DEA Drugs and Chemicals of Concern: Kratom

In February 2008, I received an inquiry from a colleague in the San Francisco Bay area who was treating a patient for kratom dependence. I had only a distant memory of this substance and; as it turns out a very mistaken one. I was under the impression that kratom leaves are a mild stimulant used in Southeast Asia like betel nut or like khat in the Middle East. Yet, my colleague was treating his patient with Suboxone® for kratom withdrawal symptoms resembling those found in opioid dependence. As I thought about this I recalled a “short communication” article that I had reviewed in 1988 for the Journal of Psychoactive drugs regarding contradictory psychoactive properties of kratom use. (KRL Jansen and CJ Prast, 1988. Psychoactive properties of mitragynine (kratom), J. Psychoactive Drugs, 20(4):455-457). In revisiting this article, I find contradictions in how some researchers describe the effects of kratom as similar to opium, leading to stupor and habitual use while others found its leaves to be a stimulant like cocaine – chewed, swallowed like tea, or occasionally smoked to increase work output and tolerance to intense sunlight.I was unaware of kratom use migrating to the U.S., so on a whim I logged on to the Drugs and Chemicals of Concern web site and was surprised to see that it was, indeed, listed. Although I might have missed its listing on my past visits to the site, I believe that kratom is a fairly recent addition. Kratom, Salvia divinorum and dextromethorphan were the three non-controlled, non-prescription, psychoactive substances of concern listed.

Some claim that kratom (Mitragyna speciosa) has been used by humans for thousands of years in Thailand and Malaysia where it grows indigenously. It is a tree from the same botanical family (Rubianceae) as the coffee tree and grows up to 50 feet tall. Its leaves are used in low doses (2-6 gm) as a stimulant or in high doses (16-25 gm) as a sedative. Other uses include easing pain, treating opiate addiction and diarrhea, and use as a recreational drug. Although over 25 alkaloids have been identified in kratom leaves, the three principal ones are: mitragynine (9-methoxy-corynantheidine), mitraphylline, and 7-hydroxymitragynine. Recent research indicates 7-hydroxymitragynine is the primary active chemical and that it is more powerful than morphine (KM Babu, CR McCurdy and EW Boyer, 2008. Opioid receptors and legal highs: Salvia divinorum and kratom. Clin Toxicol (Phila), 46(2):146-152). Although this alkaloid is structurally more related to yohimbine and other tryptamines, it is a powerful mu and delta opioid brain receptor agonist like buprenorphine (found in Suboxone®). Suboxone® is one of the major medications used in the treatment of heroin and other opioid addictions. It is fascinating that both Mitragyna speciosa and Salvia divinorum contain chemicals that stimulate the brain’s opioid receptors though neither is botanically or chemically related to the opioids. Salvinorin A, the non-alkaloid psychoactive chemical of Salvia divinorum is the primarily chemical responsible for most of its psychedelic effects. Salvinorin A has been found to be a powerful kappa opioid receptor agonist. (KM Babu, CR McCurdy and EW Boyer, 2008, Opioid receptors and legal highs: Salvia divinorum and kratom. Clin Toxicol (Phila), 46(2):146-152)

Stimulant effects from chewing 2 to 6 gm of kratom leaves occur within 5 to 10 minutes. If it is ingested as a tea, mixed with fruit juice, or made into a cola mixture the onset of action is delayed from 20 to 40 minutes. This dosage is described as making the mind more alert, while at the same time increasing both physical and sexual energy in the user. Users describe themselves as more sociable, friendly and talkative though also a bit edgy. Laborers chew kratom leaves to sustain them during hard monotonous physical tasks. Effects last for 2 to 5 hours.

Stimulant-like effects or euphoric-sedative-analgesic effects are attributed to medium dosages of 7 to 15 gm of kratom leaves while opioid-like euphoric-sedative-analgesic effects that last about 6 hours occur at dosages of 16 to 25 gm. Users say they are less sensitive to pain, sedated, euphoric (comfortable pleasure), and experience a dreamy reverie with greater appreciation of music. Negative effects at this higher dosage are very similar to those from opioids: sweating, itchiness, pupil constriction, constipation, nausea and potential hangover. Advocates of kratom use are quick to point out that the dosage schedule delineated for use does not apply to the recent rash of extract products currently found on the Internet. These extracts are alleged to be 8, 15 or even 35 times as potent as kratom leaves. Those who promote kratom use also warn that the natural leaves may vary in potency and some individuals may be more sensitive to its effects. It should not taken with other drugs, it should not be used if pregnant, while driving, or prior to a potentially hazardous situation that requires focus or alertness. (D Siebert, The Kratom User’s Guide, http://www.sagewisdom.org/kratomguide.html accessed 3/6/08)

The major drawback to kratom abuse is its ability to induce opioid-like tissue dependence with a significant withdrawal syndrome when it is used at high doses on a daily and chronic basis. Long-term use of kratom has been shown to produced anorexia, weight loss, insomnia, skin darkening, dry mouth, frequent urination, and constipation. The kratom withdrawal syndrome consists of symptoms of hostility, aggression, emotional labilitly, wet nose, achy muscles and bones, and jerky movement of the limbs. Some kratom addicts also exhibited psychotic symptoms that included hallucinations, delusion and confusion. (http://www.deadiversion.usdoj.gov/drugs_concern/kratom.htm, accessed 3/6/08)

Since kratom dependence appears to be related to its agonist effects at the opioid mu receptor, I look forward to my San Francisco colleague’s report on the effectiveness of using buprenorphine (Suboxone®) to treat kratom addiction. Similarly, various internet sites claim that kratom has been used effectively to treat other opioid drug dependencies including buprenorphine dependence (EW Boyer, KM Babu, GE Macalino, 2007, Self-treatment of opioid withdrawal with a dietary supplement, Kratom. Am J Addict, 16(5):352-356).

At least 4,000 plants and fungi have been found to produce interesting psychoactive chemicals. The vast majority of these plants or the psychoactive chemicals they contain have never made it to the DEA’s list of Drugs and Chemicals of Concern. I have forgotten how fascinating these natural psychoactive substances can be and can’t help but believe that researching them will ultimately lead science to new and even more enthralling neurotransmitters in our brains. Such discoveries have great potential to either provide us with a better understanding or further baffle our understanding of the human mind.

Darryl S. Inaba, PharmD., CADC III