Kratom

Kratom (Mitragyna speciosa) is a medicinal leaf harvested from a large tree native to Southeast Asia in the Rubiaceae, first documented by Dutch colonial botanist Korthals. It is botanically related to the Corynanthe, Cinchona and Uncaria genera and shares some similar biochemistry. It is in the same family as coffee, and the psychoactive plant Psychotria viridis. Other species in the Mitragyna genus are used medicinally in Africa, and also used for their wood.

It is used for its psychoactive effects in its native region, with some use elsewhere in the world. In Southeast Asia the fresh leaves are usually chewed, often continuously, by workers or manual laborers seeking a numbing, stimulating effect. Elsewhere, the leaves are often made into a tea or extracted into water and then evaporated into a tar that can be swallowed. Kratom is not often smoked, although this method does provide some effect.

Kratom contains many alkaloids including mitragynine (once thought to be the primary active), mitraphylline, and 7-hydroxymitragynine (which is currently the most likely candidate for the primary active chemical in the plant). Although structurally related to yohimbine and other tryptamines, its pharmacology is quite different, acting primarily as a mu-opioid receptor agonist. It also shares some adrenergic receptor activity similar to that of yohimbine. Kratom also contains alkaloids found in uña de gato, which are thought to play a beneficial role on the immune system and lower blood pressure, as well as epicatechin, a powerful antioxidant also found in dark chocolate and closely related to the EGCG that gives green tea its beneficial effects. Other active chemicals in kratom include raubasine (best known from Rauwolfia serpentina) and some yohimbe alkaloids such as corynantheidine.

Kratom has many potential medicinal uses, for example as a low grade analgesic comparable to codeine or propoxyphene, as an alternative to methadone, and as a source of other chemicals with a wide range of beneficial activities which could be isolated from the psychoactive constituents.

Effects
Kratom's pharmacology shares some elements of the activity of other substances including opiates and yohimbine. The comparison to opiates is valid at doses high enough to produce these effects. Kratom has the ability to alleviate withdrawal in people dependent on opiates owing to the mu receptor agonism of mitragynine and 7-hydroxymitragynine. Kratom may cause constipation at these doses. It produces analgesia similar to weaker opiates such as codeine. Kratom also has a yohimbe-like stimulant activity, and uncaria-like immunostimulant activity. Kratom's effects are reported to be relatively short-lived, typically fading after a few hours. Some experience nausea after drinking kratom tea; this may in large part be due to the extremely bitter taste which can be remedied with a teaspoon of hot chocolate or cocoa per mug.

Addiction and Habituation
Kratom use is potentially habit-forming, and people who use it continuously may experience withdrawals upon cessation. Ethnological researchers conducting a survey of long-time kratom users in Southeast Asia reported a belief that users may develop dark patches of skin discoloration on their cheeks, however there seems no actual documentation of this occurring. No long term human studies have been done, so any assessment of long term consequences of kratom must be extrapolated from animal studies and the few reports from anthropologists.

The potential addictiveness of kratom's primary active component, 7-hydroxymitragynine has been demonstrated in a study by Matsumoto et al. In an animal model, this study demonstrated tolerance, cross-tolerance with morphine, and naloxone-precipitated withdrawal from 7-hydroxymitragynine. The withdrawal symptoms were nearly identical to those from morphine, indicating that the drug might produce dependence in humans similar to other opiates. Anecdotal evidence (see next paragraph) would seem to lend credence to this theory; however, no human research has been done and many of those people reporting addiction are using kratom either as a home remedy for opiate addiction or in conjunction with an ongoing opiate dependence, which makes scientifically definitive claims difficult at this time.

Anecdotal evidence of kratom helping with opiate withdrawal is widespread on the Internet, most often found in various chat forums that are either dedicated to kratom or recreational drug use in general. However some people claim that the kratom withdrawal syndrome resembles that of opiates, only milder and shorter-lasting. Some people have mentioned mild depression following cessation of physical symptoms, and have noted that this makes quitting kratom use very difficult. The physical withdrawal symptoms most often noted are fatigue and agitation. Other opiate-like withdrawal symptoms have been mentioned (e.g. sweating, chills, diarrhea) but are apparently much milder and less common than those caused by withdrawal from opiates, if in fact they appear at all. Physical symptoms of kratom withdrawal seem to last up to four or five days, then cease completely. Other than the aforementioned depression, protracted withdrawal episodes are rarely mentioned.

Minor Alkaloids
It is interesting to note that whole Mitragyna speciosa leaf also contains a partial mu-opioid agonist (9-hydroxycorynantheidine), and a mu-opioid antagonist (corynantheidine). The combination of a full agonist (such as 7-hydroxymitragynine and Mitragynine) with an antagonist or partial agonist may be compared to the use of partial opioid-agonists to interrupt opiate addiction. Buprenorphine is one such example of a partial agonist/antagonist that is FDA approved to treat addiction. It may be that ingesting whole kratom does not have the same addictive potential as 7-OHM alone.

Furthermore, kratom contains at least one alkaloid (rhynchophylline) that is a calcium channel blocker, and reduces NMDA-induced current. There is considerable research as to the role of NMDA receptor activity in the formation of dependence, and the symptoms of withdrawal. In 2005, Inturrisi demonstrated that co-administration of d-methadone (the isomer that lacks opioid activity, but is an NMDA antagonist) in small doses with morphine prevented the development of morphine tolerance in rats. The presence of rhynchophylline in kratom should be investigated in order to determine its potential to modify the development of dependence.

Legal Status
Kratom is a controlled substance in Thailand, Australia, Malaysia and Myanmar (Burma). A handful of people in Malaysia and possibly other countries are lobbying their governments to allow medical research into kratom as a potential prescription substance. However as of January 2007, Malaysia is moving to make kratom more illegal rather than less, and plans to reclassify it under the dangerous drugs law rather than the less severe poisonous substances laws.

The U.S. Drug Enforcement Administration has become aware of kratom in recent months, and has added it to their list of "Drugs and Chemicals of Concern." This list does not appear to indicate anything other than that the DEA has noticed the existence of a substance and has come to believe it may be a problem of some sort.