Cannabidiol in the treatment of anxiety disorders: a narrative review

doi:10.15406/ipmrj.2025.10.00398

eISSN: 2574-9838

International Physical Medicine & Rehabilitation Journal

Narative Review Volume 10 Issue 2

Cannabidiol in the treatment of anxiety disorders: a narrative review

Eduardo Aliende Perin

Verify Captcha

Regret for the inconvenience: we are taking measures to prevent fraudulent form submissions by extractors and page crawlers. Please type the correct Captcha word to see email ID.

MD Psychiatrist, Federal University of São Paulo, Brazil

Correspondence: Eduardo Aliende Perin, MD Psychiatrist, Federal University of Sao Paulo, Sao Paulo, Brazil

Received: July 07, 2025 | Published: July 16, 2025

Citation: Perin EA. Cannabidiol in the treatment of anxiety disorders: a narrative review. Int Phys Med Rehab J. 2025;10(2):47-48. DOI: 10.15406/ipmrj.2025.10.00398

Download PDF

Abstract

Anxiety disorders are the most prevalent class of psychiatric illnesses worldwide and are frequently underdiagnosed and undertreated. Despite the efficacy of first-line treatments such as cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs), many patients experience adverse effects or inadequate response. Cannabidiol (CBD), a non-intoxicating phytocannabinoid derived from Cannabis sativa, has emerged as a potential anxiolytic due to its multimodal pharmacological actions. This narrative review examines the neurobiological rationale, mechanisms of action, and current clinical evidence for CBD in anxiety disorders. While early findings-particularly in social anxiety disorder (SAD)-are promising, the literature remains limited and heterogeneous. Further large-scale trials are essential to determine efficacy, optimal dosing, and long-term safety.

Keywords: cannabidiol, anxiety, endocannabinoid system, social anxiety, 5-HT1A receptor, GABA-A receptor, clinical trials

Introduction

Anxiety disorders affect over 300 million individuals globally, with higher prevalence among women and onset typically occurring in adolescence.^1–3 These conditions contribute significantly to global disability and healthcare burden. Despite this, only about 25% of affected individuals receive adequate treatment.¹ These disorders encompass a range of diagnoses including generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, agoraphobia, and specific phobias. They are often chronic, debilitating, and frequently comorbid with depression and substance use disorders. Anxiety disorders are associated with elevated allostatic load, altered neuroendocrine responses, and structural and functional changes in limbic and prefrontal brain regions.

Current treatments and limitations

Evidence-based guidelines from institutions such as the National Institute for Health and Care Excellence⁴ and the World Federation of Societies of Biological Psychiatry^5,6 recommend CBT and pharmacological interventions-namely SSRIs and SNRIs-as first-line treatments. However, SSRIs (e.g., sertraline, escitalopram) and SNRIs (e.g., venlafaxine, duloxetine) are often associated with adverse effects including sexual dysfunction, weight gain, gastrointestinal disturbances, insomnia, and withdrawal symptoms, all of which impact adherence.^4,6 Moreover, treatment resistance is common. Approximately 30–50% of patients fail to achieve remission with first-line treatments, and up to 20% discontinue pharmacotherapy due to side effects. Benzodiazepines, while effective for acute symptom relief, carry risks of sedation, dependence, cognitive impairment, and are not recommended for long-term use. These limitations underscore the urgency to identify alternative or adjunctive treatments that are effective, well-tolerated, and safe for chronic use.

The Endocannabinoid system and rationale for CBD use

The endocannabinoid system (ECS) is an extensive neuromodulatory network that includes endogenous ligands (AEA and 2-AG), receptors (CB1R and CB2R), and enzymes responsible for their synthesis and degradation. The ECS is involved in a wide array of physiological processes including mood regulation, stress response, fear extinction, neurogenesis, and synaptic plasticity. In anxiety disorders, ECS dysregulation has been observed-characterized by reduced AEA levels, increased FAAH activity, and altered CB1R expression in regions such as the amygdala, hippocampus, and prefrontal cortex.⁷ These findings suggest that pharmacologically enhancing ECS signaling could restore emotional homeostasis and reduce anxiety symptoms.

