Major Depressive Disorder (MDD), Treatment-resistant Depression (TRD)
Conditions
Keywords
Cannabidiol, Cannabinoids, Major Depressive Disorder, Treatment-Resistant Depression, Mood Disorders
Brief summary
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
DRUGFull-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.
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.
Sponsors
Universidade do Sul de Santa Catarina
Federal University of Latin American Integration
Associação Cannabis Sem Fronteiras - ACSF
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
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. The placebo formulation will be matched to the active intervention in appearance, color, packaging, and administration conditions to maintain blinding. Treatment allocation codes will be restricted to designated personnel not directly involved in participant assessments, clinical follow-up, or outcome evaluations and will only be accessed in cases of medical necessity or after completion of the study.
Intervention model description
This study is designed as a multicenter, randomized, double-blind, placebo-controlled clinical trial with a parallel-group assignment. Participants will be randomly allocated in a 1:1 ratio to either the intervention group receiving full-spectrum cannabidiol (CBD) oil or the placebo group receiving a matched placebo formulation with similar organoleptic characteristics and administration conditions. Participants will remain in their assigned group throughout the 12-week intervention period, with no crossover between treatments. Clinical assessments will be conducted at baseline, Week 4, and Week 12, with additional remote follow-up visits performed throughout the study to monitor treatment adherence, tolerability, adverse events, and dose adjustments. Blood samples will be collected at baseline and after 12 weeks to evaluate inflammatory and neuroendocrine biomarkers associated with treatment response.
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Depressive Symptom Severity Assessed by the Hamilton Depression Rating Scale (HAM-17) | Baseline, Week 4, and Week 12 | Depressive symptoms will be assessed using the 17-item Hamilton Depression Rating Scale (HAM-17), a clinician-administered instrument that evaluates depressive symptom severity. HAM-17 assessments will be performed at baseline, Week 4, and Week 12. The primary endpoint is the change in HAM-17 total score from baseline to Week 12. Changes from baseline to Week 4 will be evaluated as an intermediate assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Anxiety Symptoms Assessed by the Generalized Anxiety Disorder Scale (GAD-7) | Baseline, Week 4, and Week 12 | Anxiety symptoms will be assessed using the Generalized Anxiety Disorder Scale (GAD-7), a 7-item self-report instrument that evaluates the frequency of anxiety-related symptoms. Each item is scored from 0 to 3, resulting in a total score ranging from 0 to 21. Higher scores indicate greater anxiety symptom severity. GAD-7 assessments will be performed at baseline, Week 4, and Week 12. The secondary endpoint is the change in GAD-7 total score from baseline to Week 12, with Week 4 evaluated as an intermediate assessment. |
| Change in Insomnia Severity Assessed by the Insomnia Severity Index (ISI) | Baseline, Week 4, and Week 12 | Sleep disturbances will be assessed using the Insomnia Severity Index (ISI), a 7-item self-report instrument that evaluates the severity of insomnia symptoms, sleep dissatisfaction, interference with daily functioning, and distress associated with sleep difficulties during the previous two weeks. Each item is scored from 0 to 4, resulting in a total score ranging from 0 to 28, with higher scores indicating greater insomnia severity. ISI assessments will be performed at baseline, Week 4, and Week 12. The secondary endpoint is the change in ISI total score from baseline to Week 12, with Week 4 evaluated as an intermediate assessment. |
| Change in Health-Related Quality of Life Assessed by the Short Form-36 Health Survey (SF-36) | Baseline, Week 4, and Week 12 | Health-related quality of life will be assessed using the 36-item Short Form Health Survey (SF-36), a validated self-report instrument composed of eight domains: physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health. Scores for each domain range from 0 to 100, with higher scores indicating better health-related quality of life. Assessments will be performed at baseline, Week 4, and Week 12. The secondary endpoint is the change in SF-36 domain scores from baseline to Week 12, with Week 4 evaluated as an intermediate assessment. |
| Frequency and Severity of Adverse Effects Assessed by the UKU Side Effect Rating Scale | Week 4 and Week 12 | Treatment tolerability and adverse effects will be assessed using the UKU Side Effect Rating Scale, a standardized instrument developed to systematically evaluate adverse effects associated with psychopharmacological treatments. The UKU assesses psychiatric, neurological, autonomic, and other general side effects. Each item is scored on a scale ranging from 0 (absent) to 3 (severe), with higher scores indicating a greater burden of adverse effects. Assessments will be performed at Week 4 and Week 12 to evaluate the safety and tolerability of the intervention. |
| Change in Inflammatory Biomarkers | Baseline and Week 12 | Inflammatory biomarkers will be assessed in serum samples collected at baseline and after 12 weeks of treatment. Biomarkers will include tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), and C-reactive protein (CRP). Concentrations will be measured using enzyme-linked immunosorbent assay (ELISA) and expressed in picograms per milliliter (pg/mL), except for CRP when applicable. The secondary endpoint is the change in inflammatory biomarker concentrations from baseline to Week 12. |
| Change in Neuroendocrine Biomarkers | Baseline and Week 12 | Neuroendocrine biomarkers will be assessed in serum samples collected at baseline and after 12 weeks of treatment. Biomarkers will include brain-derived neurotrophic factor (BDNF) and cortisol, which are associated with neuroplasticity, stress regulation, and the pathophysiology of major depressive disorder. Concentrations will be measured using validated laboratory methods and expressed according to standard laboratory units. The secondary endpoint is the change in neuroendocrine biomarker concentrations from baseline to Week 12. |
Countries
Brazil
Contacts
CONTACTRafael Mariano Bitencourt, PhD
Outcome results
None listed