For Better or Worse: Self-reported Changes in Kratom and Other Substance Use as a Result of the COVID-19 Pandemic.

Background: Kratom is taken to self-treat pain and symptoms of psychiatric disorders, including substance-use disorders (SUDs) and opioid withdrawal. Before COVID-19, kratom use was increasing in the US, however, there are few published data on whether that trend continued during the COVID-19 pandemic, which could have affected kratom use in multiple ways. Aim: To examine COVID-19-related changes in kratom use and how these changes were experienced, relative to changes in other commonly used substances. Methods: Using Amazon Mechanical Turk, 2615 evaluable surveys were completed between September 2020 and March 2021. Responses from past-month and past-year kratom-using adults (N = 174) indicating changes for the better or worse were examined using generalized linear mixed effects models, and relevant open-text responses (n = 85) were thematically coded. Results: For kratom 33% (n = 58) reported a Covid-related increase and 24% (n = 42) reported a Covid-related decrease. Controlling for changes in amount used, alcohol (OR = 5.02), tobacco (OR = 4.72), and nonmedical opioid use (OR = 3.42) were all more likely to have changed for the worse, compared with kratom use. Relative to decreases in kratom use, decreases in alcohol (OR = 3.21) and tobacco (OR = 6.18) use were more likely to be changes for the better. Cannabis use was the only substance to display a probability lower than 50% of being a decrease for the better, and of the increases, cannabis use displayed the highest probability of being for the better. Conclusions: Increases in kratom and cannabis use were less likely than alcohol and tobacco to be reported as changes for the worse, and decreases in kratom and cannabis use were more likely than alcohol and tobacco to be reported as changes for the better. These findings indicate that people differently conceptualize their relationships with kratom and cannabis, compared to their relationships with alcohol and tobacco.

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.

Kratom use as more than a "self-treatment".

Background: Mitragyna speciosa (kratom) is increasingly used in the United States for its pharmacological effects. Kratom's relative novelty makes for a dynamic situation, such that use motivations are not firmly established and may be changing. Investigators and clinicians require frequent updates on kratom trends.Objectives: To assess the current state of kratom-use initiation, sourcing, motivations, preference, conceptualizations, and perceived stigma, using survey responses from current and former users.Methods: Between April-May 2021 we recontacted 289 respondents who reported lifetime kratom use (on an unrelated survey) to answer kratom-specific questions.Results: The sample (N=129) was majority female (51.9%) and white (71.9%). Most (69.0%) reported first trying kratom after 2015. Mean age of use initiation (29.9 years) was older than for other substances, including opioids. Kratom ranked as a preferred substance by 48.5%. The strongest drug association with past-year kratom use was vaped nicotine (OR=3.31,95% CI 1.23-8.88). Use was less likely among those prescribed buprenorphine in the past year (OR=0.03, CI 0.01-0.28). Past-month cannabis use (OR=4.18,CI 1.80-9.72) had the strongest association with past-month kratom use. Over 40 use motivations were endorsed, many (but not all) supporting the "self-treatment" narrative of kratom use, including use as an opioid, alcohol, or stimulant substitute. Treatment shortfalls were associated with decisions to try kratom.Conclusions: Kratom use motivations are diversifying, with multiple factors driving use. As sales continue to increase, the public-health, clinical, and policy responses to kratom should be grounded in rigorous bench-to-bedside scientific research. Comprehensive study of kratom is currently lacking.

Getting "clean" from nonsuicidal self-injury: Experiences of addiction on the subreddit r/selfharm.

