LEAF Trial - THC+CBD for Alzheimer's Disease Agitation (NCT05644262)

LEAF Trial - THC+CBD for Alzheimer's Disease Agitation (NCT05644262)

Overview

The LEAF trial (Life's End Benefits of cannaBidiol and tetrahydrocannabinol) is a Phase 2 clinical trial investigating the safety and efficacy of oral THC+CBD combination therapy for agitation in [Alzheimer's Disease](/diseases/alzheimers-disease) (AD). This multicenter, double-blind, placebo-controlled trial represents a significant step in evaluating cannabinoid-based treatments for neuropsychiatric symptoms in dementia.

Trial Details

LEAF Trial - THC+CBD for Alzheimer's Disease Agitation (NCT05644262)

Overview

The LEAF trial (Life's End Benefits of cannaBidiol and tetrahydrocannabinol) is a Phase 2 clinical trial investigating the safety and efficacy of oral THC+CBD combination therapy for agitation in [Alzheimer's Disease](/diseases/alzheimers-disease) (AD). This multicenter, double-blind, placebo-controlled trial represents a significant step in evaluating cannabinoid-based treatments for neuropsychiatric symptoms in dementia.

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT05644262 |
| Status | Recruiting |
| Phase | Phase 2 |
| Sponsor | NYU Langone Health |
| Intervention | Oral THC+CBD (cannabinoid combination) |
| Acronym | LEAF |
| Purpose | Treatment |
| Study Type | Interventional |
| Enrollment | 120 participants (estimated) |
| Study Design | Multicenter, double-blind, placebo-controlled |

Mechanism of Action

The combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) works through multiple mechanisms relevant to AD agitation:

CB1 Receptor-Mediated Effects

• THC is a potent agonist at CB1 receptors, which are abundantly expressed in brain regions involved in emotion regulation, memory, and anxiety
• CB1 activation modulates neurotransmitter release (glutamate, GABA, serotonin)
• May reduce agitation through anxiolytic and calming effects

CB2 Receptor-Mediated Effects

• CBD acts as a negative allosteric modulator of CB1 and agonist of CB2 receptors
• CB2 receptor activation on microglia may reduce neuroinflammation
• Anti-inflammatory properties may indirectly improve behavioral symptoms

Combined THC+CBD Rationale

• CBD attenuates some of THC's psychoactive effects, potentially improving tolerability
• The combination may provide synergistic therapeutic effects
• CBD's neuroprotective properties may complement THC's behavioral effects

Rationale for Cannabinoid Therapy in AD Agitation

Agitation affects up to 70% of AD patients during the disease course and represents a major unmet medical need:

• Current treatments are inadequate — Antipsychotics show modest efficacy but carry significant risks (stroke, mortality, falls)
• Caregiver burden — Agitation is the strongest predictor of institutionalization
• Preliminary evidence — Smaller trials with nabilone (synthetic THC) and CBD alone have shown promise for dementia-related agitation
• Different mechanism — Cannabinoids work through novel pathways distinct from existing treatments

Study Design

Randomized Controlled Trial

• Design: Multicenter, double-blind, randomized, placebo-controlled, parallel-group
• Allocation: 1:1 randomization to THC+CBD or placebo
• Duration: Treatment phase with follow-up assessment

Treatment Protocol

• THC+CBD Arm: Oral cannabinoid combination at specified doses
• Placebo Arm: Identical-appearing placebo
• Blinding: Participant, care provider, investigator, and outcomes assessor blinded

Key Eligibility Criteria

Inclusion:

• Age ≥60 years (typical)
• Diagnosis of Alzheimer's disease or related dementia
• Clinically significant agitation
• Stable medication regimen

• Current cannabis use or history of cannabis use disorder
• Uncontrolled cardiovascular disease
• Significant psychiatric comorbidities
• History of psychosis

Outcome Measures

Primary Outcomes

Secondary Outcomes

Clinical Context

Comparison with Related Trials

| Trial | Compound | Phase | Status | Notes |
|-------|----------|-------|--------|-------|
| NCT04516057 (NAB-IT) | Nabilone (synthetic THC) | Phase 3 | Recruiting | Single cannabinoid |
| LEAF (NCT05644262) | THC+CBD | Phase 2 | Recruiting | Combination therapy |
| NCT05543681 (IGC-AD1) | Cannabis extract | Phase 2 | Recruiting | Whole-plant extract |

Advantages of THC+CBD Combination

• CBD may mitigate THC-related adverse effects
• Potentially broader mechanism coverage
• May allow lower THC doses for improved safety

Safety Considerations

Known Effects of Cannabinoids

• CNS effects: Sedation, dizziness, cognitive impairment
• Cardiovascular: Orthostatic hypotension, tachycardia
• Psychiatric: Anxiety, psychosis (rare at therapeutic doses)
• Gastrointestinal: Nausea, appetite changes

Monitoring Requirements

• Regular vital sign assessment
• Psychiatric monitoring for mood changes
• Cognitive function monitoring
• Adverse event tracking

Related Mechanisms

• [Cannabinoid Signaling in Neurodegeneration](/mechanisms/cannabinoid-signaling)
• [Neuropsychiatric Symptoms in AD](/mechanisms/neuropsychiatric-symptoms-ad)
• [Agitation in Dementia](/mechanisms/dementia-agitation)
• [Neuroinflammation in Alzheimer's Disease](/mechanisms/neuroinflammation-alzheimers)

Related Pages

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Nabilone for Agitation in AD (NCT04516057)](/clinical-trials/nabilone-ad-agitation-nct04516057)
• [Agitation in Dementia](/mechanisms/dementia-agitation)
• [NYU Langone Health](/institutions/nyu-langone-health)
• [Cannabinoid Therapeutics](/therapeutics/cannabinoid-therapeutics)

External Links

• [ClinicalTrials.gov - NCT05644262](https://clinicaltrials.gov/study/NCT05644262)
• [LEAF Trial - NYU Langone](https://med.nyu.edu/research/clinical-trials/leaf-trial)

References