In Southeast Asia, kratom has long been used for the management of pain and opium withdrawal.
6,9–11,14 In the West, kratom is increasingly being used by individuals for the self-management of pain or withdrawal from opioid drugs such as heroin and prescription pain relievers.
20,27 It is these aspects of kratom pharmacology that have received the most scientific attention. Although to our knowledge, no well-controlled clinical studies on the effects of kratom on humans have been published, there is evidence
30–38 that kratom, kratom extracts, and molecules isolated from kratom can alleviate various forms of pain in animal models. Studies have used a variety of methods including hot plate,
35,37,39 tail flick,
32,39 writhing,
37,38 and pressure/inflammation
35,38 tests in mice
32,35,38,39 and rats,
35,37 as well as more elaborate tests in dogs and cats.
35 In addition, a variety of chemical compounds have been isolated from kratom and shown to exhibit opioid-like activity on smooth muscle systems
31,33,34 and in ligand-binding studies.
39,40 Most notably, many of the central nervous system and peripheral effects of these kratom-derived substances are sensitive to inhibition by opioid antagonists.
31–34,39–41
Most of the opioid-like activity of kratom has been attributed to the presence of the indole alkaloids, mitragynine and 7-hydroxymitragynine. Both compounds have been shown to have analgesic and antinociceptive effects in animals, although 7-hydroxymitragynime is more potent.
30,32,40 These agents also produce opioid-like effects on organs such as the intestines and male internal genitalia.
33,34 Moreover, when they are given to animals for 5 days or longer, both compounds produce a state of physical dependence, with withdrawal symptoms that resemble those of opioid withdrawal.
31,32,41 In addition, ligand-binding studies and those using opioid antagonists indicate that these effects are largely mediated by means of actions on μ- and δ-type opioid receptors.
30,31,33 Along with these various central nervous system effects, kratom also appears to have anti-inflammatory activity.
38 Utar et al
42 recently found that mitragynine can inhibit lipopolysaccharide-stimulated cyclooxygenase-2 expression and prostaglandin E2 production. In addition to direct mediation by means of opioid receptors, the antinociceptive effects of mitragynine appear to involve the activation of descending noradrenergic and serotonergic pathways in the spinal cord.
43 Additionally, animal studies have shown that mitragynine may stimulate postsynaptic α
2-adrenergic receptors and possibly even block 5-hydroxytryptamine
2A receptors.
33 Although kratom contains lower levels of 7-hydroxymitragynine than mitragynine, it has been suggested that 7-hydroxymitragynine is more potent and has better oral bioavailability and blood brain-barrier penetration than mitragynine,
30,40 making it the predominant mediator of analgesic effects of kratom in the body.
Other compounds that have been isolated from kratom and implicated in some of its effects include speciociliatine, speciogynine, and paynatheine.
30,40 These compounds have been shown to modulate intestinal smooth muscle function and behavioral response in animals.
33,34,40,44 However, these effects were not inhibited by the opioid receptor antagonist naloxone, suggesting that they involve opioid-independent mechanisms.
40,44 It remains to be determined how these compounds may contribute to the overall actions of kratom in vivo.
In spite of the fact that kratom has been widely touted and used as a “legal opioid,”
23,31 few scientific studies have addressed the psychoactive properties of kratom.
6,9,11,12 Most of the available information is based on anecdotal reports and patient experiences. The general subjective effects of kratom have been summarized in various reviews.
6,9,12,30 In addition, many individuals have posted descriptions of their personal kratom experiences on Web sites such as Erowid, Sagewisdom, and WebMD.
24–26 As noted previously, kratom produces an unusual combination of stimulant- and opioid-like effects. These effects are highly dependent on the dose of kratom and can vary markedly from one individual to another. Low to moderate doses (1-5 g of raw leaves) usually produce a mild stimulant effect that most individuals perceive as pleasant but not as intense as those of amphetamine-like drugs.
24,25 Some individuals, however, report that these low-dose effects are mainly characterized by an unpleasant sense of anxiety and internal agitation.
24–26 It is noteworthy that those who have used kratom products for pain management tend to view the stimulant effects of kratom as being more desirable than the sedative effects of traditional opioids.
24–26
Opioid-like effects, such as analgesia, constipation, euphoria, and sedation are typically associated with the use of moderate-high doses of kratom (5-15 g). As with the lower-dose effects, the higher-dose effects may be either euphoric or dysphoric, depending on the individual. Of note, the euphoric effects of kratom generally tend to be less intense than those of opium and opioid drugs.
6,10,11,25 Nevertheless, kratom is still sought by drug users.