Kratom addiction per DSM-5 SUD criteria, and kratom physical dependence: Insights from dosing amount versus frequency.

BACKGROUND: Kratom products are widely used in the United States, with inadequate understanding of how dosing amounts/frequencies relate to outcomes. METHODS: Between July-November 2022, we enrolled 395 active US adult kratom consumers into a remote study with a baseline survey. We examined self-reported typical dose amounts and frequencies across people and product types, and their associations with outcomes: multiple regression was used to examine whether amounts and frequencies (doses/day) were associated with acute effects, withdrawal symptoms, scores on the Subjective Opioid Withdrawal Scale (SOWS), and addiction (operationalized as DSM-5-based symptoms of kratom-use disorder, KUD). RESULTS: Participants were 54.9% male, aged 38.1 on average, and 81.3% White. Mean length of kratom use was 5.7 years. Most (95.9%) reported regularly using whole-leaf kratom products; 16 (4.1%) reported regular extract use. SOWS scores were mild to moderate on average (13.5, SD 11.9). KUD symptom counts were mostly in the mild/moderate range (80.7%). Withdrawal and KUD symptoms were more closely associated with dose frequency than dose amount. Men reported more acute effects, withdrawal symptoms with cessation, and KUD symptoms than women. CONCLUSIONS: Greater dose amount and frequency were systematically related to the number of withdrawal symptoms upon cessation and to KUD symptoms; the relationship was stronger for dose frequency than amount. Men may have more acute effects and more withdrawal and KUD symptoms than women. Although kratom may be used nonproblematically by some consumers, physical dependence (tolerance, withdrawal, or use to avoid withdrawal) and KUD become more likely with increasing dose frequency.

An update on the clinical pharmacology of kratom: uses, abuse potential, and future considerations.

INTRODUCTION: Kratom (Mitragyna speciosa) has generated substantial clinical and scientific interest as a complex natural product. Its predominant alkaloid mitragynine and several stereoisomers have been studied for activity in opioid, adrenergic, and serotonin receptors. While awaiting clinical trial results, the pre-clinical evidence suggests a range of potential therapeutic applications for kratom with careful consideration of potential adverse effects. AREAS COVERED: The focus of this review is on the pharmacology, pharmacokinetics, and potential drug-drug interactions of kratom and its individual alkaloids. A discussion on the clinical pharmacology and toxicology of kratom is followed by a summary of user surveys and the evolving concepts of tolerance, dependence, and withdrawal associated with kratom use disorder. EXPERT OPINION: With the increasing use of kratom in clinical practice, clinicians should be aware of the potential benefits and adverse effects associated with kratom. While many patients may benefit from kratom use with few or no reported adverse effects, escalating dose and increased use frequency raise the risk for toxic events in the setting of polysubstance use or development of a use disorder.

Responses to a "Typical" Morning Dose of Kratom in People Who Use Kratom Regularly: A Direct-Observation Study.

INTRODUCTION: Use of kratom has outpaced systematic study of its effects, with most studies reliant on retrospective self-report. METHODS: We aimed to assess acute effects following kratom use in adults who use regularly, and quantify alkaloids in the products, urine, and plasma. Between July and November 2022, 10 adults came to our clinic and orally self-administered their typical kratom dose; blinding procedures were not used. Physiological measures included blood pressure, respiratory rate, heart rate, pulse oximetry, temperature, and pupil diameter. Subjective outcomes included Subjective Opioid Withdrawal Scale, Addiction Research Center Inventory, and Drug Effects Questionnaire. Psychomotor performance was also assessed. RESULTS: Participants were 6 men and 4 women, mean age 41.2 years. Nine were non-Hispanic White; 1 was biracial. They had used kratom for 6.6 years (SD, 3.8 years) on average (2.0-14.1). Sessions were 190.89 minutes on average (SD, 15.10 minutes). Mean session dose was 5.16 g (median, 4.38 g; range, 1.1-10.9 g) leaf powder. Relative to baseline, physiological changes were minor. However, pupil diameter decreased (right, b = -0.70, P < 0.01; left, b = -0.73, P < 0.01) 40-80 minutes postdose and remained below baseline >160 minutes. Subjective Opioid Withdrawal Scale pre-dosing was mild (5.5 ± 3.3) and decreased postdose (b = [-4.0, -2.9], P < 0.01). Drug Effects Questionnaire "feeling effects" increased to 40/100 (SD, 30.5) within 40 minutes and remained above baseline 80 to 120 minutes (b = 19.0, P = 0.04), peaking at 72.7/100; 6 participants rated euphoria as mild on the Addiction Research Center Inventory Morphine-Benzedrine-scale. Psychomotor performance did not reliably improve or deteriorate postdosing. CONCLUSIONS: Among regular consumers, we found few clinically significant differences pre- and post-kratom dosing. Alkaloidal contents in products were within expected ranges.

