Can Acamprosate (Campral) cause anxiety in patients, especially those with a history of anxiety disorders or underlying psychiatric conditions?

Can Acamprosate Cause Anxiety?

Yes, acamprosate can cause anxiety as a documented adverse effect, though paradoxically it may also reduce anxiety symptoms in some patients through its mechanism of action on glutamate-GABA neurotransmitter balance. 1

Documented Anxiety as an Adverse Effect

• Anxiety was reported as a common adverse event in controlled clinical trials, occurring at a rate of at least 3% and greater than placebo in acamprosate-treated patients 1
• Anxiety was specifically cited as one of the adverse events leading to treatment discontinuation in less than 1% of patients, but was nevertheless more common in acamprosate-treated patients compared to placebo 1
• The FDA label explicitly lists anxiety among the adverse reactions that warrant monitoring during acamprosate treatment 1

Mechanism: The Paradox of Anxiety Effects

The relationship between acamprosate and anxiety is complex due to its pharmacological mechanism:

• Acamprosate modulates N-methyl-D-aspartic acid (NMDA) receptor transmission and may have indirect effects on GABA-A receptor transmission, which theoretically should reduce anxiety 2
• The drug decreases brain glutamate and increases β-endorphins, which in preclinical and clinical studies has been associated with diminished arousal, anxiety, and insomnia 2
• Despite these anxiety-reducing mechanisms, clinical trial data shows anxiety can emerge as an adverse effect, suggesting individual variability in response 1

Clinical Context: Anxiety in Alcohol Use Disorder Populations

• Patients with alcohol use disorder have high baseline rates of anxiety disorders, with history of alcohol or substance use/abuse being a recognized risk factor for generalized anxiety disorder 3
• Distinguishing between acamprosate-induced anxiety versus underlying anxiety disorders or alcohol withdrawal-related anxiety is critical for appropriate management 1
• Acamprosate should only be initiated 3-7 days after last alcohol consumption and after withdrawal symptoms have resolved, as it does not eliminate or diminish withdrawal symptoms (which include anxiety) 4, 1

Evidence for Anxiety Reduction (The Other Side)

Interestingly, there is contradictory evidence suggesting acamprosate may actually help anxiety:

• In an open-label augmentation study, acamprosate reduced anxiety symptoms in patients with treatment-resistant anxiety disorders, with 62% achieving remission on Hamilton Anxiety Rating Scale 5
• Baseline anxiety symptomatology was identified as a predictor of better response to acamprosate in a pooled analysis of 1,485 alcohol-dependent patients 6
• The drug's subjective effects relate to diminished arousal, anxiety, and insomnia in both preclinical and clinical settings 2

Clinical Management Algorithm

When anxiety emerges during acamprosate treatment:

1. First, rule out alcohol relapse or withdrawal - many anxiety events in trials occurred in the context of alcohol relapse 1
2. Assess timing of symptom onset - if anxiety appears early in treatment, consider it may be a direct adverse effect 1
3. Evaluate severity using standardized tools such as GAD-7 scale to quantify symptom burden 3
4. For mild anxiety (GAD-7 score 0-4): Continue acamprosate with close monitoring and psychosocial support 3
5. For moderate anxiety (GAD-7 score 5-9): Consider dose reduction or adding targeted anxiety management while continuing alcohol use disorder treatment 3
6. For severe anxiety (GAD-7 score ≥10) or anxiety leading to functional impairment: Discontinue acamprosate and refer to psychiatry for comprehensive evaluation 3, 1

Critical Monitoring Points

• Families and caregivers must be alerted to monitor for emergence of anxiety symptoms and report them to healthcare providers 1
• Patients with pre-existing anxiety disorders or comorbid psychiatric conditions require closer monitoring when starting acamprosate 3
• The interrelationship between alcohol dependence, depression, anxiety, and suicidality is complex, requiring vigilant assessment throughout treatment 1

Common Pitfall to Avoid

Do not assume all anxiety in acamprosate-treated patients is drug-induced - the baseline prevalence of anxiety disorders in alcohol-dependent populations is high, and anxiety may represent underlying psychiatric comorbidity, alcohol withdrawal, or relapse rather than medication adverse effect 3, 1. Careful temporal assessment and consideration of alternative causes is essential before attributing anxiety solely to acamprosate.