Kirsten Smith is conducting a clinical trial at the Johns Hopkins behavioral pharmacology research unit to evaluate the pharmacokinetics/pharmacodynamics and behavioral pharmacology of an acute dose of kratom, along with spontaneous kratom withdrawal from discontinued use among chronic kratom consumers. This is the first study to empirically evaluate kratom withdrawal symptoms.

The psychoactive botanical kratom is a relatively new substance to the United States, with the first documented use in 2004. Studying real-world kratom use among U.S. adults is what led Smith to investigate disordered use. With any substance that has rewarding and behaviorally reinforcing effects, it seemed only natural to start assessing people who use kratom for physical dependence symptoms (tolerance, withdrawal) and DSM-5-derived substance use disorder for kratom (KUD).

In absence of systemic studies in assessment, diagnosis and treatment of KUD, Smith co-authored the review paper, “Controversies in Assessment, Diagnosis, and Treatment of Kratom Use Disorder,” “to distill the available knowledge into an algorithm for decision-making” for the clinician to provide individualized patient care.

Do you have case studies to illustrate the decision-making algorithm proposed in the review paper?
KES: No. We have some systematic reviews and the review paper cited above in which two colleagues from the National Institute on Drug Abuse Intramural Research Program and I proposed one very simple algorithm, though it is not grounded in one particular case study. A few M.D.s and I will be presenting on KUD at the ASAM 2025 Conference, and will include several case studies to aid clinicians in their decision-making on treating patients who use kratom and who meet criteria for KUD. We will discuss the need for more complete case reports and clinical toxicology reports to be published to inform any decision-making algorithm. We encourage anyone attending ASAM 2025 to attend our full session.

Ultimately, such guides are only that - a guide - as the individual patient will inevitably have person-level characteristics (health, age), and factors related to their kratom and other substance use (over-the-counter and prescription meds, supplements, illicit drugs) that will inform clinical decision-making. In the US, the use of kratom is either occurring, on the one end, among fairly healthy adults or, on the other end of the spectrum, among people with complicated health histories and presentations. This latter group often has comorbidities and uses more than one substance.

What are key things that clinicians need to know about KUD?
KES: A noteworthy feature of KUD is that some of the hallmarks of severe addiction are not widely endorsed (e.g., physically hazardous use, use despite causing or worsening of symptoms, giving up important role obligations, etc.). After symptoms related to physical dependence, craving is the most common symptom.

Clinicians must assess KUD not only for kratom generally, but also ideally with a specifier for the type of kratom product used. Kratom products in the U.S. include whole-leaf and extract products. Some blended products contain kratom plus other psychoactive ingredients, such as kava or caffeine, which complicates KUD assessment and diagnosis. This context of product type, dose amount, formulation and even brand name, etc. are essential elements to capture as part of assessing kratom use or KUD at this time.

The products now under the broad “kratom” umbrella are growing and diversifying. A good analogy is to consider how CBD, Delta-8, Delta-9, cannabis, high-THC cannabis and synthetic cannabinoids all fall under a cannabis umbrella, but they could hardly be considered the same. Importantly, some products now advertised as “kratom” are not actually kratom (I appreciate this is confusing). Within the past year, there has been a rise in novel, semi-synthetic formulations of 7-hydroxymitragynine (7OH), which is an alkaloid found in trace amounts in some harvested kratom leaves but is more accurately classified as an active metabolite of kratom’s major alkaloid, mitragynine. These 7OH products are not considered to be kratom by any scientific experts on kratom.

These product details related to kratom-specific assessment for both use and KUD will be helpful to clinicians, along with documenting any co-morbid SUDs, remitted SUDs, and the patient’s history - as collectively they will inform what intervention might be used in KUD.

What are the recommended clinical assessment and diagnostic approaches to KUD?
KES: Although kratom is a relatively new substance to the United States and its pharmacology is quite unique, it is not unlike other substances with psychoactive properties with rewarding effects. Because kratom acts on multiple systems in the human body, with its alkaloids having alpha-adrenergic, opioidergic, serotonergic and dopaminergic (and possibly adenosinergic) activity, it is important that clinicians do not “lump” kratom into another classification. This has been done most often with opioids, wherein clinicians treat kratom as an opioid although there is little basis for this. While some kratom alkaloids act as partial agonists and mu opioid receptors (MOR), most of these have other activity, in particular kratom’s major alkaloid, mitragynine. Kratom alkaloids are structurally distinct from classical opioids.

