In describing their rationale for banning kratom, the DEA emphasized that kratom and mitragynines have been reported to produce some opioidlike effects. Most of the scientific evidence that kratom may have opioidlike activity is derived from the results of animal studies and ligand-binding studies, which have suggested that mitragynines may interact with opioid receptors.
1,3,24,25 In addition, anecdotal reports and commentaries indicate that some of the effects of kratom in humans resemble those of opioid agonist drugs.
4,5,26 Although no well-controlled clinical trials have been done, strong evidence demonstrates that the effects of kratom are actually quite different from those of classic opioids.
4,5,26 For example, at low to moderate doses, kratom has mild stimulant properties, unlike opioids, which are mainly sedating. In addition, kratom does not usually produce an intense high or euphoria.
1,2,13-15 Importantly, even at very high doses, kratom does not depress respiration.
4 At the molecular level, mitragynines are structurally quite different from traditional opioids such as morphine.
1,27 Moreover, recent studies indicate that even though the mitragynines can interact with opioid receptors, their molecular actions are different from those of opioids. In 2 elegant studies, Váradi et al
28 and Kruegel et al
29 showed that several mitragynine analogs acted as agonists at µ opioid receptors and antagonists at δ opioid receptors. Most notably, even though they activated the G-protein–mediated signaling pathway, much like traditional opioids, they did not “recruit” β-arrestin-2, which has been implicated as a mediator of opioid side effects and dependence.
30 Using a mouse model, Váradi et al
28 showed that kratom-based drugs had marked analgesic effects but with far fewer side effects, slower development of tolerance, and lower potential for dependence than morphine. Based on all of the evidence, it is clear that kratom and its mitragynine constituents are not opioids and that they should not be classified as such.