection was complete. We determined, using the Kappa statistic, the degree of interobserver agreement between coders.
The period between November 1, 2004, and October 31, 2005, saw a dramatic increase in the number of Kratom mentions on Drugbuyers (see Figure 1). We identified 170 topic threads describing sources of Kratom (including 38 Internet vendors primarily from the United States, United Kingdom, Netherlands, and France), promotions from Web sites selling the herb, and online introductions to new forum participants. In addition, 72 total threads (42%) contained information on the pharmacology, dosing, and route of administration of Kratom. Twenty-seven threads described indications for Kratom; selected themes related to Kratom use are presented in Table 1. While a single thread described using Kratom as a stimulant and as an antidepressant, members overwhelmingly used Kratom for self-treatment of withdrawal from opioid analgesic agents.4 Despite the subjective nature of the study, there was a substantial agreement between coders (K ¼ 0.65, bias index 0.03, prevalence 0.88).
These data suggest striking increases in the use of Kratom to modulate opioid withdrawal by individuals who procure opioid analgesic agents from Internet pharmacies. A large proportion of Drugbuyer’s members self-treat chronic pain without physician supervision; the appropriation of responsibility for chronic pain management suggests that Drugbuyer’s members are committed to using, not quitting, opioids. At the same time, members distinguish themselves from addicts because drugs improve their ability to function rather than limit it.4 Because they patronize Internet pharmacies but shun physicians, pain clinics, and drug treatment centers, Drugbuyer’s members lie at the intersection of pain treatment and paths to abuse and addiction.4 To ameliorate the social and economic costs of chronic opioid analgesic abuse, Drugbuyer’s members take medication ‘‘holidays’’, or temporary periods of intentional abstinence, that are intended to decrease opioid tolerance as well as the cost of treatment once opioid therapy is resumed. At $10 to $40 per ounce of plant material (and a recommended dose of 1–8 grams), Kratom is an economical alternative to established opioid replacement therapies such as buprenorphine that are available from Internet pharmacies.12,13 Interestingly, the upsurge in mentions coincided with a 2005 U.S. National Drug Intelligence Center report describing potential applications for Kratom, including treatment of opioid withdrawal.11 The increased use of Kratom has led to its being listed as a drug of concern by the U.S. Drug Enforcement Administration. This exploratory study provides preliminary information on reasons for which Kratom is used; it does not, however, explain why some Drugbuyer’s members select a home remedy for opioid withdrawal in lieu of formal drug treatment programs. This preference may reflect the increasing interest in alternative therapies such as dietary supplements, herbal products, and others for chronic medical problems.14,15 Alternatively, Drugbuyer’s members may feel that their opioid use is not problematic, or that drug treatment is reserved for users of illicit substances. 4 In this vulnerable population, the utilization of and barriers to formal drug treatment, as well as the reasons for which pain treatment and addiction management clinicians have failed to engage members of this community, are unknown. This study highlights the potential of the Web as a tool for identifying emerging drug practices in hidden populations. Proposals that the systematic assessment of first-person reports of drug use episodes from online drug encyclopedias (e.g., ‘‘trip reports’’ on http://www.erowid. org) could identify sentinel drug use events have not borne fruit.16 For a number of reasons (e.g., a fraction of the trip reports submitted to online encyclopedias are selected for release, Webmasters stop releasing reports related to some common drugs, and submissions are edited by the Web site staff), online encyclopedias cannot provide systematic surveillance data on drug use behaviors. 17 Because submissions to Web sites such as Drugbuyers.com are automatically entered and undergo no screening, these messages offer a real-time glimpse at the drug-taking behaviors of the community populating that forum. Furthermore, the use of boardnames (a unique moniker by which individuals are known to the online community) on webforums confers additional advantages for drug use surveillance. For example, specific individuals who introduce new drug use information and behaviors to the online population can be identified. Because these persons may serve as opinion leaders for the virtual community, their effect on drug use knowledge, attitudes, and behaviors of the online population can be assessed. The dissemination of drug use information, as well as changes in drug use behavior, can, therefore, be tracked through social networks of Web-based drug users. We recognize that our data are preliminary and our study population is selective. Nonetheless, these findings raise important questions regarding the impact of the Internet on drug abuse behaviors of distinct populations. Understanding the relationship between online pharmacies, chronic pain, and Internet-based information on treatment for opioid withdrawal may be important to the generation of effective opioid analgesic abuse prevention strategies for maturing adults who suffer from chronic pain. Additional research in this area is urgently needed.
This research was supported by grant R21DA22677 from the National Institutes of Health, Bethesda, Md (Dr. Boyer).
1. Compton W, Volkow N. Major increases in opioid analgesic abuse in the United States: concerns and strategies. Drug Alcohol Depend. 2006;81:103–117. 2. Siegal H, Carlson R, Kenne D, Swora M. Probable relationship between opioid abuse and heroin use. Am Fam Physician. 2003;67:942–945. 3. Forman R. Availability of opioids on the Internet. JAMA. 2003;290:889. 4. Boyer E. Internet pharmacies and online opioid purchases. Community Epidemiology Work Group Annual Meeting. Phoenix, Ariz.: National Institutes on Drug Abuse; January 18–20, 2006. 5. Shellard EJ. Ethnopharmacology of Kratom and the mitragyna alkaloids. J Ethnopharmacol. 1989;25:123–124. 6. Shellard E. The alkaloids of Mitragyna with special reference. Bull Narc. 1974;26:41–55. 7. Yamamoto LT, Horie S, Takayama H, et al. Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa. General Pharmacology 1999;33:73–81. 8. Thongpradichote S, Matsumoto K, Tohda M, et al. Identification of opioid receptor subtypes in antinociceptive actions of supraspinallyadministered mitragynine in mice. Life Sci. 1998;62:1371–1378. 9. Matsumoto K, Yamamoto LT, Watanabe K, et al. Inhibitory effect of mitragynine, an analgesic alkaloid from Thai herbal medicine, on neurogenic contraction of the vas deferens. Life Sci. 2005;78:187–194. 10. Grewal K. Observation on the pharmacology of mitragynine. J Pharmacol Exp Ther. 1932;46:251–271. 11. Herbal drug update: Kratom. National Drug Intelligence Center 2005;4:4. 12. Siebert D. Available at: http://www.sagewisdom.org/kratomguide. html. Accessed 6 August 2007. 13. Psychoactive herbs. Available at: http://psychoactiveherbs.com/ catalog/index.phb?cPath=21_31. Accessed 6 August 2007. 14. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med. 1993;328: 246–252. 15. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a followup national survey. JAMA. 1998;280:1569–1575. 16. Condon T. Drugs, youth and the Internet. In: Conference on Drugs, Youth and the Internet. Bethesda, MD.: National Institutes on Drug Abuse; 2002. 17. Erowid E. Procedure for inclusion of trip reports on Erowid.org. In: Conference on Drugs, Youth and the Internet. Bethesda, MD.: National Institutes on Drug Abuse; 2002.