Medication Reference Card: Severe Alcohol Use Disorder

Prazosin + Cyproheptadine

Aubin et al. 2024 protocol · For severe AUD (>100 g/day men, >60 g/day women) · Off-label, specialist initiation

Dr Basanth Kenchaiah
FRANZCP · Cert. Addiction Psych. · MBBS · DPM · DNB (Psychiatry) Addiction Psychiatrist v1.2 · October 2026

Audience Clinicians

Purpose Prescribing reference for the prazosin + cyproheptadine combination in severe alcohol use disorder: specialist-initiated.

Key messages

Alpha-1 antagonist (prazosin) + serotonin/histamine antagonist (cyproheptadine): reduces craving in severe AUD
Follow Aubin 2024 protocol; prazosin especially useful when PTSD-related hyperarousal drives heavy drinking
Monitor orthostatic hypotension with prazosin; start low and titrate; specialist-only initiation recommended

For Patients

This combination of two medications, prazosin and cyproheptadine, has shown promising results in people with very heavy alcohol use. Prazosin reduces the fight-or-flight response that can trigger drinking, while cyproheptadine helps calm serotonin-related craving signals.

Particularly useful when comorbid with:

Severe AUD (>100 g/day men, >60 g/day women): validated in this population PTSD (prazosin: nightmares, hyperarousal) Hyperadrenergic states / autonomic dysregulation Hypertension with AUD (prazosin dual benefit) Failed standard first-line agents

For Clinicians

Mechanism

Prazosin: Alpha-1 adrenergic receptor antagonist; reduces noradrenergic hyperactivity (stress/craving circuitry), lowers autonomic arousal driving relapse. Well established for PTSD nightmares. Cyproheptadine: Serotonin (5-HT2A/5-HT2C) and H1 histamine antagonist; modulates serotonergic reward pathways and appetite dysregulation in severe AUD. Combined, the agents address both adrenergic and serotonergic components of severe AUD craving circuitry.

Dosing

Aubin et al. 2024 protocol: Prazosin extended-release 10 mg/day + Cyproheptadine 12 mg/day (4 mg TDS). Initiation: start prazosin at 1–2 mg nocte and titrate gradually over 1–2 weeks to minimise orthostatic hypotension. Measure standing BP before each dose increase. Specialist initiation recommended; off-label in Australia.

Evidence

Aubin et al. Addiction 2024 (RCT): combination significantly reduced daily alcohol intake by >23 g/day vs placebo in patients with severe AUD (>100 g/day men, >60 g/day women). Well-tolerated. Prazosin monotherapy: Simpson et al. Alcohol Clin Exp Res 2015 showed reduced heavy drinking days in comorbid PTSD-AUD population. Emerging evidence only; not yet in major guidelines.

Cautions

Orthostatic hypotension with prazosin: first-dose effect; start low, take at bedtime, rise slowly
Avoid prazosin with PDE5 inhibitors (sildenafil, tadalafil): severe hypotension risk
Cyproheptadine: sedation, weight gain, anticholinergic effects (dry mouth, urinary hesitancy)
Monitor BP at each dose titration step
Combination is off-label in Australia; requires documented specialist discussion
Not validated in mild-to-moderate AUD; evidence limited to severe AUD population