Background & Aims: Previous studies have shown that nonsuicidal self-injury (NSSI) has addictive features, and an addiction model of NSSI has been considered. Addictive features have been associated with severity of NSSI and adverse psychological experiences. Yet, there is debate over the extent to which NSSI and substance use disorders (SUDs) are similar experientially. Methods: To evaluate the extent that people who self-injure experience NSSI like an addiction, we coded the posts of users of the subreddit r/selfharm (n = 500) for each of 11 DSM-5 SUD criteria adapted to NSSI. Results: A majority (76.8%) of users endorsed at least two adapted SUD criteria in their posts, indicative of mild, moderate, or severe addiction. The most frequently endorsed criteria were urges or cravings (67.6%), escalating severity or tolerance (46.7%), and NSSI that is particularly hazardous. User-level addictive features positively predicted number of methods used for NSSI, number of psychiatric disorders, and particularly hazardous NSSI, but not suicidality. We also observed frequent use of language and concepts common in SUD recovery circles like Alcoholics Anonymous. Discussion & Conclusion: Our findings support previous work describing the addiction potential of NSSI and associating addictive features with clinical severity. These results suggest that NSSI and SUD may share experiential similarities, which has implications for the treatment of NSSI. We also contribute to a growing body of work that uses social media as a window into the subjective experiences of stigmatized populations.

Searching for a Signal: Self-Reported Kratom Dose-Effect Relationships Among a Sample of US Adults With Regular Kratom Use Histories.

There is limited understanding regarding kratom use among US adults. Although motivations for use are increasingly understood, typical kratom doses, threshold of (low and high) doses for perceived effectiveness, and effects produced during cessation are not well documented. We aimed to extend prior survey work by recruiting adults with current and past kratom exposure. Our goal was to better understand kratom dosing, changes in routines, and perception of effects, including time to onset, duration, and variability of beneficial and adverse outcomes from use and cessation. Among respondents who reported experiencing acute kratom effects, we also sought to determine if effects were perceived as helpful or unhelpful in meeting daily obligations. Finally, we attempted to detect any signal of a relationship between the amount of kratom consumed weekly and weeks of regular use with ratings of beneficial effects from use and ratings of adverse effects from cessation. We conducted an online survey between April-May 2021 by re-recruiting participants from a separate study who reported lifetime kratom use. A total of 129 evaluable surveys were collected. Most (59.7%) had used kratom >100 times and reported currently or having previously used kratom >4 times per week (62 weeks on average). Under half (41.9%) reported that they considered themselves to be a current "regular kratom user." A majority (79.8%) reported experiencing acute effects from their typical kratom dose and that onset of effects began in minutes but dissipated within hours. Over a quarter reported that they had increased their kratom dose since use initiation, whereas 18.6% had decreased. Greater severity of unwanted effects from ≥1 day of kratom cessation was predicted by more weeks of regular kratom use (ß = 6.74, p = 0.02). Acute kratom effects were largely reported as compatible with, and sometimes helpful in, meeting daily obligations. In the absence of human laboratory studies, survey methods must be refined to more precisely assess dose-effect relationships. These can help inform the development of controlled observational and experimental studies needed to advance the public health understanding of kratom product use.

Nonfatal opioid overdoses before and after Covid-19: Regional variation in rates of change.

BACKGROUND: The Covid-19 pandemic and its accompanying public-health orders (PHOs) have led to (potentially countervailing) changes in various risk factors for overdose. To assess whether the net effects of these factors varied geographically, we examined regional variation in the impact of the PHOs on counts of nonfatal overdoses, which have received less attention than fatal overdoses, despite their public health significance. METHODS: Data were collected from the Overdose Detection Mapping Application Program (ODMAP), which recorded suspected overdoses between July 1, 2018 and October 25, 2020. We used segmented regression models to assess the impact of PHOs on nonfatal-overdose trends in Washington DC and the five geographical regions of Maryland, using a historical control time series to adjust for normative changes in overdoses that occurred around mid-March (when the PHOs were issued). RESULTS: The mean level change in nonfatal opioid overdoses immediately after mid-March was not reliably different in the Covid-19 year versus the preceding control time series for any region. However, the rate of increase in nonfatal overdose was steeper after mid-March in the Covid-19 year versus the preceding year for Maryland as a whole (B = 2.36; 95% CI, 0.65 to 4.06; p = .007) and for certain subregions. No differences were observed for Washington DC. CONCLUSIONS: The pandemic and its accompanying PHOs were associated with steeper increases in nonfatal opioid overdoses in most but not all of the regions we assessed, with a net effect that was deleterious for the Maryland region as a whole.

Longitudinal patterns of momentary stress during outpatient opioid agonist treatment: A growth-mixture-model approach to classifying patients.