The Subject Is a Patient.

Although it is common in academic and government research settings to speak of study participants as "subjects," this perspective piece argues against doing so. In particular, the relationship of the study physician with study participants is unique and still retains many elements of the usual patient-physician relationship that exists in general clinical practice.

The Opioid Overdose Resuscitation Education for Addiction Counselors and Trainees (Opioid Overdose REACT) naloxone response education pilot project improved confidence and knowledge among addiction counselors and trainees.

INTRODUCTION: Community programs to teach nonmedical laypeople how to recognize an opioid overdose and effectively resuscitate the victim using naloxone have proliferated recently as a significant component of harm-reduction efforts. Although many such programs target laypeople like first responders or friends and family members of people who use drugs, there are currently no programs that specifically target addiction counselors, despite their work with a client population at high risk of an opioid overdose. METHODS: The four-hour curriculum designed by the authors covered opioid agonist and antagonist pharmacology; opioid toxidrome signs; legal implications and indications for using the naloxone kits; and hands-on training. Participants were two cohorts of addiction counselors and addiction counseling trainees at our institution and an affiliated Opioid Treatment Program methadone clinic. Surveys testing participant knowledge and confidence were conducted at baseline, immediately post-training, six months post-training, and 12 months post-training. RESULTS: Overall, opioid and naloxone pharmacology knowledge, as well as the confidence to intervene in an overdose emergency, improved among participants in both cohorts. Knowledge scores at baseline (n = 36, median 5/10) improved significantly immediately post-training (n = 31, median 7/10, P < 0.0001, Wilcoxon signed-rank test) and were sustained six (n = 19) and 12 months (n = 11) later. Two participants reported using their naloxone kits to successfully reverse a client overdose in the 12 months after taking the course. DISCUSSION: These results from our knowledge translation pilot project suggest that our educational program to train addiction counselors in opioid pharmacology and toxicology, allowing them to recognize and respond to an opioid overdose, is feasible and could be effective. Specific barriers to implementing such educational programs include cost, stigma, and unclear best practice for designing and conducting these programs. CONCLUSIONS: Further study of providing opioid pharmacology education and overdose and naloxone training to addiction counselors and counseling trainees appears to be warranted.

Examining the paradoxical effects of kratom: a narrative inquiry.

Introduction: Surveys and case reports have documented kratom use in the United States (US) for over a decade. However, those reports have generally not examined in depth the role kratom plays in the lives of those who use it regularly for sustained periods. Until there are controlled studies of the pharmacology and subjective effects of kratom alkaloids in humans, one of the best sources of insight on kratom-product use remains qualitative data with nuanced descriptions of kratom effects from those who use it regularly. Method: We conducted semistructured qualitative interviews with adults who regularly use kratom products, as part of a laboratory study of kratom-product self-administration. This qualitative component of the study was conducted as a narrative case-report series (n = 10). Results: Despite some differences among participants, all experienced acute combination effects that were largely, even simultaneously, analgesic and stimulatory. Most participants had decreased their dosages over time, and one planned to quit. Five of the 10 participants met DSM-5-based criteria for kratom-use disorder (3 mild, 1 moderate, 1 severe, by symptoms counts). When kratom was inadvertently taken in larger than intended doses, participants described a constellation of symptoms that they called "the wobbles" (a jittery feeling accompanied by what seemed to be nystagmus); this was rare, but could be of scientific and clinical interest as a possible manifestation of serotonin syndrome. Most participants described tolerance but considered kratom generally safe at low-moderate doses, providing perceived benefits with less potential risk for adverse effects compared to pharmaceuticals or illicit drugs. Discussion: In-depth interview data like these help confirm and clarify findings from larger survey studies and clinician-driven case reports. They are needed to inform the policy practice regarding kratom and may also help inform future experimental designs.

Decreased Clinical Toxicity and Two-Phase Elimination Kinetics Observed After Intravenous Iron Sucrose Overdose.