CBD modulates the ECS and interacts with multiple receptor systems:

Inhibits FAAH, increasing AEA availability⁷
Negative allosteric modulation of CB1R, attenuating hyperexcitability⁸
Partial agonism at CB2R, conferring anti-inflammatory effects⁸
5-HT1A receptor agonism, a key anxiolytic pathway⁸
TRPV1 receptor activation, which modulates stress and pain responses⁷
Antagonism at GPR55 and activation of PPARγ, which influence neuro-inflammation and gene expression⁸
Positive allosteric modulation of GABA-A receptors⁸

These multimodal effects may converge to reduce hyperactivity in cortico-limbic circuits implicated in anxiety.

Acute use of Cannabidiol in anxiety

Initial studies led by Brazilian researchers demonstrated the anxiolytic efficacy of acute oral CBD. In the classic simulated public speaking test (SPST), Zuardi et al.⁹ found that 300 mg CBD reduced anxiety in healthy volunteers. Bergamaschi et al.¹⁰ confirmed these findings in patients with SAD, showing significant reductions in subjective anxiety compared to placebo. Crippa et al.¹¹ further demonstrated that CBD reduced activity in limbic and paralimbic areas during fMRI tasks. Linares et al.¹² confirmed a bell-shaped dose-response curve, with 300 mg showing greater anxiolytic effect than 150 mg or 600 mg. However, replication studies have yielded mixed results. Kwee et al.¹³ reported no benefit from 300 mg CBD in augmenting exposure therapy in patients with SAD or panic disorder. Bloomfield et al.¹⁴ and Stanley et al.¹⁵ also failed to find anxiolytic effects in healthy individuals. These discrepancies may stem from differences in experimental design, clinical status of participants, or outcome sensitivity.

Chronic use of Cannabidiol in anxiety

While most early trials used single-dose paradigms, more recent studies have evaluated chronic administration. Masataka¹⁶ found that 300 mg/day of CBD for four weeks significantly reduced LSAS scores in adolescents with SAD. In a trial by Gournay et al.,¹⁷ chronic-but not acute-CBD administration reduced somatic anxiety symptoms in individuals with high trait worry. Open-label studies have also shown encouraging results. Taylor et al.,¹⁸ using a full-spectrum CBD-rich extract (approx. 30 mg/day), observed significant improvements in Beck Anxiety Inventory (BAI) and Overall Anxiety Severity and Impairment Scale (OASIS) scores over four weeks in patients with moderate-to-severe anxiety. The treatment was well tolerated. These findings suggest that chronic administration may be necessary for certain anxiolytic mechanisms to emerge, particularly those involving neuroplastic changes.

Pharmacokinetics, safety, and dosing considerations

CBD exhibits variable bioavailability depending on route of administration. Oral CBD has low and erratic absorption (6-20%) due to first-pass metabolism, while sublingual and inhaled routes offer higher bioavailability. Metabolism occurs primarily via CYP3A4 and CYP2C19. CBD is generally well tolerated, with most adverse events being mild-to-moderate and transient: sedation, gastrointestinal discomfort, and dry mouth are most commonly reported. However, high doses may affect liver enzymes or interact with other medications (e.g., SSRIs, anticonvulsants). The optimal dosing for anxiety remains unclear. Most trials use 300-600 mg for acute effects and 25-100 mg/day in chronic formulations. A bell-shaped dose-response curve has been observed in multiple studies.

Discussion

The collective evidence suggests that CBD is a biologically plausible and clinically promising compound for the treatment of anxiety disorders. It acts on multiple neurotransmitter and neuromodulatory systems implicated in anxiety, including the serotonergic, endocannabinoid, vanilloid, and GABAergic systems.^7,8 Clinical findings are most robust for social anxiety disorder in the context of acute stress paradigms. Emerging data also support the efficacy of chronic CBD use, particularly for somatic anxiety symptoms and worry. However, the evidence base is still limited by small samples, heterogeneity of study designs, inconsistent outcome measures, and short follow-up durations. Furthermore, there is a need for standardized formulations, head-to-head comparisons with established treatments, and exploration of potential synergistic effects when combined with psychotherapy.

Conclusion

Cannabidiol represents a novel and well-tolerated compound with demonstrated anxiolytic properties in both preclinical and early-phase clinical studies. Its complex pharmacology, favorable safety profile, and lack of abuse liability make it an appealing candidate for future anxiety therapeutics. However, its clinical utility remains preliminary. Large-scale, rigorously designed RCTs are needed to confirm its efficacy, define optimal dosing regimens, and clarify its role in integrated treatment models for anxiety disorders.