From the Editor
For many of our patients, the pull of alcohol can be strong with devastating effects. In recent months, semaglutide, better known for its weight-loss properties, has generated some buzz. Could semaglutide help those with alcohol problems?
In the first selection, Christian S. Hendershot (of the University of Southern California) and his co-authors attempt to answer that question in a new paper for JAMA Psychiatry. They conducted an RCT with 48 participants randomized to semaglutide or placebo over nine weeks, measuring alcohol consumption and craving outcomes, and finding that people taking semaglutide consumed less alcohol by some measures. “These findings provide initial prospective evidence that low-dose semaglutide can reduce craving and some drinking outcomes, justifying larger clinical trials to evaluate GLP-1RAs for alcohol use disorder.” We consider the paper and its implications.
In the second selection, Joshua L. Gowin (of the University of Colorado) and his co-authors explore the impact of heavy lifetime and recent cannabis use on brain function in a new paper for JAMA Network Open. They analyzed data from more than 1 000 young adults, including brain imaging, focusing on tasks administered during fMRIs sessions. “Cannabis use is associated with short- and long-term brain function outcomes, especially during working memory tasks.”
Finally, we explore the latest news with articles from The New York Times and The Free Press, and a new report from the Brookings Institution. The topics: Oregon’s decriminalization, Robert F. Kennedy’s nomination, and decriminalization across North America.
DG
Selection 1: “Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial”
Christian S. Hendershot, Michael P. Bremmer, Michael B. Paladino, et al.
JAMA Psychiatry, 12 February 2025
Alcohol use is a leading modifiable cause of morbidity and mortality, accounting for an estimated 4% to 5% of disease burden and 2.6 million deaths per year globally. Alcohol is causally linked to more than 200 medical and disability conditions, with increased risks of common diseases (including cardiovascular disease, liver disease, and cancers) accounting for a large proportion of alcohol-related morbidity… While roughly 29% and 11% of US adults meet lifetime and past-year criteria for alcohol use disorder (AUD), respectively, less than 10% of those with AUD report past-year treatment and less than 2% receive pharmacotherapy, defining one of the largest known health care treatment gaps…
Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are incretin mimetic therapies with exceptional efficacy for the treatment of diabetes and obesity. Semaglutide, a long-acting GLP-1RA with superior efficacy to older GLP-1RA medications, received FDA approval for diabetes in 2017 and obesity in 2021. Rapidly increasing prescription rates have been accompanied by reports of reductions in alcohol use and craving during treatment. These observations were predated by substantial preclinical evidence that GLP-1RAs reduce voluntary alcohol consumption and attenuate alcohol reinforcement, suggesting potential clinical applications of GLP-1RAs for AUD.
So begins a paper by Hendershot et al.
Here’s what they did:
- They conducted a prospective phase 2 randomized clinical trial to evaluate the effects of semaglutide in non–treatment-seeking adults with AUD.
- Enrollment, which occurred at a US academic medical center, took place from September 2022 to February 2024.
- “Participants received semaglutide (0.25 mg/week for 4 weeks, 0.5 mg/week for 4 weeks, and 1.0 mg for 1 week) or placebo at weekly clinic visits.”
- The primary outcome: laboratory alcohol self-administration. Secondary outcomes included changes in alcohol consumption and craving.
- In terms of the self-administration: “Participants were presented with their preferred beverage and brand and could elect to delay drinking for up to 50 minutes for monetary reinforcement. Thereafter, participants were instructed to consume at their preferred pace to achieve preferred effects over 120 minutes.”
Here’s what they found:
- A total of 504 individuals were assessed, with most excluded due to eligibility criteria. 48 participants were randomized.
- Demographics. 71% were female; the mean age was 39.9 years; most had BMI greater than 30 (n = 27) or 25.0-29.9 (n = 20). On average, participants endorsed moderate AUD severity.
- Consumption. “Low-dose semaglutide reduced the amount of alcohol consumed during a posttreatment laboratory self-administration task, with evidence of medium to large effect sizes for grams of alcohol consumed (β, −0.48…) and peak breath alcohol concentration (β, −0.46…).”
- Drinks. “Semaglutide treatment did not affect average drinks per calendar day or number of drinking days, but significantly reduced drinks per drinking day (β, −0.41…) and weekly alcohol craving (β, −0.39…), also predicting greater reductions in heavy drinking over time relative to placebo (β, 0.84…).”
A few thoughts:
1. This is a good study published in an impressive journal.
2. The main findings in a sentence: “Over 9 weeks of treatment, semaglutide led to reductions in some but not all measures of weekly consumption, significantly reduced weekly alcohol craving relative to placebo, and led to greater relative reductions in cigarettes per day in a subgroup of participants with current cigarette use.”
