“Fear and anxiety perform essential protective roles, yet when they become dysregulated, they can trap trauma survivors in persistent hypervigilance and distress. Post-traumatic stress disorder (PTSD) manifests as intrusive memories, avoidance, and heightened arousal long after the precipitating event. Although current pharmacotherapies – including selective serotonin reuptake inhibitors, adrenergic blockers, benzodiazepines, and atypical antipsychotics – provide relief for some, many patients contend with residual symptoms or intolerable adverse effects.

Recent discoveries position the endocannabinoid system as a pivotal regulator of fear acquisition, consolidation, and extinction. Clinical observations of altered anandamide levels and cannabinoid receptor CB₁ upregulation in individuals with severe PTSD underscore the therapeutic potential of restoring endocannabinoid tone.

Preclinical studies demonstrate that direct CB₁ agonists, fatty acid amide hydrolase (FAAH) inhibitors, and phytocannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD) can facilitate extinction learning and attenuate anxiety-like behaviours.

Preliminary human trials report that nabilone alleviates trauma-related nightmares and that acute cannabinoid administration modulates amygdala reactivity to a threat. Yet optimal dosing strategies, sex-specific responses, and ideal THC:CBD ratios remain to be defined. Self-medication with cannabis can offer transient relief but carries a risk of cannabis use disorder and potential worsening of PTSD symptoms. By elucidating molecular targets – including CB₁, CB₂, FAAH, and monoacylglycerol lipase – this review outlines a strategic framework for next-generation cannabinoid-based interventions.

Harnessing the endocannabinoid system promises to expand the therapeutic arsenal for PTSD, offering hope for more effective and better-tolerated treatments.”

https://pubmed.ncbi.nlm.nih.gov/40789309/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2647-8030