Cannabinoid Medication for Alzheimer's Disease

(CALM-IT Trial)

Recruiting at 4 trial locations

Overseen By CALM-IT Coordinating Centre

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sunnybrook Health Sciences Centre

Must be taking: Cognitive enhancers

Must not be taking: Antidepressants, Antipsychotics, Anticonvulsants, Marijuana

Disqualifiers: Cardiovascular disease, Renal impairment, Psychiatric disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 15

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new medication, JZP541 (a cannabinoid medication), to determine its effectiveness in managing agitation in people with Alzheimer's disease. Participants will receive either the CBD treatment or a placebo to compare effects. The trial aims to assess the treatment's efficacy and explore any biological markers related to agitation. Ideal participants are those diagnosed with Alzheimer's, experiencing significant agitation, and having a caregiver to assist them during the study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that if you are taking cognitive-enhancing medications, your dosage must be stable for at least 3 months before joining. You cannot change psychotropic medications shortly before or during the trial, and you must stop using anticonvulsant medications and strong inducers of CYP3A4 at least 14 days before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CBD, a compound from cannabis, has been studied for its safety in treating issues related to Alzheimer's. Studies have found that low-dose cannabis extracts, such as THC-CBD, can safely help manage dementia symptoms in Alzheimer's patients. Participants in these studies generally handled the treatments well, experiencing only mild and manageable side effects.

Other research confirms that using CBD in moderate doses is safe for people at risk of Alzheimer's. The CBD used in these studies is very pure, ensuring safety and consistency. This information provides reassurance about the safety of using CBD to treat Alzheimer's-related agitation. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Researchers are excited about JZP541 for Alzheimer's disease because it introduces cannabidiol (CBD) as a potential treatment option. Unlike standard treatments like cholinesterase inhibitors and NMDA receptor antagonists, which focus on managing symptoms, JZP541 targets the endocannabinoid system, which may play a role in neuroprotection and inflammation reduction. This novel mechanism could provide a fresh approach to slowing the progression of Alzheimer's, offering hope for more effective management of the disease.

What evidence suggests that this treatment might be an effective treatment for Alzheimer's?

Research has shown that cannabidiol (CBD), which participants in this trial may receive, might help reduce restlessness in people with Alzheimer's disease. Previous studies suggest that low-dose cannabis extract, including CBD, could improve Alzheimer's symptoms. In one study, 45% of patients showed a significant decrease in problems with thinking and memory when using cannabis extracts. Another study found that synthetic cannabis reduced restlessness in Alzheimer's patients, indicating that CBD might be effective. These findings support the potential of CBD as a helpful treatment for managing restlessness in Alzheimer's disease. ^{1 2 3 4 6}

Who Is on the Research Team?

Krista L. Lanctot, PhD

Principal Investigator

Sunnybrook Research Institute

Giovanni Marotta

Principal Investigator

Sunnybrook Health Sciences Centre

Are You a Good Fit for This Trial?

This trial is for people aged 55+ with Alzheimer's Disease who experience significant agitation. Participants must have a stable dose of cognitive-enhancing meds for 3 months, and a caregiver able to assist. They should not have certain liver issues, recent drug or alcohol dependence, uncontrolled cardiovascular disease, or be using cannabis products.

Inclusion Criteria

I am 55 or older. If female, I am post-menopausal or will follow birth control rules. If male, I will use contraception if my partner can have children.

I have been diagnosed with significant agitation.

I can give my consent or have someone who can decide for me.

Exclusion Criteria

I have used marijuana or cannabinoid products within the last week.

I have not had a stroke in the last 3 months.

My heart's electrical activity (QT interval) is longer than normal or I have risk factors for a specific heart rhythm problem.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment Phase 1

Participants receive either CBD or placebo for the first treatment phase

9.5 weeks

6 visits (in-person), 4 visits (telephone)

Treatment Phase 2

Participants cross-over to the opposite treatment (CBD or placebo) for the second treatment phase

9.5 weeks

6 visits (in-person), 4 visits (telephone)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• JZP541

Trial Overview The CALM-IT study tests JZP541 against a placebo in managing Alzheimer's-related agitation. It's randomized and double-blind, meaning neither the researchers nor participants know who gets the real medicine versus the placebo during the trial.