3. The result is promising.
4. That said, we need to maintain perspective.
5. Start here: the study used laboratory conditions. Remember: participants spent two hours in a lab room surrounded by alcohol – not quite “real world” conditions. As well, most participants had moderate severity alcohol use disorder. What about those with severe AUD?
6. In The New York Times, W. Kyle Simmons (of Oklahoma State University) comments on the amount of research being conducted: “you can’t even keep up.” Well said. That article, by the way, mentions five different studies. No doubt, our understanding of semaglutide and alcohol will be better informed in the coming months. (Of course, some of this research may be affected by NIMH program cuts.)
7. Like all studies, there are limitations. The authors note several, including: “Among several study limitations are the modest sample size and short-term treatment duration, both reflecting the phase 2 stage of this trial.” The study also lacked gender balance.
8. Many thanks to Dr. Tony George for helping me understand this study better.
The full JAMA Psych paper can be found here:
https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2829811
Selection 2: “Brain Function Outcomes of Recent and Lifetime Cannabis Use”
Joshua L. Gowin, Jarrod M. Ellingson, Hollis C. Karoly, et al.
JAMA Network Open, 28 January 2025
As more states and countries have legalized the production and sale of cannabis for recreational and medical use, there has been an associated increase in the potency of cannabis products, cannabis use rates, and prevalence of cannabis use disorder… Despite these negative effects, there is an increasing perception that cannabis is harmless. Thus, better understanding of recent and long-term effects of cannabis is critical for informing public health policies. Meta-analytic evidence indicates that short-term effects of cannabis include decreases in cognitive performance (eg, episodic verbal memory), but these reductions may not persist after 72 hours of abstinence…
Numerous brain imaging studies have examined the effects of cannabis on brain function. For example, relative to nonusers, frequent cannabis users showed a greater response to cannabis cues in the striatum and medial PFC, and activation of these regions correlated with cannabis craving. There may also be developmental interaction effects. For example, individuals with cannabis dependence, relative to matched control participants, showed greater functional connectivity density (ie, hyperconnectivity with surrounding regions) in the ventral striatum, and effects were more pronounced in individuals who began cannabis use earlier in life. Evidence has indicated that cannabis use reduces neural activation related to memory, executive function, emotion, reward processing, and social processing, but most of these previous studies had fewer than 30 participants with cannabis use history.
Here’s what they did:
- They conducted a cross-sectional study drawing data from the Human Connectome Project (collected between August 2012 and 2015).
- Young adults (aged 22-36 years) were included with magnetic resonance imaging (MRI), urine toxicology, and cannabis use data.
- History of heavy cannabis use was assessed using the Semi-Structured Assessment for the Genetics of Alcoholism, and they had greater than 1 000 uses.
- Main outcome: “Brain activation was assessed during each of the 7 tasks administered during the functional MRI session (working memory, reward, emotion, language, motor, relational assessment, and theory of mind).”
Here’s what they found:
- 1 003 adults participated.
- Demographics. The mean age was 28.7 years; most were women (53.1%) and White (76.0%).
- Use. For lifetime history criteria, 8.8% of participants were classified as heavy cannabis users, 17.8% as moderate users, and 73.4% as nonusers. Heavy lifetime users were more likely to be male, to have lower income, and to have lower levels of education than nonusers.
- Heavy use. “Heavy lifetime use was associated with lower activation on the working memory task.” Such use showed a small to moderate effect size.
- Regions. “Regions associated with a history of heavy use included the anterior insula, medial prefrontal cortex, and dorsolateral prefrontal cortex.”
- Recent use. “Recent cannabis use was associated with poorer performance and lower brain activation in the working memory and motor tasks, but the associations between recent use and brain activation did not survive false discovery rate correction.”
A few thoughts:
1. This is an impressive study published in a reasonable journal.
2. The main finding in a sentence: “Heavy lifetime cannabis use was associated with lower brain activation only during the working memory task, and this association remained after excluding individuals with recent use.”
3. It’s interesting that cannabis didn’t influence the other six functions. As the first author noted in another publication: “It was kind of interesting that the working memory finding emerged as being the only thing that actually reached the threshold that we call significant.”
4. The memory finding is, of course, consistent with past work.
5. To pick up a point made by the authors – increasingly, patients view cannabis as harmless. This study (like others) points us in a different direction, suggesting brain impact for heavy users.
