Kratom.org

Using kratom, an opioid-like plant, can lead to dangerous side effects, such as opioid withdrawal symptoms and euphoria, when combined with other opioids. Because of these risks, the Food and Drug Administration (FDA) recommends against the use of kratom for medical purposes. In addition, the FDA warns consumers against purchasing kratom products and has called for more research on the safety of kratom.

Kratom has been associated with opioid-like effects, including euphoria, pain relief, and reduced pain signals. However, these effects can also result in drowsiness, lightheadedness, and dry mouth. The main compounds in kratom, mitragynine and odt (an opioid metabolite), interact with opioid receptors in the brain, causing the effects of kratom.

Mitragynine inhibits cytochrome P450 (CYP) 3A and CYP2C9 in human liver microsomes (HLMs) by 24-47%. Mitragynine has been shown to interact with multiple opioid receptors. The CYP3A inhibition of mitragynine is concentration-dependent, and the IC50 value shifts leftwards in a concentration-dependent manner. This suggests that mitragynine may function as a reversible or nonreversible inhibitor of CYP3A. Alternatively, the CYP3A inhibition may be due to partial reversal of inhibition or increased microsomal binding. Whether or not these factors explain the decreased availability of mitragynine in the primary incubation could be a question of debate. source: kratom.org

Similarly, mitragynine inhibits CYP2D6 activity by 35%. A previous study reported that mitragynine acted as a reversible CYP3A inhibitor, and did not account for mitragynine as a time-dependent inhibitor. In the present study, mitragynine was used as a marker constituent to assess kratom-drug interactions. In addition to mitragynine, a second drug, odt, was added to the study cocktail to simulate the effects of kratom. 

In the present study, a physiologically-based pharmacokinetic model was used to evaluate the pharmacokinetic interactions of kratom and benzodiazepines. The model predicted that the risks of drug interactions would be primarily opioid-like, with the potential for euphoria, reduced blood pressure, and reduced concentration. This model is also applicable to other CYP2D6 drug substrates, and can be used to assess the interaction risks for kratom and other CYP2D6 drugs.

Kratom and benzodiazepines have been associated with the potential for drowsiness, lightheadedness, low blood pressure, and dry mouth. However, this may only be an effect of kratom, and not of benzodiazepines. Benzodiazepines are commonly prescribed for anxiety disorders. In the short term, benzodiazepines can suppress panic attacks, but in the long term they can result in reduced blood pressure and lightheadedness. In addition, because benzodiazepines require extremely high doses to cause toxicity, they may increase the risks of kratom-drug interactions.

The results from the kratom-drug interaction study indicated that kratom can have a reversible inhibition of CYP3A, and that this inhibition may be triggered by a low dose of kratom. This resulted in a more robust quantitative prediction of the risks of kratom-drug interaction. The models and the findings from this study can guide future kratom-drug interaction studies.

The CDC reported that over 22% of kratom overdose deaths involved benzodiazepines. In the United States, calls to poison control centers for kratom exposure increased 52-fold from 2011 to 2017. The FDA has recommended against the use of kratom for recreational purposes, and has warned consumers against kratom products. Despite these warnings, many people take kratom for its opioid-like effects, or for pain relief. In some cases, kratom users report giddiness, heightened sexual desire, lessened stress, and lessened anxiety.