How Is the Trial Designed?

Group I: Placebo Experimental Treatment 1 Intervention

Participants randomized to the placebo will be titrated up to a maximum dose of 800 mg/day

Group II: CBD Experimental Treatment 1 Intervention

Participants randomized to the CBD arm will be titrated up to a maximum dose of 800 mg/day

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Weston Brain Institute

Collaborator

Trials

13

Recruited

990+

Published Research Related to This Trial

Cannabinoids have shown potential neuroprotective effects against Alzheimer's disease by reducing the harmful impacts of beta-amyloid and tau phosphorylation, which are key contributors to neuronal damage.

Targeting cannabinoid receptors may help decrease neuroinflammation associated with Alzheimer's without causing psychoactive effects, suggesting a multi-faceted therapeutic approach that supports brain repair mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alzheimer's disease; taking the edge off with cannabinoids? Campbell, VA., Gowran, A.[2018]

Targeting the endocannabinoid system, particularly through the activation of CB1 and CB2 receptors, shows promise as a therapeutic approach for Alzheimer's disease by mitigating harmful effects of β-amyloid peptides and tau phosphorylation.

Cannabinoid compounds not only reduce neuroinflammation and oxidative stress but also promote the brain's repair mechanisms, suggesting a multifaceted role in potentially slowing the progression of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cannabinoids for treatment of Alzheimer's disease: moving toward the clinic. Aso, E., Ferrer, I.[2021]

In a study of 30 Alzheimer's disease patients aged 65-90, the administration of a THC:CBD cannabis extract for 12 weeks significantly reduced symptoms such as agitation, irritability, and sleep disturbances, improving caregiver distress.

The study also found that 45% of patients showed a significant decrease in cognitive impairment, indicating potential efficacy of cannabis extracts in managing severe symptoms of Alzheimer's disease, despite limitations like the small sample size and lack of a control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral THC: CBD cannabis extract in main symptoms of Alzheimer disease: agitation and weight loss. Palmieri, B., Vadalà, M.[2023]

Two randomized controlled trials of a synthetic form of tetrahydrocannabinol found it to be well tolerated but ineffective in significantly improving neuropsychiatric symptoms in dementia patients, as measured by the neuropsychiatric inventory (NPI).

Some case reports and open-label trials suggest that synthetic cannabinoids may help reduce agitation and other behavioral symptoms when used as an additional treatment, indicating a potential benefit that requires further investigation through well-controlled clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Cannabinoids in Treating Dementia. Weier, M., Hall, W.[2022]

The study highlights a potential new therapeutic approach for Alzheimer's disease by modulating the endocannabinoid system to reduce neuroinflammation, specifically targeting interleukin-1β, an inflammatory cytokine.

Using minocycline in a transgenic mouse model, the research suggests that inhibiting interleukin-1β can enhance the beneficial effects seen with the genetic deletion of fatty acid amide hydrolase, impacting both molecular markers and behavioral outcomes related to memory impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of interleukin 1-beta in the inflammatory response in a fatty acid amide hydrolase-knockout mouse model of Alzheimer's disease. Aparicio, N., Grande, MT., Ruiz de Martín Esteban, S., et al.[2019]

In a systematic review of 26 studies involving 1050 rodents with Alzheimer's-like symptoms, cannabinoid treatment significantly improved cognitive function, as shown by reduced escape latency and enhanced ability to recognize novel objects.

Cannabinoids also led to a significant decrease in amyloid-beta plaques and pro-inflammatory markers, suggesting that they may help protect against neuroinflammation and promote cognitive stability in Alzheimer's disease models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory role of the endocannabinoid system on glial cells toward cognitive function in Alzheimer's disease: A systematic review and meta-analysis of animal studies. Kamaruzzaman, MA., Romli, MH., Abas, R., et al.[2023]

The endocannabinoid system is significantly impacted in Alzheimer's disease (AD), and phytocannabinoids like CBD and THC show promise in reversing cognitive deficits and improving cognition in animal models of AD.

Using a multi-cannabinoid approach, such as whole plant extracts or specific CBD:THC combinations, may enhance therapeutic effects compared to using individual cannabinoid isolates, but more clinical studies are needed to optimize treatment strategies and assess side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic properties of multi-cannabinoid treatment strategies for Alzheimer's disease. Coles, M., Steiner-Lim, GZ., Karl, T.[2022]

In a one-year study involving 51 older adults with Alzheimer's disease, nizatidine did not show any significant effect on delaying cognitive decline compared to a placebo.

