This Week in Addiction Medicine from ASAM

Lead: Examining the prevalence of mono-versus polysubstance use in the general population

Why do we focus on the exception and not the rule? Examining the prevalence of mono- versus polysubstance use in the general population.
Addiction
Most literature on substance use disorders (SUD) is focused on single drug classifications and does not typically include polysubstance use (PSU), particularly in treatment studies where persons with PSU are often excluded. Using the National Survey on Drug Use and Health (NSDUH) from 2015 to 2019 this study assesses the prevalence of PSU versus mono-use patterns. They found that among those who reported use of at least one substance in the last year, the majority (64%) reported mono-use, primarily alcohol use (90%). However, among those with 2 or more diagnostic criteria for SUD, mono-use was much less frequent (26%) and even less frequent among those who sought care for SUD (22%). Given these findings the authors contend research should include those with PSU whenever possible and consideration of PSU should be part of clinical evaluations and treatment.  
 
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Lead: Questioning the Right to Pain Relief and Its Role in the Opioid Epidemic

Lead Story:
 
Questioning the Right to Pain Relief and Its Role in the Opioid Epidemic
Mayo Clinic Proceedings
The Harrison Act of 1914 helped establish opioids as specific painkillers that had a distinct capacity to induce addiction. This understanding of opioids as having distinct and separable analgesic and addictive potential was challenged by the 1970s discovery of an endogenous opioid system, which integrates pain and reward functions to support survival.  Modern pain neurophysiology places the patient with pain in a passive position from which it makes sense to assert a right to pain relief. To prevent future opioid epidemics, the authors advocate for the abandonment of clinical outpatient use of pain intensity scores. They redefine the medical necessity of pain treatment as less about the reduction of pain intensity and more about the capacity to pursue personally valued activities.
 
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Lead: Xylazine effects on opioid-induced brain hypoxia

Xylazine effects on opioid-induced brain hypoxia
Psychopharmacology
Xylazine has emerged in recent years as an adulterant in an increasing number of opioid-positive overdose deaths in the United States. Although its exact role in opioid-induced overdose deaths is largely unknown, xylazine is known to depress vital functions and cause hypotension, bradycardia, hypothermia, and respiratory depression. This study examined the brain-specific hypothermic and hypoxic effects of xylazine and its mixtures with fentanyl and heroin in freely moving rats. It found that xylazine exacerbates the life-threatening effects of opioids, proposing worsened brain hypoxia as the mechanism contributing to xylazine-positive opioid-overdose deaths.
 
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Lead: Psychedelics reopen the social reward learning critical period

Lead Story:
Psychedelics reopen the social reward learning critical period 
Nature
Psychedelics have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies. This study demonstrates in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelic drugs. Notably, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Finally, identification of differentially expressed genes in the ‘open state’ versus the ‘closed state’ provides evidence that reorganization of the extracellular matrix is a common downstream mechanism underlying psychedelic drug-mediated critical period reopening.
 
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Lead: Reduced Stress-Related Neural Network Activity Mediates the Effect of Alcohol on Cardiovascular Risk

Lead Story: 
Reduced Stress-Related Neural Network Activity Mediates the Effect of Alcohol on Cardiovascular Risk
Journal of the American College of Cardiology
Chronic stress is associated with major adverse cardiovascular events (MACE) via increased stress-related neural network activity (SNA). Light/moderate alcohol consumption (ACl/m) has been linked to lower MACE risk, but the mechanisms are unclear. This study evaluated whether the association between ACl/m and MACE is mediated by decreased SNA. Individuals enrolled in the Mass General Brigham Biobank who completed a health behavior survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography, enabling assessment of SNA. Alcohol consumption was classified as none/minimal, light/moderate, or high (14 drinks/week, respectively).  ACl/m associates with reduced MACE risk, in part, by lowering the activity of a stress-related brain network known for its association with cardiovascular disease. Given alcohol’s potential health detriments, new interventions with similar effects on SNA are needed.
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Lead: Signaling-specific inhibition of the CB1 receptor for cannabis use disorder

Lead Story
Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials 
Nature Medicine
Cannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the first of a new pharmacological class, is a signaling-specific inhibitor of the cannabinoid receptor 1 (CB1-SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ9-tetrahydrocannabinol (THC) binding without modifying behavior per se. In mice and non-human primates, AEF0117 decreased cannabinoid self-administration and THC-related behavioral impairment without producing significant adverse effects. In healthy human volunteers with CUD, AEF0117 was well tolerated and did not precipitate cannabis withdrawal. These data suggest that AEF0117 is a safe and potentially efficacious treatment for CUD.
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Lead: Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression

Lead Story: 
Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression
The New England Journal of Medicine
While electroconvulsive therapy (ECT) has been used for several years for treatment-resistant major depression, ketamine has been relatively recently approved. The authors conducted an open label, randomized, noninferiority trial with 403 patients to compare the effectiveness of ketamine to ECT. The ketamine was found to be noninferior to ECT for treatment response as reported by decrease in depressive symptoms. Further, both were associated with improved quality of life, but the ECT group did have a greater decline in memory performance. Of note, this trial excluded patients with major depression with psychosis, and previous studies have found that ketamine is inferior to ECT among those patients.
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Special Episode: Why Patients Transition Off Methadone

Special Guests:
Ashish P. Thakrar and Jarratt D. Pytell
 
Article Referenced:  
Ashish P. Thakrar, Jarratt D. Pytell, Kenneth B. Stoller, Vickie Walters, Roger D. Weiss, Geetanjali Chander, Transitioning off methadone: A qualitative study exploring why patients discontinue methadone treatment for opioid use disorder, Journal of Substance Use and Addiction Treatment, Volume 150, 2023, 209055, ISSN 2949-8759. 
 
ASAM Resources: 
2020 National Practice Guideline for the Treatment of Opioid Use Disorder 
OUD Treatment Education 
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Lead: Increasing overdose deaths among Black Americans

Lead Story
Increasing overdose deaths among Black Americans: a review of the literature
The Lancet Psychiatry
This scoping review analyzed the many and varied factors contributing to the recent rise in opioid overdose death rates among Black Americans. Differences in structural and social determinants of health; unequal access, use, and continuity of SUD and harm reduction services; variability in fentanyl exposure and risk; and changes in social and economic conditions were all found to play a role. Black Americans historically are less likely to have access to treatment services than White Americans. Work to reform the criminal legal system, expand access, address provider bias, and fund equity-improving programs need to happen to affect change.
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Lead: Practice-Based Guidelines: Buprenorphine in the Age of Fentanyl

Lead Story
The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission 
JCI Insight
Evidence suggests that the glucagon-like-peptide-1 (GLP-1) system may be involved in the neurobiology of addiction. The authors studied the impact of semaglutide, a long acting GLP-1 analogue, on alcohol use in mice and rat models and found a decrease in binge-like alcohol drinking in both mice and rats. They also found  reduced alcohol intake in rates with dependence. The proposed mechanism for this effect is modulation of central GABA neurotransmission and supports the potential role of the GLP-1 system as a potential pharmacotherapeutic target for alcohol use disorder.  
 
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