BACKGROUND: Management of oral iron overdoses is well-established, but there is limited literature regarding intravenous iron sucrose overdoses. Indications for administering deferoxamine after oral iron overdoses include clinical signs and symptoms of toxicity, along with a serum iron concentration ≥ 500 µg/dL. Reported signs and symptoms of iron sucrose overdose do not appear to correlate with those of oral iron overdoses. CASE REPORT: We present a case of intravenous iron sucrose overdose in a clinically well-appearing patient with a presenting serum iron concentration that was several times higher than the usual threshold concentration for initiating deferoxamine treatment. A 21-year-old woman presented to the emergency department after an accidental intravenous iron sucrose overdose. The patient received a home infusion of 1000 mg iron sucrose, which was five times the prescribed dose. Her presenting serum iron concentration was 1799 µg/dL, with bicarbonate and anion gap both within normal limits and an unremarkable physical examination. Because she did not have evidence of severe iron toxicity, she was treated supportively and deferoxamine was not administered. Her serum iron concentration decreased below the toxic range over the next 14 h, and she was discharged home the next day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This patient was managed successfully with expectant care alone, suggesting that iron sucrose overdose has much lower toxicity than oral iron salt overdose. This discrepancy between measured iron concentrations and clinical presentation may be explained by the elimination kinetics of iron sucrose having separate redistribution and elimination phases.

Rates and types of urine drug screen false negative results compared with confirmatory toxicology testing in major trauma patients.

BACKGROUND: Trauma centers are required to screen patients for alcohol use, and if necessary, intervene and refer to treatment (SBIRT). Similar screening for illicit drug use is recommended but not required. Urine drug screening (UDS) underestimates problematic substance use. This study aimed to estimate the types and rates of UDS false negatives (FN) compared to comprehensive testing by liquid chromatography-mass spectrometry (LC-MS) in trauma patients. METHODS: We performed a prospective cohort study of deidentified urine samples from adult trauma and burn activation patients. Both UDS and LC-MS comprehensive testing of >200 analytes were performed by a reference laboratory on all samples. Iatrogenic medications were excluded from the FN count. Crosstab analyses were conducted for UDS versus LC-MS outcomes to establish FN types and rates. We dichotomized the results by creating an "intentionality" variable (intentional injuries by self/others versus accidental injuries). A series of crosstabs with odds ratios considered intentionality by substance class and demographics. Statistically significant variables by Chi-Square were assessed by logistic regression. RESULTS: Psychoactive FN were detected in 56/100 urine samples analyzed; the most frequent included anticonvulsants (primarily gabapentin, N = 13), opioid agonists (N = 12), antihistamines (primarily diphenhydramine, N = 10), and phenethylamines (primarily bupropion, N = 5). Nonpsychoactive FN were detected in 70/100 samples; the most common were nicotine (N = 33), caffeine (N = 23), acetaminophen (N = 22), and antidepressants (N = 12). Of substance classes included in the UDS and also tested by LC-MS, FN occurred for opiates (3%), amphetamines (5%) and opioids (25%). Polypharmacy was associated with fall injuries in elderly patients. Cocaine (p = 0.015) and cannabinoids (p = 0.002) were significantly associated with intentionality. CONCLUSIONS: Our results indicate that FN for potentially important psychoactive and nonpsychoactive substances are common when toxicologic testing is limited to routine UDS in trauma patients. We recommend expanding SBIRT in this patient population to include misuse of tobacco products, prescription analgesics, and over-the-counter antihistamines.

Need for clarity and context in case reports on kratom use, assessment, and intervention.

This Letter to the Editor is a response to Broyan and colleagues who recently published a Case Report presenting data on 28 patients in the United States who identified kratom as their primary substance of use and who were subsequently induced on buprenorphine/naloxone for a reported diagnosis of kratom use disorder. We applaud the authors for helping to advance the science on kratom and recognize the difficulties in conducting kratom-related clinical assessment and research. However, a number of inconsistences and generalizations were identified in this Case Report, which also lacked some critical context. Importantly, such inconsistencies and generalizations can be observed throughout kratom-specific case reports. We feel this is now an important opportunity to highlight these issues that are present in the Broyan and colleagues Case report but emphasize that they are not unique to it. We do this with the hope that by acknowledging these issues it can help inform editors, clinicians, and researchers who may not be familiar with kratom and, as a result of this unfamiliarity, may inadvertently present findings in a manner that could confuse readers and even misinform clinical researchers and practitioners.

Failure of chelator-provoked urine testing results to predict heavy metal toxicity in a prospective cohort of patients referred for medical toxicology evaluation.

