Reference

Hendershot, C. S., Bremmer, M. P., Paladino, M. B., Kostantinis, G., Gilmore, T. A., Sullivan, N. R., Tow, A. C., Dermody, S. S., Prince, M. A., Jordan, R., McKee, S. A., Fletcher, P. J., Claus, E. D., & Klein, K. R. (2025). Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2024.4789


Blue: Important conclusions

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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

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Semaglutide treatment did not affect average drinks per calendar day or number of drinking days, but significantly reduced drinks per drinking day

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Residualized change models of laboratory self-administration indicated that semaglutide reduced g-ETOH and peak BrAC among participants who engaged in a self-administration task at posttreatment

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descriptive data suggesting the possibility of earlier deescalation in consumption among participants treated with semaglutide, perhaps consistent with a satiety effect

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semaglutide significantly reduced alcohol craving and drinks per drinking day

  • la diferencia es importante. Normalizar las bebidas por día natural no da diferencias. Pero si se ve una reducción en el consumo de bebidas en aquellos días en los que se decide beber. ??? no lo entiendo.

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the proportion of participants with zero heavy drinking days increased significantly in the semaglutide group across the 2 dose phases. Semaglutide did not alter the proportion of abstinent vs drinking days.

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By comparison, approved (and effective) AUD medications, including naltrexone, generally show small effect sizes in both clinical trials15,48,49 and laboratory studies of self-administration and other outcomes.35,50 While preliminary, the current effect size estimates are promising,

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this study used the 2 lowest clinical doses of semaglutide, whereas doses for weight reduction reach 2.4 mg/week.

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semaglutiderelated reductions in drinking quantity occurred absent volitional attempts to reduce drinking. In contrast to treatment-seeking participants, this sample is arguably representative of the majority of those with AUD exposed to GLP-1RAs in general medical settings.

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Since the FDA approval of the first AUD medication (disulfiram) in 1951, only 2 medications (naltrexone and acamprosate) have received subsequent FDA approval for AUD.12,52

Yellow: Interesting

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To evaluate the effects of once-weekly subcutaneous semaglutide on alcohol consumption and craving in adults with alcohol use disorder (AUD).

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This was a phase 2, double-blind, randomized, parallel-arm trial involving 9 weeks of outpatient treatment. Enrollment occurred at an academic medical center in the US from September 2022 to February 2024. Of 504 potential participants assessed, 48 non–treatment-seeking participants with AUD were randomized.

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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.

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laboratory alcohol self-administration, measured at pretreatment and posttreatment (0.5 mg/week). Secondary and exploratory outcomes, including prospective changes in alcohol consumption and craving, were assessed at outpatient visits.

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A significant treatment-by-time interaction indicated that semaglutide treatment predicted greater relative reductions in cigarettes per day in a subsample of individuals with current cigarette use

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ClinicalTrials.gov Identifier: NCT05520775

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2.6 million deaths per year globally.1,2 Alcohol

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alcohol use disorder (AUD)

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This phase 2 clinical trial used a hybrid design, combining clinical outpatient and human laboratory components, to evaluate the effects of semaglutide in non–treatment-seeking adults with AUD. The outpatient sequence involved 9 weeks of medication or placebo (weeks 1-9) and a final assessment visit (week 10). Objective laboratory alcohol self-administration was assessed at pretreatment (prior to week 1) and between weeks 8 and 9 (at 0.5 mg/week).

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Non–treatment-seeking adults with AUD were recruited via online and public advertisements. Primary inclusion criteria included age 21 to 65 years, reporting past-year DSM-5 criteria for AUD, past-month endorsement of more than 7 (women) or more than 14 (men) standard drinks in a week with 2 or more heavy drinking episodes (4 or more drinks for women and 5 or more for men), and ability to attend weekly clinic visits and pretreatment and posttreatment laboratory sessions.

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exclusion criteria included currently seeking treatment for alcohol problems or actively attempting to reduce consumption; past use of GLP-1 receptor agonists; weight loss medications; body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) less than 23; past-year substance use disorder other than AUD, tobacco use disorder, or mild cannabis use disorder; recent (30-day) use of illicit drugs except cannabis; history of diabetes, and current medical or neurological illness precluding participation based on physician judgement

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Subcutaneous semaglutide was administered according to standard practice, with dose increases every 4 weeks.

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(0.25 mg/week for weeks 1-4 and 0.5 mg/week for weeks 5-8)

  • **dosis crecientes, por qué? cuál es la dosis normal de ozempic? Lo habitual para T2D (ozempic):
  • 4 semanas 0.25 mg semanalmente
  • mantenimiento 0.5 mg semanalmente. Podría aumentarse hasta 1.
  • Maximo tolerable 2 mg.

Para peso (wegovy):

  • 4 semanas 0.25 mg

  • 4 semanas 0.5 mg

  • 4 semanas 1 mg

  • 4 semanas 1.7 mg

  • mantenimiento 2.4 mg**

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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.37

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Weekly Consumption and Craving Weekly consumption was assessed using calendar-based methods38 supplemented with daily logs to facilitate recall. Outcomes included average drinks per calendar day (registered secondary outcome), with additional quantity and frequency outcomes common to AUD trials (drinks per drinking day, number of heavy drinking days, number of drinking vs abstinent days), and weekly craving39 examined as exploratory and hypothesis-generating outcomes.

  • heavy drinking days: en los que se consumen más de 4 bebidas en mujeres o 5 en hombres.

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aracteristic Mean (SD) Placebo Semaglutide Total Randomized, No. 24 24 48

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This prospective clinical trial examined changes in laboratory and naturalistic alcohol consumption following weekly semaglutide treatment

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Green: Agree with the paper

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semaglutide reduced posttreatment laboratory consumption with a medium to large effect size for grams of alcohol consumed (β, −0.48; 95% CI, −0.85 to −0.11; P = .01) and peak breath alcohol concentration (β, −0.46; 95% CI, −0.87 to −0.06; P = .03)

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Medication effects were nonsignificant for drinks per calendar day

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(β, −0.27; 95% CI, −0.63 to 0.09; P = .17) and significant for drinks per drinking day (β, −0.41; 95% CI, −0.73 to −0.09; P = .04).

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greater reductions in heavy drinking days over time in the semaglutide group relative to the placebo group

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There was no evidence that semaglutide altered number of drinking vs abstinent days

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Semaglutide significantly reduced weekly craving (β, −0.39; 95% CI, −0.73 to −0.06; P = .01).

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Medication effect sizes were mostly small (by convention, Cohen d = 0.20) through week 4 and increased during weeks 5 to 8, with large effect sizes (defined as d = 0.80) observed for drinks per drinking day and heavy drinking days.

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  • la semaglutida hacía sus efectos sobre el peso.

Red: Disagree with the paper

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  • el curioso efecto placebo. Por el hecho de estar en el trial recibiendo placebo los participantes bebían menos días a la semana, y menos bebidas al día también.

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Studies with treatment-seeking samples are needed to determine whether GLP-1RAs can facilitate abstinence or prevent relapse.

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modest sample size and short-term treatment duration, both reflecting the phase 2 stage of this trial.

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Another limitation is the moderate level of AUD severity of this sample, with consumption levels below those of most treatment-seeking samples.

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studies with heavier drinkers are necessary.

Purple: To learn more

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A standardized procedure37 was used to estimate voluntary alcohol consumption and ability to delay drinking.