Cannabidiol Oil for Treatment-Resistant Major Depression

Official title

Effects of Full-Spectrum Cannabidiol Oil on Symptoms of Treatment-Resistant Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial

Overview

Major depressive disorder is one of the leading causes of disability worldwide, and a substantial proportion of patients do not achieve adequate improvement with conventional antidepressant treatments. Cannabidiol (CBD), a non-intoxicating cannabinoid derived from Cannabis sativa, has shown potential anxiolytic, anti-inflammatory, and neurobiological effects that may be relevant for depressive disorders. The ANANDA trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy, safety, and tolerability of full-spectrum cannabidiol oil as an adjunctive treatment in adults with treatment-resistant major depressive disorder. A total of 120 participants will be randomly assigned to receive either full-spectrum cannabidiol oil or placebo for 12 weeks while maintaining stable antidepressant treatment. Clinical assessments of depressive symptoms, anxiety, sleep quality, perceived stress, and adverse effects will be performed at baseline, Week 4, and Week 12. Blood samples will be collected at baseline and after 12 weeks to investigate inflammatory and neuroendocrine biomarkers. The primary objective is to evaluate changes in depressive symptoms after 12 weeks of treatment. Secondary objectives include the assessment of anxiety, sleep quality, perceived stress, biological markers, safety, and tolerability. The findings of this study may contribute to the development of new therapeutic approaches for treatment-resistant depression and provide additional evidence regarding the clinical use of cannabidiol in psychiatric disorders.

Detailed description

Major depressive disorder (MDD) is a highly prevalent psychiatric condition and one of the leading causes of disability worldwide. Despite the availability of several antidepressant treatments, approximately one-third of patients do not achieve adequate symptom remission after multiple treatment attempts, characterizing treatment-resistant depression. This condition is associated with substantial functional impairment, reduced quality of life, increased healthcare utilization, and elevated suicide risk.

The endocannabinoid system has emerged as a promising target for the treatment of mood disorders because of its involvement in emotional regulation, stress response, neuroplasticity, neuroinflammation, and neurotransmitter modulation. Cannabidiol (CBD), a non-intoxicating phytocannabinoid derived from Cannabis sativa, has demonstrated anxiolytic, anti-inflammatory, neuroprotective, and antidepressant-like effects in preclinical studies, while preliminary clinical evidence suggests potential benefits in psychiatric disorders.

The ANANDA trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial designed to evaluate the efficacy, safety, and tolerability of full-spectrum cannabidiol oil as adjunctive therapy in adults with treatment-resistant major depressive disorder.

The study will be conducted at the University of Southern Santa Catarina (UNISUL) and the Federal University for Latin American Integration (UNILA). A total of 120 participants diagnosed with treatment-resistant major depressive disorder will be randomized in a 1:1 ratio to receive either full-spectrum cannabidiol oil or placebo for 12 weeks while maintaining stable antidepressant treatment.

Randomization will be performed using a computer-generated allocation sequence. Participants, investigators, healthcare providers, outcome assessors, and members of the research team responsible for participant follow-up and data analysis will remain blinded to treatment allocation throughout the study period. The placebo formulation will be matched to the active intervention in appearance, color, packaging, and administration conditions to maintain blinding.

Clinical evaluations will be performed at baseline, Week 4, and Week 12 using validated instruments for depressive symptoms, anxiety, sleep quality, perceived stress, adverse effects, and quality of life. Biological samples will be collected at baseline and after 12 weeks of treatment to assess inflammatory and neuroendocrine biomarkers potentially associated with treatment response.

The primary outcome is the change in depressive symptom severity measured by the Montgomery-Åsberg Depression Rating Scale after 12 weeks of treatment. Secondary outcomes include changes in anxiety symptoms, sleep quality, perceived stress, biological markers, safety, and treatment tolerability.

The results of this study may contribute to a better understanding of the therapeutic potential of cannabidiol in treatment-resistant depression and may provide evidence to support future clinical applications of cannabinoid-based interventions in psychiatry.

Interventions

• Drug Full-spectrum CBD oil 100 mg/mL
  Full-spectrum Cannabis sativa extract containing cannabidiol (CBD) 100 mg/mL and tetrahydrocannabinol (THC) 3.33 mg/mL, administered sublingually for 12 weeks according to a structured dose titration schedule. Treatment will begin with low doses and may be gradually adjusted based on clinical response and tolerability, respecting predefined safety limits established in the study protocol.
• Drug Placebo oil (MCT oil)
  Placebo comparator consisting of medium-chain triglyceride (MCT) oil administered sublingually for 12 weeks according to the same dose titration schedule used in the experimental group. The placebo formulation is matched to the active intervention in appearance, color, viscosity, packaging, and administration conditions to maintain blinding throughout the study. Treatment adherence, tolerability, and adverse events will be monitored throughout the intervention period.

Primary outcome measures

• Change in Depressive Symptom Severity Assessed by the Hamilton Depression Rating Scale (HAM-17) [Time frame: Baseline, Week 4, and Week 12]

Secondary outcome measures (6)

• Change in Anxiety Symptoms Assessed by the Generalized Anxiety Disorder Scale (GAD-7) [Time frame: Baseline, Week 4, and Week 12]
• Change in Insomnia Severity Assessed by the Insomnia Severity Index (ISI) [Time frame: Baseline, Week 4, and Week 12]
• Change in Health-Related Quality of Life Assessed by the Short Form-36 Health Survey (SF-36) [Time frame: Baseline, Week 4, and Week 12]
• Frequency and Severity of Adverse Effects Assessed by the UKU Side Effect Rating Scale [Time frame: Week 4 and Week 12]
• Change in Inflammatory Biomarkers [Time frame: Baseline and Week 12]
• Change in Neuroendocrine Biomarkers [Time frame: Baseline and Week 12]

Eligibility criteria

Inclusion criteria

• Adults aged 18 to 69 years
• Diagnosis of Major Depressive Disorder (MDD)
• Persistent depressive symptoms despite ongoing antidepressant treatment
• Stable antidepressant treatment for at least four weeks before enrollment
• Residence in Brazil
• Ability to understand study procedures and comply with study requirements
• Provision of written informed consent

Exclusion criteria

• Current use of cannabis-derived products or cannabinoid-based medications
• Diagnosis of bipolar disorder, schizophrenia, or other psychotic disorders
• Current substance use disorder, except nicotine or caffeine
• Pregnancy or breastfeeding
• Severe or unstable medical conditions that may interfere with study participation
• History of hypersensitivity or allergy to Cannabis sativa products or MCT oil
• Active suicidal ideation or significant suicide risk requiring immediate intervention
• Participation in another clinical trial within the previous 30 days
• Inability to comply with study procedures or follow-up assessments

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Brazil · 1 center

• Universidade do Sul de Santa Catarina - UNISUL — Tubarão

Identifiers

NCT: NCT07696871 · CEP-UNISUL-8469525 · RBR-6n6wzsx · U1111-1337-1000 · CAAE 88825025.3.0000.0261

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