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 (AD). This multicenter, double-blind, placebo-controlled trial represents a significant step in evaluating cannabinoid-based treatments for neuropsychiatric symptoms in dementia.
| 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 |
The combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) works through multiple mechanisms relevant to AD agitation:
- 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
- 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
- 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
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
¶ 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
- THC+CBD Arm: Oral cannabinoid combination at specified doses
- Placebo Arm: Identical-appearing placebo
- Blinding: Participant, care provider, investigator, and outcomes assessor blinded
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
| Measure |
Timeframe |
| Cohen-Mansfield Agitation Inventory (CMAI) |
Baseline to endpoint |
| Neuropsychiatric Inventory (NPI) |
Baseline to endpoint |
| 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 |
| 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 |
- CBD may mitigate THC-related adverse effects
- Potentially broader mechanism coverage
- May allow lower THC doses for improved safety
- CNS effects: Sedation, dizziness, cognitive impairment
- Cardiovascular: Orthostatic hypotension, tachycardia
- Psychiatric: Anxiety, psychosis (rare at therapeutic doses)
- Gastrointestinal: Nausea, appetite changes
- Regular vital sign assessment
- Psychiatric monitoring for mood changes
- Cognitive function monitoring
- Adverse event tracking