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

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

Overview

flowchart TD clinical_trials_leaf_thc_cbd_a["LEAF Trial - THC+CBD for Alzheimers Disease Agit"] clinical_trials_leaf_thc_cbd_a["Trial"] clinical_trials_leaf_thc_cbd_a -->|"related to"| clinical_trials_leaf_thc_cbd_a style clinical_trials_leaf_thc_cbd_a fill:#81c784,stroke:#333,color:#000 clinical_trials_leaf_thc_cbd_a["THC+CBD"] clinical_trials_leaf_thc_cbd_a -->|"related to"| clinical_trials_leaf_thc_cbd_a style clinical_trials_leaf_thc_cbd_a fill:#81c784,stroke:#333,color:#000 clinical_trials_leaf_thc_cbd_a["Alzheimer"] clinical_trials_leaf_thc_cbd_a -->|"related to"| clinical_trials_leaf_thc_cbd_a style clinical_trials_leaf_thc_cbd_a fill:#81c784,stroke:#333,color:#000 clinical_trials_leaf_thc_cbd_a["Life"] clinical_trials_leaf_thc_cbd_a -->|"related to"| clinical_trials_leaf_thc_cbd_a style clinical_trials_leaf_thc_cbd_a fill:#81c784,stroke:#333,color:#000 style clinical_trials_leaf_thc_cbd_a fill:#4fc3f7,stroke:#333,color:#000

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

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

Overview

Mermaid diagram (expand to render)

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

Exclusion:

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

Outcome Measures

Primary Outcomes

| Measure | Timeframe |
|--------|-----------|
| Cohen-Mansfield Agitation Inventory (CMAI) | Baseline to endpoint |
| Neuropsychiatric Inventory (NPI) | Baseline to endpoint |

Secondary Outcomes

| Measure | Timeframe |
|--------|-----------|
| Cognitive function (MMSE or similar) | Baseline to endpoint |
| Functional status | Baseline to endpoint |
| Caregiver burden | Baseline to endpoint |
| Safety and tolerability | Throughout study |

Clinical Context

| 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

[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)

[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

[NCT05644262 - LEAF Trial](https://clinicaltrials.gov/study/NCT05644262)

[LEAF Trial - NYU Langone Health](https://med.nyu.edu/research/clinical-trials/leaf-trial)

[Weston et al., Cannabinoids for neuropsychiatric symptoms in dementia (2024)](https://doi.org/10.1016/j.gpb.2024.02.008)

[Acharya et al., Cannabinoid-based therapy for Alzheimer's disease agitation (2022)](https://doi.org/10.1038/s41582-022-00689-0)

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

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

Overview

Trial Details

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

Overview

Trial Details

Mechanism of Action

CB1 Receptor-Mediated Effects

CB2 Receptor-Mediated Effects

Combined THC+CBD Rationale

Rationale for Cannabinoid Therapy in AD Agitation

Study Design

Randomized Controlled Trial

Treatment Protocol

Key Eligibility Criteria

Outcome Measures

Primary Outcomes

Secondary Outcomes

Clinical Context

Comparison with Related Trials

Advantages of THC+CBD Combination

Safety Considerations

Known Effects of Cannabinoids

Monitoring Requirements

Related Mechanisms

Related Pages

External Links

References