StanleyH. Weiss

Objective: Patients with opioid use disorder (OUD) have impaired attention, inhibition control, and memory function. The aldehyde dehydrogenase 2(ALDH2) gene has been associated with OUD and ALDH2 gene polymorphisms may affect aldehyde metabolism and cognitive function in other substance use disorder. Therefore, we aimed to investigate whether ALDH2 genotypes have significant effects on neuropsychological functions in OUD patients undergoing methadone maintenance therapy (MMT). Methods: OUD patients undergoing MMT were investigated and followed-up for 12 weeks. ALDH2 gene polymorphisms were genotyped. Connors' Continuous Performance Test (CPT) and the Wechsler Memory Scale-Revised (WMS-R) were administered at baseline and after 12 weeks of MMT. Multivariate linear regressions and generalized estimating equations (GEEs) were used to examine the correlation between the ALDH2 genotypes and performance on the CPTs and WMS-R. Results: We enrolled 86 patients at baseline; 61 patients completed the end-of-study assessments. The GEE analysis showed that, after the 12 weeks of MMT, OUD patients with the ALDH2*1/*2＋*2/*2 (ALDH2 inactive) genotypes had significantly higher commission error T-scores (p= 0.03), significantly lower hit reaction time T-scores (p= 0.04), and significantly lower WMS-R visual memory index scores (p= 0.03) than did patients with the ALDH21*/*1 (ALDH2 active) genotype. Conclusion: OUD patients with the ALDH2 inactive genotypes performed worse in cognitive domains of attention, impulse control, and memory than did those with the ALDH2 active genotype. We conclude that the ALDH2 gene is important in OUD and is associated with neuropsychological performance after MMT.

Current healthcare policy in New Jersey (NJ) {1} and in several other states (New York [NY] {2}, Pennsylvania [PA] {3}, and New Mexico [NM] {4}) have included opioid use disorder as a qualifying condition under their medical cannabis programs. Several states have in part relied on a popularly cited statistic from the Bachhuber et al. {5} study in making this determination (including a review article that has emphasized it {6}, and which NJ in large part seems to have relied {1}); viz., their finding of an approximately 24.8% reduction in the expected number of opioid overdose deaths in states with medical cannabis laws compared to those without such laws during the eleven-year period 1999-2010. We have been concerned that these state-wide data, not being built upon individual level data, were ripe for bias as an ecological analysis. This new study by Shover et al. is an important advance in our knowledge on this issue. It illustrates some limitations of the Bachhuber study. Shover et al. comment upon the ecological fallacy issue. Shover and colleagues extended the time period of analysis up to 2017. They demonstrate a reversal in the trend of opioid overdose-related deaths in states with medical cannabis laws: a 23% increase in opioid overdose mortality. The authors do not claim that their findings demonstrate an adverse effect. Rather, their conclusion is that it is more likely that these findings are simply associations drawn from aggregate data, and that these studies are prototypical of a study design where the ecological fallacy pertains. The prior support for a beneficial effect of cannabis use, leading to a reduction in opioid overdose, has been demonstrated as not sustainable by the updated data. Those relying upon it, for determining suitable medicinal uses of cannabis, now need to reassess their policies and adequacy of justification. Several states have allowed opioid use disorder as a qualifying condition for their medical cannabis programs citing the Bachhuber et al. statistic. The new work by Shover et al. undermines that justification. We would recommend revision of those state policies, with the help of experts in the field who can critically review all of the existing data.

This article reports on a simple and straightforward way to improve the use of statistics in science.

The mu-opioid receptor (MOR) plays an important role in the rewarding properties of ethanol. In a series of animal experiments, the authors explored the issue of association between chronic alcohol use and MOR in response to opioids. Their finding in rats is that chronic ethanol drinking alters the ability of MOR to endocytose in response to opioid peptides, and thus promotes tolerance to the effects of opioids. If these findings were to be confirmed in human studies, especially of actual behavior, this would have important implications for treatment goals and thus would have ramifications for clinical practice. This study is an excellent example within the field of human addiction for how exploring basic science research in animal models may then apply to human studies and clinical applicability, and thus is a great teaching example.

There are innumerable methodological weaknesses to this article. This study purports to be a nested case-control analysis. It disputes the findings from a large, well performed double-blind clinical trial published in the New England Journal of Medicine the preceding year {1}. The authors of the current study mis-interpret and mis-represent several aspects of that trial. A primary finding of that clinical trial was "risk of moderate or severe exacerbations" were similar among those who discontinued inhaled glucocorticoids as compared to those who continued. In an accompanying editorial {2} and in correspondence several months later (several letters -- {3}) this is not under dispute. Among the limitations of the current study are the following: In this current study, the authors do not know whether patients in fact ever took a prescribed medication, nor any specific aspects about its use (such as when it might have actually been stopped, or whether it was tapered). Many physicians do taper steroids in patients. In the NEJM study, the description of who was eligible makes it clear that they could be anticipated to be sicker and have a higher frequency of the outcomes of interest as compared to the authors' study; thus the difference in rates is far from a surprise. In this current study, few details on the specifics of the methodology are given, nor the problems encountered, nor their rationale concerning how they handled such problems. They do not describe their matching algorithms, and seem to assume neither false positive nor false negative matches. It could be anticipated that they would not be able to find 10 properly matched controls given the size of the study (only a bit bigger than 10 times the number of cases!), and indeed they admit they even found no matches for some cases at all; but how many is not enumerated. The controls had a prior history of the outcome of interest excluded: so, again it is not surprising that their controls had lower rates of outcomes than cases over their observation period. There are over a dozen major methodological issues, as well as clear mis-characterization or mis-understandings of literature they cite and describe. In my opinion, the reader's confidence in this single study should be low. It would be wise to defer implementing their findings to influence clinical practice until others using other, more robust study designs confirm them -- especially as the aforementioned randomized trial had very disparate findings.

The third member of the family of human T-cell leukemia (lymphotropic) retroviruses, HTLV-III, has emerged as the likely etiologic agent of the acquired immunodeficiency syndrome (AIDS).^1,2 There is a recognized need for a serological assay for HTLV-III that could be used for epidemiologic studies and screening of defined populations. Ideally, such a test would be reproducible, specific, sensitive,³ relatively inexpensive, timely, and noninvasive.…