Cannabinoid Medication for Alzheimer's Disease

(CALM-IT Trial)

Recruiting at 2 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

Trial Summary

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.

What data supports the effectiveness of the drug JZP541 for Alzheimer's disease?

While there is no direct data on JZP541, similar drugs like memantine, which is used for moderate to severe Alzheimer's disease, have shown effectiveness in improving cognitive function. This suggests that JZP541 might also be beneficial for Alzheimer's patients. ^{1 2 3 4 5}

Is cannabinoid medication safe for humans?

Cannabinoid medications, including those with CBD and THC, have been studied for their safety in humans, showing potential benefits like reducing inflammation and protecting brain cells. However, more clinical studies are needed to fully understand their safety and optimal use, especially in older adults with Alzheimer's disease. ^{6 7 8 9 10}

How is the drug JZP541 different from other Alzheimer's treatments?

JZP541 is unique because it targets the endocannabinoid system, which may help protect brain cells, reduce inflammation, and support brain repair mechanisms, unlike current treatments that do not address these aspects. ^{7 8 9 11 12}

What is the purpose of this trial?

CALM-IT is a Randomized, double-blind, placebo-controlled cross-over clinical trial. Safety and efficacy of cannabidiol (CBD) capsules assessed for managing agitation in patients with AD and to identify novel biomarkers of agitation severity and treatment response.

Research Team

Krista L. Lanctot, PhD

Principal Investigator

Sunnybrook Research Institute

Giovanni Marotta

Principal Investigator

Sunnybrook Health Sciences Centre

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

H2 histamine receptor blockade in the treatment of Alzheimer disease: a randomized, double-blind, placebo-controlled trial of nizatidine. [2019]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Memantine (Ebixa) in clinical practice - results of an observational study. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. [2021]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. [2022]

5. China 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]. [2018]

6. Italy pubmed.ncbi.nlm.nih.gov

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

7. Switzerland 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. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Alzheimer's disease; taking the edge off with cannabinoids? [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic properties of multi-cannabinoid treatment strategies for Alzheimer's disease. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

The Use of Cannabinoids in Treating Dementia. [2022]

11. England 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. [2019]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Cannabinoids for treatment of Alzheimer's disease: moving toward the clinic. [2021]