INTRODUCTION: Provoked urine testing (PUT), involving chelating agent administration prior to measuring urine metal excretion levels, is used by some alternative health care practitioners to diagnose patients with heavy metal poisoning. Multiple medical societies have advised against this practice due to its presumed unreliability, expense, and lack of validation. However, no prospective study of the predictive value of PUT for heavy metal poisoning has been undertaken. METHODS: This study utilized the Toxicology Consortium's prospective case registry to evaluate the reliability of PUT for diagnosing heavy metal poisoning. Inclusion criteria were toxicology clinic patients with PUT results who were subsequently evaluated by a board-certified medical toxicologist and had a determination made regarding whether their signs and symptoms were likely related or unrelated to toxicologic exposures. The primary outcome was the positive predictive value of PUT for heavy metal toxicity as diagnosed by the evaluating medical toxicologist. Patients presenting to participating toxicology clinics without PUT served as a comparison group. RESULTS: 74 of 106 cases presenting with PUT results met inclusion criteria and were analyzed. 15 cases were determined by the examining toxicologist to be likely related to a toxicologic exposure. Only three cases were found to be related to heavy metal exposure, giving a positive predictive value of 4.3%. 20.2% of patients with PUT were found to have signs or symptoms related to any toxicologic exposure, compared to 14.3% of clinic patients without PUT. Demographics of toxicology clinic patients with and without PUT results were not significantly different except for age. DISCUSSION: Our results provide empiric support that PUT is an inaccurate predictor of a diagnosis of heavy metal poisoning by a board-certified medical toxicologist. Given the inability to properly interpret PUT results along with the increased cost burden and risk of false positives, PUT should not be performed.

Comparison of Vitamin B12, Vitamin D, and Folic Acid Blood Levels in Plumbism Patients and Controls in Eastern Iran.

The aim of this study was to evaluate the blood levels of folic acid, vitamin B12, and 25-hydroxyvitamin D (25-OHD) in patients with lead poisoning compared with control subjects in Eastern Iran. This analytical case-control study was conducted on 40 lead-poisoned patients who were referred to Imam Reza Hospital in Birjand from 2018 to 2019. Blood samples were collected from an additional 40 individuals without lead poisoning as a control group. The results indicated that the mean vitamin B12, vitamin D, and folic acid levels for the case group were 356.5 ± 200.1 pg/ml, 24.38 ± 9.5 ng/ml, and 7.4 ± 3.7 ng/ml, respectively. Mean folic acid level in the case group was significantly lower than control group (7.4 ng/ml vs. 12.70 pg/ml, P = 0.001), whereas the mean of the vitamin D levels at the case group was significantly higher than that of the control group (24.3 ng/ml vs. 20.1 ng/ml, P = 0.03). Moreover, mean vitamin B12 levels were significantly lower in the case group in comparison with the control group (356.5 pg/ml vs. 500.8 pg/ml) (P < 0.001). In the control group, 3 patients had folic acid below normal level (< 6 ng/mL) while 12 cases had folic acid below normal (P < 0.05). Also, none of the control group had low vitamin B12 concentrations (< 180 pg/ml), while 7 cases had vitamin b12 below normal (P < 0.05). Our results suggest that lead may induce folate and vitamin B12 dysregulation. Although we found that vitamin D levels were insufficient in both case and control groups, they were significantly higher in the case group. The interpretation of this result is unclear given inconsistent literature reports on this relationship.

A Case Report of a Severe, Unusually Delayed Anaphylactoid Reaction to Intravenous N-Acetylcysteine During Treatment of Acute Acetaminophen Toxicity in an Adolescent.