Despite initial hopes for nizatidine as a treatment to slow symptom progression in Alzheimer's, the trial results indicate it is ineffective for this purpose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

H2 histamine receptor blockade in the treatment of Alzheimer disease: a randomized, double-blind, placebo-controlled trial of nizatidine. Carlson, MC., Tschanz, JT., Norton, MC., et al.[2019]

In a 6-month observational study involving patients with moderate to severe Alzheimer's disease, memantine treatment at 20 mg/day led to significant improvements in cognitive function and daily activities, with 78.8% of patients showing improvement or stabilization.

Memantine was well-tolerated by patients, reinforcing its safety profile and efficacy as previously established in controlled clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memantine (Ebixa) in clinical practice - results of an observational study. Calabrese, P., Essner, U., Forstl, H.[2013]

In a double-blind, randomized, placebo-controlled trial involving subjects with multiple sclerosis and cognitive impairment, memantine did not show any significant improvement in cognitive performance compared to placebo, as measured by the PASAT and CVLT-II tests.

While memantine was generally safe with no serious adverse events reported, it was associated with increased fatigue and neurological side effects, and family members reported less cognitive improvement and more neuropsychiatric symptoms in those taking memantine compared to those on placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Lovera, JF., Frohman, E., Brown, TR., et al.[2021]

In a study of 371 subjects with mild-to-moderate Alzheimer's disease, the 5-HT6 receptor antagonist SB-742457 showed a significant improvement in caregiver-reported outcomes (CIBIC+) at a 35 mg dose compared to placebo, suggesting potential efficacy in treating Alzheimer's symptoms.

The treatment was generally safe and well tolerated, with adverse events reported in 24-37% of participants receiving SB-742457, which is comparable to the 29% in the placebo group, indicating a similar safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. Maher-Edwards, G., Zvartau-Hind, M., Hunter, AJ., et al.[2022]

Akatinol memantine significantly improved cognitive function, behavior, and mood in patients with mild to moderate Alzheimer's disease, showing similar efficacy to donepezil over a 16-week treatment period with 100 participants.

The treatment was found to be safe, with only mild and transient adverse events reported in 6% of patients, indicating that akatinol memantine is a viable option for managing Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical efficacy and safety of akatinol memantine in treatment of mild to moderate Alzheimer disease: a donepezil-controlled, randomized trial]. Hu, HT., Zhang, ZX., Yao, JL., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41160460/

A randomized clinical trial of low-dose cannabis extract in ... We initially demonstrate that low-dose THC-CBD potentially can be an effective and safe therapeutic option for AD-related dementia. Nonetheless, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06014424

NCT06014424 | Cannabidiol Medication Intervention Trial This study will look at whether CBD is an effective treatment for agitation in Alzheimer's disease (AD). This naturally derived CBD is highly pure (99%) and ...

3. journals.sagepub.com journals.sagepub.com/doi/10.1177/13872877251389608

A randomized clinical trial of low-dose cannabis extract ... Preclinical and clinical evidence suggest that low-dose cannabinoids could ameliorate Alzheimer's disease (AD) signs and symptoms.

4. hopkinsmedicine.org hopkinsmedicine.org/news/newsroom/news-releases/2024/10/clinical-trial-shows-synthetic-cannabis-reduces-agitation-in-alzheimers-disease

Clinical Trial Shows Synthetic Cannabis Reduces Agitation ... New study from @HopkinsMedicine shows synthetic cannabis reduces agitation in patients with Alzheimer's disease. › In a study led by the ...

5. withpower.com withpower.com/trial/phase-2-alzheimer-disease-8-2023-f998d

Cannabinoid Medication for Alzheimer's Disease The study also found that 45% of patients showed a significant decrease in cognitive impairment, indicating potential efficacy of cannabis extracts in managing ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05822362

CBD for Individuals at Risk for Alzheimer's Disease The current study will test the hypothesis that a moderate dose of CBD will improve measures of Alzheimer's disease progression, cognitive function, pain, sleep ...