Can semaglutide (glucagon-like peptide-1 receptor agonist) cause anxiety?

Semaglutide and Anxiety: Clinical Evidence and Considerations

Semaglutide can both cause anxiety as an adverse effect in some patients and potentially reduce anxiety risk in others, with the overall evidence suggesting psychiatric effects should be monitored during treatment. 1, 2

Psychiatric Effects of Semaglutide

Reported Psychiatric Adverse Events

• Depression is the most commonly reported psychiatric adverse event associated with semaglutide (50.3% of psychiatric reports), followed by anxiety (38.7%) and suicidal ideation (19.6%) 1
• Psychiatric adverse events comprise only about 1.2% of total adverse event reports for GLP-1 receptor agonists, but some cases have resulted in severe outcomes 1
• Case reports have documented semaglutide-associated depression in patients with and without previous psychiatric history 3

Potential Protective Effects

• Population-based cohort studies have shown a decreased risk of anxiety in diabetic patients receiving GLP-1 receptor agonists compared to non-users (adjusted HR 0.8,95% CI: 0.67-0.95) 2
• The absolute incidence reduction appears greater for anxiety (2.13 per 1,000 person-years) than for depression (0.41 per 1,000 person-years) 2
• Longer duration of GLP-1 receptor agonist treatment (>180 days) was associated with greater reduction in anxiety risk (adjusted HR 0.41,95% CI: 0.27-0.61) 2

Mechanism of Action and CNS Effects

• GLP-1 receptors are expressed in multiple brain regions including the hypothalamus, brainstem nuclei, hippocampus, neocortex, spinal cord, and cerebellum 4
• These receptors mediate not only metabolic functions but also potentially affect mood and anxiety through central nervous system pathways 4, 5
• The ubiquitous expression of GLP-1 receptors throughout the body, including in the brain, may explain both the therapeutic effects and potential psychiatric adverse effects 4

Clinical Considerations and Monitoring

Risk Assessment

• Patients with pre-existing psychiatric conditions may require closer monitoring when initiating semaglutide 3, 1
• Social media analysis has revealed user reports of both improvement and deterioration in mood, anxiety, and sleep patterns after initiating GLP-1 receptor agonists 6
• Recent population-based cohort studies have not found evidence of increased risk of suicidal ideation and self-injury with GLP-1 receptor agonists compared to SGLT-2 inhibitors, though uncertainty remains due to wide confidence intervals 7

Management of Psychiatric Symptoms

• If psychiatric symptoms emerge during semaglutide treatment, consider:
  • Evaluating the temporal relationship between medication initiation and symptom onset 3
  • Assessing for other potential causes of anxiety or mood changes 1
  • Considering dose reduction or medication discontinuation if symptoms are severe or persistent 3

Common Side Effects and Their Relationship to Anxiety

• Gastrointestinal effects are the most common adverse effects of semaglutide, including nausea, vomiting, diarrhea, and abdominal pain 4
• These physical symptoms may contribute to or exacerbate anxiety in some patients 4
• Gradual dose titration may help mitigate gastrointestinal side effects and potentially reduce associated anxiety 4

Practical Recommendations

• Screen for pre-existing psychiatric conditions before initiating semaglutide 3, 1
• Start with the lowest dose and titrate gradually to minimize side effects that could contribute to anxiety 4
• Monitor for emergence or worsening of anxiety, depression, or suicidal ideation, particularly in the first months of treatment 3, 1
• Educate patients about potential psychiatric effects and encourage them to report mood changes or anxiety symptoms 6
• Consider the benefit-risk profile in patients with a history of psychiatric disorders 3, 1

While the evidence regarding semaglutide and anxiety is mixed, clinicians should remain vigilant about potential psychiatric effects while recognizing that for many patients, the medication may not cause psychiatric adverse effects and could even have beneficial effects on anxiety in some populations 1, 2.