Bupropion for PTSD: Evidence Summary
Bupropion is not recommended for treating PTSD symptoms, as it has failed to demonstrate efficacy in controlled trials and is not included in current evidence-based treatment guidelines. 1, 2
Guideline Recommendations
The 2023 VA/DoD Clinical Practice Guideline for PTSD does not recommend bupropion as a treatment option for PTSD. 1 The guideline strongly recommends:
- First-line treatment: Trauma-focused psychotherapies (Prolonged Exposure, Cognitive Processing Therapy, or EMDR), with 40-87% of patients no longer meeting PTSD criteria after 9-15 sessions 3
- First-line pharmacotherapy (when psychotherapy unavailable or preferred): Paroxetine, Sertraline, or Venlafaxine 3
- Medications to avoid: Benzodiazepines are strongly recommended AGAINST, as 63% of patients receiving benzodiazepines developed PTSD at 6 months compared to only 23% receiving placebo 3
Evidence Against Bupropion in PTSD
Controlled Trial Data
The only placebo-controlled trial of bupropion SR in PTSD (n=30,8 weeks) found no significant difference between bupropion and placebo in reducing PTSD symptoms. 4 Both groups showed symptom reduction, suggesting a placebo effect rather than medication efficacy. 4
Open-Label Study Findings
An earlier open-label study (n=17 veterans, 6 weeks) showed that while patients reported global improvement and decreased depressive symptoms, PTSD-specific symptoms (intrusion, avoidance, total CAPS scores) remained mostly unchanged. 5 Only hyperarousal symptoms showed modest improvement, which was less significant than changes in depression. 5
Expert Consensus
A comprehensive 2004 review classified bupropion as ineffective for PTSD based on open-label study results, recommending it should not be used for this indication. 2 The Cochrane systematic review of PTSD pharmacotherapy (35 RCTs, 4597 participants) did not include bupropion among effective agents, with SSRIs showing the strongest evidence. 6
Limited Exception: Comorbid Methamphetamine Use Disorder
A 2025 case series (n=4) suggested potential benefit when PTSD co-occurs with methamphetamine use disorder, showing greater PTSD symptom reduction and lower relapse rates compared to serotonergic agents alone. 7 However, this represents preliminary case-level evidence only and cannot override the negative controlled trial data for PTSD treatment generally. 7
Clinical Algorithm for PTSD Treatment
Step 1: Offer trauma-focused psychotherapy (PE, CPT, or EMDR) as first-line treatment 1, 3
Step 2: If psychotherapy is unavailable, refused, or insufficient, initiate SSRI monotherapy:
- Sertraline or Paroxetine (FDA-approved for PTSD) 2, 6
- Continue for minimum 6-12 months after symptom remission to prevent relapse (26-52% relapse rate with discontinuation vs. 5-16% with continuation) 3
Step 3: If SSRI ineffective or not tolerated, switch to Venlafaxine (serotonin-norepinephrine reuptake inhibitor) 3, 2
Step 4: For persistent nightmares despite adequate PTSD treatment, add Prazosin 3
Critical Pitfalls to Avoid
- Do not use bupropion as monotherapy for PTSD - it lacks efficacy for core PTSD symptoms despite potential benefits for comorbid depression 5, 4
- Do not prescribe benzodiazepines - they worsen PTSD outcomes and increase chronicity risk 3
- Do not delay trauma-focused therapy for prolonged medication trials - psychotherapy shows more durable benefits with lower relapse rates than medication alone 3