# NCT06548490: Semaglutide for OUD Phase 2 RCT

**Type:** Clinical Trial Protocol
**Status:** Active (ongoing, no results)
**Phase:** 2
**Design:** Randomized, double-blind, placebo-controlled
**Registration:** NCT06548490
**Principal Investigator:** Patricia S. Grigson, Penn State
**Funding:** NIH
**Publication:** Addiction Science & Clinical Practice, 2025

## Trial Design

**Population:**
- 200 participants with treatment-refractory opioid use disorder
- Already receiving standard MOUD (buprenorphine or methadone)
- Outpatient setting
- Three sites

**Intervention:**
- Semaglutide vs. placebo
- 12-week treatment period
- Added to existing MOUD background therapy

**Primary Endpoint:**
- Opioid abstinence (confirmed by urine drug screens + self-report)

## Scientific Rationale

**Preclinical Evidence:**
- Rodent models show GLP-1 receptor agonists reduce opioid self-administration
- Mechanism: GLP-1 receptors in ventral tegmental area modulate dopamine reward circuits

**Clinical Evidence (pre-trial):**
- Residential OUD population studies show decreased craving measures
- Qeadan 2025 real-world data: 40% lower opioid overdose rate in GLP-1 RA users
- No completed controlled trials in outpatient OUD as of protocol publication

## Safety Considerations

**Documented Concerns:**
- Pancreatic cysts and cancer risk
- Hypoglycemia
- Muscle cramps
- Cognitive slowing
- Drug interactions with buprenorphine/methadone

**Population Risk:**
- Treatment-refractory patients represent high-difficulty population
- Higher baseline risk for adverse outcomes

## Significance

**Why This Trial Matters:**
- Only active well-powered Phase 2 RCT for GLP-1 in OUD
- Tests whether real-world observational signal (Qeadan 2025) holds under controlled conditions
- Specifically targets treatment-refractory population (not achieving abstinence with standard MOUD)
- Will determine if GLP-1 reward circuit mechanism extends beyond food/alcohol to opioids

**Expected Timeline:**
- Results anticipated 2026-2027
- Positive result would elevate GLP-1 OUD mechanism claim from "experimental" to "likely" confidence
- Null result would suggest mechanism specificity to food/alcohol reward circuits

## Timeline

- **2025** — Protocol published in Addiction Science & Clinical Practice
- **2025-2026** — Trial enrollment and treatment ongoing
- **2026-2027** — Results expected (monitoring required)

## Research Context

Patricia Grigson is a leading addiction neuroscience researcher at Penn State College of Medicine. This NIH-funded trial represents the first rigorous controlled test of GLP-1 receptor agonists for opioid use disorder in an outpatient population already receiving medication-assisted treatment.

## Monitoring Notes

**Status:** Protocol-only publication. No results available as of April 2026.

**Action Required:** Monitor for results publication Q3/Q4 2026 or early 2027. Results will directly inform whether the GLP-1 reward circuit mechanism claim can extend to opioids with "likely" confidence.

**KB Impact:** When results publish, this becomes a primary source for evaluating the OUD extension of the existing claim "glp1-receptor-agonists-address-substance-use-disorders-through-mesolimbic-dopamine-modulation"