Endocannabinoid signaling as a potential biomarker in anxiety spectrum disorders – A case series

INTRODUCTION

The endocannabinoid system (ECS) is a complex, intricate neuromodulatory network involved in regulating anxiety, mood, and stress responses. It comprises endogenous ligands such as anandamide (AEA) and 2-arachidonoylglycerol, as well as cannabinoid receptors (CB1 and CB2) receptors distributed throughout the brain.^[1]

ECS components are highly expressed in brain regions that regulate emotional processing, including the prefrontal cortex, amygdala, hippocampus, and bed nucleus of the stria terminalis.^[1] Dysregulation in this system has been implicated in anxiety and trauma-related disorders.^[2] Cannabidiol (CBD), a non-intoxicating compound derived from Cannabis sativa, modulates the ECS indirectly through inhibition of fatty acid amide hydrolase (FAAH), activation of serotonin 1A receptor (5HT1A),^[3] and desensitization of transient receptor potential vanilloid 1 receptors.^[2] Unlike tetrahydrocannabinol (THC), CBD is well tolerated across a wide dosing range.^[4] CBD, by inhibiting the FAAH enzyme, enhances CB1 receptor activation, thereby increasing endocannabinoid levels.^[5] This may regulate long-term fear learning and anxiety expression. It modulates anxiety-like behavior in a dose-dependent (biphasic) manner, with low doses showing anxiolytic effects and high doses potentially anxiogenic.^[2] In psychiatric settings, CBD has shown tolerability and efficacy, particularly in social anxiety disorder during public speaking tasks as demonstrated in both clinical^[6] and neuroimaging studies,^[7] as well as in early psychosis and schizophrenia studies.^[2] Endocannabinoid signaling thus represents an underutilized anxiolytic neuromodulatory system. FAAH inhibition remains a promising therapeutic strategy for anxiety.^[5] With the current understanding of dysfunction in serotoninergic/nor-epinephrine tone (and its downstream mechanisms) causing anxiety disorders, we highlight the following critical questions. Can a signaling problem in ECS be a causative/contributory factor in the pathogenesis of anxiety symptoms? Can low anandamide levels (ECS signaling dysfunction) be treated with CBD (exogenous cannabinoid) to improve anxiety symptoms? Additionally will peripheral cannabinoid levels increase post CBD treatment in anxiety spectrum disorders?

This case series is a novel attempt to explore the association between clinical improvement in anxiety spectrum disorders and peripheral serum anandamide levels following CBD treatment. A theranostic-based approach is presented in the case series to see the potential biomarker-based trajectory for CBD treatment in anxiety.

CASE SERIES

DISCUSSION

A theranostic-based approach is presented in the case series to see the potential biomarker-based trajectory for the use of CBD in anxiety. Emerging evidence suggests that CBD can be a promising treatment option for individuals with anxiety spectrum illnesses, especially social anxiety disorder. CBD is one candidate medication that may have certain benefits over current pharmacotherapies, including the absence of sedation, reduced abuse liability, and faster course of action. Recent meta-analytic evidence supports CBD’s anxiolytic efficacy. A 2024 meta-analysis of 8 clinical studies (n = 316) showed a significant reduction in anxiety symptoms (Hedges’ g = −0.92).^[8] Larger trials with longitudinal biomarker tracking are needed. To gain more insight about ECS involvement in anxiety, it is worth noting that rimonabant, a cannabinoid type-1 receptor antagonist previously used to treat obesity, was associated with psychiatric side effects such as increased anxiety behavior, depression, or even suicidality.^[8]

With the case scenarios discussed, post-treatment with CBD, symptom improvement correlated with higher levels of S. Anandamide (in upper limits of normal range). This suggests a promising correlation between clinical improvement and biomarker elevation. This aligns with preclinical studies showing increased AEA following CBD administration.^[2] However, peripheral AEA may not reflect central ECS tone and is affected by stress, diet, and metabolic factors.^[9] However, the absence of baseline anandamide levels in our cases limits this interpretation. During the past decade, an increasing effort has been made to map clinical biomarkers in psychiatry for precision medicine and diagnostics. Measuring ECS activity through simple blood investigations and tailoring individualized treatment accordingly is an important and practical clinical strategy in the theranostics of anxiety . Therefore, in a subset of patients, as mentioned in the aforementioned cases, adding CBD possibly improves pre-treatment low levels and shows better clinical response. The manifestation of psychiatric disorders is often the result of an interplay between multiple biological systems, beyond the traditionally emphasized serotonergic dysfunction. Causative mechanisms involving alternate neurobiological pathways, such as the ECS, deserve deeper exploration and an exciting direction for future clinical research. Translational models of ECS dysfunction and CBD response are increasingly being validated across disorders with high anxiety load,^[10] underscoring the need for biomarker-guided approaches in psychiatry.

CONCLUSION

This case series illustrates a proof of concept of the potential clinical improvement in a subset of anxiety spectrum disorders following CBD augmentation. Elevated serum anandamide levels during clinical remission raise the hypothesis that peripheral endocannabinoid markers may serve as response indicators. These findings pave the way for exploration of ECS-based biomarkers in psychiatric practice. Comparison of pre- and post-anandamide levels would have added more value to the predictive efficacy of CBD treatment.