This Week in Addiction Medicine from ASAM

Special Episode: The Future of Psychedelic Therapy and Addiction Treatment

Special Guest:
David E. Smith, MD, DFASAM
Editorial Referenced: 
The Future of Psychedelic Therapy and Addiction Treatment 
ASAM Resources: 
ASAM Clinical Guidelines
On-Demand Session: Psychedelics for Substance Use Disorders: Preparing for the Impending Paradigm Shift
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Lead: ASAM Clinical Considerations: Buprenorphine Treatment of Opioid Use Disorder

Lead Story
ASAM Clinical Considerations: Buprenorphine Treatment of Opioid Use Disorder for Individuals Using High-potency Synthetic Opioids 🔓
Journal of Addiction Medicine
This clinical considerations document is based on a narrative literature review and expert consensus and addresses considerations for changes to the clinical practice of treatment of opioid use disorder (OUD) with buprenorphine for individuals using high-potency synthetic opioids (HPSOs). Broadly, it suggests that individualized strategies for buprenorphine initiation may be needed. The experience of opioid withdrawal negatively impacts the success of buprenorphine treatment, and attention to withdrawal management before and during buprenorphine initiation should be proactively addressed. Buprenorphine dose and dosing frequency should be individualized based on patients’ treatment needs, the possibility of novel components in the drug supply should be considered during OUD treatment, and all forms of opioid agonist treatment should be offered and considered for patients.
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Lead: Recommendations for Reducing the Risk of Cannabis Use-Related Adverse Psychosis Outcomes

Lead Story: 
Recommendations for Reducing the Risk of Cannabis Use-Related Adverse Psychosis Outcomes: A Public Mental Health-Oriented Evidence Review 🔓
Journal of Dual Diagnosis
As legal controls liberalize around cannabis, the authors reviewed the literature about links between cannabis use and psychosis to make recommendations for consumers, health professionals, and policy makers to decrease risk of developing psychosis symptoms. The authors provide 11 recommendations and the level of evidence for each. Recommendations based on the most substantial evidence of linkage to psychosis include: 1) avoid use in adolescence (<16), 2) avoid cannabis with high tetrahydrocannabinol (THC) concentration, 3) limit frequency of use, 4) avoid use if experiencing psychosis symptoms or receiving treatment, and 5) avoid use if one has other risk factors for developing psychosis.
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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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