Background <p>Although current treatment guidelines recommend against cannabinoids for Post-Traumatic Stress Disorder (PTSD), their use has increased in clinical settings despite fragmented evidence. This review critically examines the efficacy, effectiveness, and safety of cannabinoid-based interventions for PTSD.</p> Methods <p>We conducted a scoping review following PRISMA-ScR guidelines. Five databases were searched up to December 22, 2024. Eligible studies included randomized controlled trials (RCTs) and observational studies, investigating cannabinoids in PTSD-diagnosed populations. Screening, extraction, and quality appraisal independently performed. Quality assessed using validated tools. Main outcomes included PTSD symptom severity and adverse events (AEs).</p> Results <p>From 1,474 screened titles, 26 studies included: 7 RCTs, 9 prospective, 9 retrospective observational studies, and one unpublished RCT, totaling 3,598 patients. Among the seven RCTs, only one demonstrated a statistically significant reduction in PTSD-related nightmares (nabilone vs. placebo). Two RCTs using inhaled or oral cannabis did not show superiority over placebo. Two additional RCTs evaluating oral THC during fear extinction tasks identified changes in neurobiological activation (e.g., increased ventromedial prefrontal cortex activity or reduced fear renewal) without clinical symptom improvement. The remaining two RCTs involving acute oral CBD administration showed minimal benefit, limited to transient mood or cognitive modulation during trauma recall. Overall, only one of the seven RCTs showed clear clinical efficacy over placebo; the rest showed no significant group differences. Observational studies frequently reported symptom improvements, particularly in nightmares, hyperarousal, sleep, and quality of life; however, these findings are limited by high risk of bias, reliance on self-reported outcomes, and lack of control groups, reducing confidence in causal interpretations. AEs were generally mild (e.g., dry mouth, dizziness). Risk of bias was high in most observational studies and moderate in RCTs.</p> Conclusions <p>The current evidence from high-quality RCTs remains insufficient to support clinical use of cannabinoids in treating PTSD. The therapeutic role of cannabinoids in PTSD should be further evaluated through rigorous RCTs.</p> Trial registration <p>The review design was developed 'a priori' to data collection initiation but was not registered in PROSPERO prior to initiation.</p>