BACKGROUND: We previously showed, in people starting treatment for opioid use disorder (OUD), that stress is neither necessary nor sufficient for lapses to drug use to occur, despite an association between the two. Both theoretical clarity and case-by-case prediction accuracy may require initial differentiation among patients. AIM: To examine: (a) evidence for distinct overall trajectories of momentary stress during OUD treatment, (b) relationships between stress trajectory and treatment response, and (c) relationships between stress trajectory and momentary changes in stress and craving prior to lapses. METHODS: We used ecological momentary assessment (EMA) to collect ratings of stress and craving 3x/day for up to 16 weeks in 211 outpatients during agonist treatment for OUD. With growth mixture models, we identified trajectories of stress. We used mixed effect models to examine trajectory-group differences in the dynamics of stress and craving just before lapses to any drug use. RESULTS: We identified four trajectories of stress: Increasing (13.7 %); Moderate and Stable (23.7 %); Declining and Increasing (18 %); and Low (44.6 %). Overall drug use and opioid craving were lowest in the Low Stress group. Overall drug use was highest in the Moderate and Stable group. Alcohol use and opioid craving were highest in the Increasing Stress group. Opioid craving increased before lapse for most groups, but stress increased before lapses for only the Moderate and Stable group. CONCLUSION: There are natural groupings of participants with distinct patterns of stress severity during OUD treatment. Momentary stress/craving/lapse associations may be better characterized when these groupings are considered first.

Therapeutic benefit with caveats?: Analyzing social media data to understand the complexities of kratom use.

BACKGROUND: Mitragyna speciosa, referred to as "kratom", is increasingly used in the United States for self-treating pain, psychiatric, and substance use disorder symptoms. It is used by some to attenuate opioid withdrawal and as a longer-term drug substitute. Most self-report data have come from online surveys, small in-person surveys, and case reports. These may not be representative of the broader kratom-using population. PURPOSE: Analyze user-generated social media posts to determine if independent, descriptive accounts are generally consistent with prior U.S. kratom survey findings and gain a more nuanced understanding of kratom use patterns. METHODS: Reddit posts mentioning kratom from 42 subreddits between June 2019-July 2020 were coded by two independent raters. FINDINGS: Relevant posts (number of comments, upvotes, and downvotes) from 1274 posts comprised the final sample (n = 280). Of the 1521 codes applied, 1273 (83.69%) were concordant. Desirable kratom effects were described among a majority, but so too were adverse effects. Reports of kratom as acute self-treatment for opioid withdrawal were more prominent compared to longer-term opioid substitution. Quantitative analysis found higher kratom doses associated (p < .001) with greater odds of reported kratom addiction (OR = 3.56) or withdrawal (OR = 5.88), with slightly lower odds of desirable effects (OR = 0.53, p = .014). Despite perceived therapeutic benefits, kratom was characterized by some in terms of addiction that, in some cases, appeared dose-dependent. Polydrug use was also prominently discussed. CONCLUSIONS: Results validated many prior survey findings while illustrating complexities of kratom use that are not being fully captured and require continued investigation.

HIF-1α- Targeting Acriflavine Provides Long Term Survival and Radiological Tumor Response in Brain Cancer Therapy.

Tumor progression, limited efficacy of current standard treatments, and the rise in patient mortality are associated with gene expression caused by the synergistic action of intratumoral hypoxia and HIF-1α activation. For this reason, recent investigations have focused on HIF-targeting therapeutic agents, with encouraging preclinical and clinical results in solid tumors. Here we describe the efficacy of a HIF-1α inhibitor, Acriflavine, and demonstrate its potency against brain cancer. This safe antibacterial dye induces cell death and apoptosis in several glioma cell lines, targets HIF-1α-mediated pathways, and decreases the level of PGK1, VEGF and HIF-1α in vitro and in vivo. Administered locally via biodegradable polymers, Acriflavine provides significant benefits in survival resulting in nearly 100% long term survival, confirmed by MRI and histological analyses. This study reports preclinical evidence that this safe, small molecule can contribute to brain tumor therapy and highlights the significance of HIF-1α-targeting molecules.