INTRODUCTION: Anaphylactoid reactions are well-documented adverse events associated with the intravenous administration of N-acetylcysteine (NAC) in patients with acetaminophen overdose. Most reactions are mild, occurring within the first 1-5 hours of initiation. This report presents the case of an adolescent with a delayed, life-threatening anaphylactoid reaction 24.5 hours after starting NAC, where discontinuing NAC could have resulted in fulminant hepatic failure (FHF) and death. CASE REPORT: A 17-year-old previously healthy female presented with nausea, vomiting, and abdominal pain 10 hours after an acute acetaminophen ingestion. Her 11-hour serum acetaminophen concentration was above the treatment line (149 µg/mL), and she had elevated transaminases (AST = 202 U/L, ALT = 284 U/L). She was treated with intravenous NAC, which was suspended for 3 hours after she developed an apparent life-threatening anaphylactoid reaction with angioedema and respiratory distress 24.5 hours after treatment initiation. Given her high risk of progression to FHF, NAC was resumed at double the previous rate along with scheduled corticosteroids and antihistamines after resolution of her symptoms. Her AST increased to 10,927 U/L, and INR peaked at 3.6, but she had no further anaphylactoid symptoms. She was discharged in her normal state of health after 6 days. DISCUSSION: Discontinuing NAC in this case of severe, delayed anaphylactoid reaction could have resulted in FHF requiring liver transplant. The reason for her reaction is unclear but could be related to patient risk factors or medication error. Guidelines for reinitiation of NAC after development of delayed anaphylactoid reactions are not well-established.  Close observation beyond the first 1-5 hours of NAC administration is warranted.

Treatment of Kratom Withdrawal and Dependence With Buprenorphine/Naloxone: A Case Series and Systematic Literature Review.

INTRODUCTION: Some opioid use disorder (OUD) patients attempt to self-treat using herbal remedies such as kratom. However, kratom use itself can paradoxically cause physical dependence and OUD. Currently, there are no guidelines for treating patients with OUD stemming from kratom use. Our empirically-based hypothesis was that there would be a correlation between the amount of kratom used and the amount of buprenorphine-naloxone required for opioid agonist therapy. METHODS: This study includes a systematic review assessing treatment of kratom-dependent patients with buprenorphine-naloxone; a case series of our kratom-dependent patients; calculation of the correlation between the kratom dose and the buprenorphine-naloxone dose required to treat kratom-associated OUD; and our proposed starting doses for using buprenorphine-naloxone to treat kratom OUD. RESULTS: The OVID MEDLINE (1946-2020) database was searched using the terms "kratom," "buprenorphine," and "case report." This search yielded 3 relevant cases of patients having kratom OUD who were treated with buprenorphine-naloxone with the amounts of all substances reported. Review of the bibliographies, citing articles, and Google Scholar turned up three additional cases, yielding 6 literature cases that were analyzed. We also analyzed 2 patients from our clinic, giving a total of 8 patients included in the Pearson correlation coefficient calculation. We found a strong correlation of 0.84 between these variables, consistent with our hypothesis. CONCLUSIONS: Based on our analysis, patients using <20 g of kratom/d could be initiated on opioid agonist therapy with 4/1 mg-8/2 mg buprenorphine-naloxone/d, while patients using kratom doses >40 g/d could be initiated with 12/3 mg-16/4 mg of buprenorphine-naloxone/day.

A comparative analysis of kratom exposure cases in Thailand and the United States from 2010-2017.

Background: Interest in the Southeast Asian natural remedy kratom has increased in Western countries recently, along with increasing concern over its potential toxic effects.Objective: To describe and compare demographics, common co-exposure substances, clinical effects, treatments, and medical outcomes of kratom "abuse" exposures in the United States (US) and Thailand.Methods: This is a retrospective analysis of kratom "abuse" exposures, defined as use when attempting to gain a psychotropic effect, reported to the National Poison Data System (NPDS) in the US and the Ramathibodi Poison Center (RPC) in Thailand from 2010 to 2017. Multivariate analysis identified risk factors for severe medical outcomes, defined as both ICU admissions and death.Results: Nine-hundred-twenty-eight cases were included (760 from NPDS and 168 from RPC). A greater proportion of cases involved co-exposures in Thailand (64.8% versus 37.4%; odds ratio [OR] = 3.10, 95% confidence interval [CI] = 2.15-4.47, p < .01). Both countries had a similar prevalence of opioid and benzodiazepine co-ingestions, but the US had more co-ingestions with other sedatives (4.6% versus 0%, OR = 0, 95% CI = 0-0.47, p < .01). Common clinical effects included tachycardia (30.4%), agitation/irritability (26.2%), and drowsiness/lethargy (21.1%). Six deaths occurred, including one single-substance exposure in the US, three multiple-substance exposures in the US, and two multiple-substance exposures in Thailand. Severe medical outcomes were reported more frequently in the US (OR = 18.82, 95% CI = 5.85-60.56, p < .01).Conclusions: Despite lower frequencies of co-ingestants overall, US kratom abuse exposures yielded greater clinical severity. This disparity may be attributable to differences in the products labeled "kratom," greater sedative co-exposures in the US, and/or differences in population genetics or use patterns.