6. Like all studies, there are limitations. The authors note several, including: “This was an uncontrolled, cross-sectional study, so the observed associations of cannabis with brain function outcomes should not be considered causal.”
The full JAMA Netw Open study can be found here:
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2829657
In the News
Part of an occasional series.
“We Thought We Were Compassionate, but We Were Too Permissive”
Nicholas Kristof
The New York Times, 8 February 2025
“As a good liberal, I used to oppose arresting people for using drugs. They need health care, not handcuffs, I thought. But then to my surprise and dismay, I found myself praying that my old pal Drew Goff would be arrested.
“Drew, 40, was homeless, using fentanyl and also selling it. His wife, who was with him, was pregnant and had overdosed 27 times, including twice in a single day. It seemed only a matter of time before Drew killed himself or one of his customers. So Drew’s mom and I confided to each other our hope that he would end up in the relative safety of prison and get treatment there.
“‘It’s the only way to save his life,’ his mom said wearily. And in the end, Drew himself agreed.”
This opinion piece, written by columnist Nicholas Kristof, describes Oregon’s decision to decriminalize possession of small amounts of illicit drugs in 2020 and its consequences. Kristof argues that the plan was a failure: fentanyl overdose deaths in Portland area rose sevenfold from 2020 to 2023; by 2023, drug deaths there were rising more quickly than elsewhere in the US. The essay reviews the statistics (some of the numbers of eye popping) but ultimately focuses on the story of Drew and his addiction.
Is there a way forward? Kristof cools to the idea of decriminalization, but thinks accessible care would be important. He also wonders about going upstream and trying to prevent these problems before they start.
As clinicians, the larger public policy debate is very relevant to our work.
https://www.nytimes.com/2025/02/08/opinion/fentanyl-addiction-drug-policy.html
“RFK Jr. Says Drug Addicts Need Tough Love. Is He Right?”
Sally Satel
The Free Press, 25 January 2025
“If Robert F. Kennedy Jr. is confirmed as the secretary of the Department of Health and Human Services in the Donald Trump administration, and if he carries out even part of his agenda, he will be a consequential – and controversial – cabinet secretary. I have deep concerns about some of his stances, including his record of objecting to vaccines, many of which are lifesaving. But in other areas, starting with addiction, his vision and values could transform lives.
“Kennedy has declared that a priority of his is addressing the U.S. drug addiction crisis, which has killed nearly a million people since 1999. The lion’s share of these deaths occurred in recent years as fentanyl – the most potent drug ever used in epidemic proportions – burst onto the black market.
“I am a psychiatrist who specializes in addiction. In addition to researching this subject, I am the medical director of a methadone clinic in Washington, D.C. So I have a vested interest in Kennedy’s policy suggestions.”
Dr. Sally Satel (of Yale University) explores the different positions of Kennedy – who, since publication of the essay, has been confirmed and is the most powerful health administrator in the United States. Tough love? Wellness farms? Anti-opioid medications? Dr. Satel weighs in, drawing from her experience, as well as the literature, noting the important roles of medications and CBT for those with opioid use disorders.
The essay is lucid and well written. Readers may conclude that Dr. Satel should have a senior role in healthcare administration. Kennedy, not so much.
https://www.thefp.com/p/sally-satel-rfk-jr-drug-addicts-need-tough-love
“The rise and fall of Pacific Northwest drug policy reform, 2020-2024”
Keith Humphreys
Brookings Institution, 4 December 2024
“In the scenic geographical stretch of North America that extends from San Francisco, California, to Vancouver, British Columbia, significant drug policy experimentation has occurred in the past four years… The reforms were undergirded by beliefs and arguments that not only opposed those dominant during the ‘war on drugs’ but also differed in many respects from traditional arguments supporting harm reduction and public health approaches to drugs. Advocates of this new approach hoped that the drug policy reforms they championed would be so clearly effective that they would serve as a model of promoting racial justice and public health for the rest of the nation. But their once popular proposals rapidly lost public support in the face of worsening drug problems, neighborhood disorder, and crime, coupled with no evidence of improvement in access to or utilization of addiction treatment, nor in the prevalence of recovery.”
Like Kristof, Keith Humphreys (of Stanford University) focuses on the experimentation with decriminalization, looking at Oregon, yes, and also Washington State and British Columbia. He traces the roots of the idea, the core changes, and the impact (from crime to overdoses). He also closes with critical questions.
We may wonder why decriminalization didn’t have the effect that it did in Portugal. Humphreys writes specifically about this, offering several differences between the North American and Portuguese experiments, including access to treatment. Readers can decide how persuasive he is.
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.
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