As part of the baseline workup for a patient with suspected KUD, clinicians should obtain not only a urine drug screen immunoassay, but also confirmatory testing with chromatography-mass spectrometry that is able to detect (and ideally, also quantitate) kratom alkaloids. Of note, mitragynine (kratom’s major alkaloid) is typically the marker for kratom. “Kratom,” as a whole botanical, cannot be tested for.

To reemphasize, much of the published clinical case report in the area of kratom assessment and diagnostic methods is highly problematic. Clinicians are encouraged to write up case reports clearly documenting their methods of assessment and diagnosis.

What are the recommended treatment approaches for patients with comorbid KUD/OUD?
KES: Treatment of KUD should be individualized for each patient based upon their specific preferences, characteristics and comorbidities. To date, medication for opioid use disorder (MOUD), specifically buprenorphine or buprenorphine-naloxone, has been the most frequent approach for treating kratom-related physical dependence or addiction in the U.S. In most of these cases, the patients were also reported to have a comorbid OUD, making MOUD a clear approach despite the current lack of data showing the safety or efficacy of MOUD in the treatment of KUD.

In cases where a patient with KUD presents with comorbid OUD, use of MOUD (not only buprenorphine, but also naltrexone or methadone when deemed clinically appropriate) should be first-line treatment, as it is for patients with OUD and other comorbid SUDs, particularly in cases that are severe.

As we wrote in our KUD review paper, there is little specific information on whether patients with comorbid KUD/OUD benefit from augmentation of MOUD with behavioral therapies like contingency management or psychotherapy. Because the risk of relapse is so high for OUD patients in the absence of MOUD, it is likely best to use these along with behavioral therapies until or unless such therapies are studied and found to be effective as standalone therapies for U.S. adults with KUD.

What are the recommended treatment approaches for patients with isolated KUD?
KES: As we discussed in our paper, isolated KUD should be considered more akin to polysubstance SUDs, as kratom contains dozens of alkaloids, many of which have actions besides MOR binding. These include kappa and delta opioid antagonism, alpha-2 adrenergic agonism, 5-HT1A agonism, and perhaps adenosinergic antagonism, along with a complex array of dopaminergic actions (some possibly antidopaminergic). As such, patients with KUD may present with at least some OUD features mixed with other SUDs, such as stimulant use disorder. The serotonin activity of kratom is often underappreciated. Such complications do not negate the importance of identifying and treating the OUD-like aspects of the patient’s KUD.

Treatment of KUD that is isolated and without co-morbid OUD should not use MOUD as a first approach to treatment for the vast majority of KUD cases, which are mild-moderate (not severe), particularly if the patient is opioid naïve. Again, the type of kratom product used and the dosing frequency are important, along with symptom severity. I believe that in many cases, management of acute withdrawal symptoms may be best followed by outpatient or inpatient treatment. It may be that some patients need behavioral interventions, but this may not be the case for everyone, and patients who are stable after withdrawal may not need continued care or any medication. Again, the most prominent features of KUD to date are tolerance, withdrawal and craving. Helping patients taper from kratom with clinically appropriate supports is likely an ideal starting place for many with KUD.

An important exception to the above guidance relates back to novel products marketed as “kratom” that contain 7-hydroxymitragynine (7OH) as the primary ingredient. Patients who are evaluated as using kratom whole-leaf or extract products, but who also use 7OH products, might reasonably be considered as having both KUD and OUD, as 7OH is a highly selective MOR agonist with binding affinity 14-22 times more potent than morphine. This is a rapidly developing and clinically confusing point that clinicians need to increasingly keep in mind. It also underscores the need for rigorous assessment methods. Before DSM-5 KUD is assessed, patients should be screened for their use of any kratom-derived products across four subtypes:

• Kratom whole-leaf products
• Kratom extract products
• Blended kratom products (i.e., those that include kratom + kava or kratom + caffeine)
• Kratom-derived synthetic products (e.g., 7-hydroxymitragynine, 7OH, or “7”)

Like for any other substance, the details surrounding use motivations and patterns will be critical in helping to intervene. For some, kratom is used in a fairly normative, noneventful or even a net beneficial way. Indeed, the mere use of kratom should not be considered as disordered or problematic use. Many millions of people are using kratom without psychosocial impairments or addiction, even if they do have some mild physical dependence. Ultimately, it is important not to confuse kratom use with KUD. Because most kratom products sold will have alkaloids that act on multiple systems, the long-term treatment of KUD with pharmacotherapy is challenging, and intervention should be tailored to each patient.