Delta-9-THC for Age-related Cognitive Decline

(THC-Aging Trial)

Overseen By Ashley Schnakenberg Martin, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Disqualifiers: Serious mental illness, Psychosis, Neurological disease, others

Compensation: Varies

Number of Visits: 2

Duration: 1 day

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how Delta-9-THC, a compound in cannabis, affects memory, attention, and heart health in adults over 21. Researchers aim to determine if aging increases sensitivity to these effects. The trial includes a placebo group and two different doses of Delta-9-THC. It suits individuals who have completed high school, speak English, and do not have serious health issues. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that delta-9-THC can affect thinking and memory in various ways, depending on the dosage and duration of use. In some studies with mice, small amounts of THC improved memory and learning in older mice, suggesting potential benefits for memory problems in older people.

However, other studies found that THC might slightly impair thinking skills in the short term, with these effects typically disappearing after a few hours. Since this trial is in its early stages, the primary goal is to assess the treatment's safety and tolerability.

This is crucial because, although THC is already used for other medical purposes, each new application requires thorough testing to ensure safety. Early results indicate that delta-9-THC is mostly safe, but researchers continue to study how different dosages might affect people, particularly as they age. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for age-related cognitive decline, such as cholinesterase inhibitors or memantine, which primarily aim to improve symptoms by boosting neurotransmitters like acetylcholine, Delta-9-THC offers a novel approach. This compound, derived from cannabis, potentially targets the endocannabinoid system, which may play a role in cognitive processes. Researchers are excited about this treatment because its distinct mechanism could offer benefits that standard medications might not, potentially addressing cognitive decline from a completely different angle. Additionally, the method of delivering Delta-9-THC intravenously could allow for more controlled dosing and quicker onset of effects.

What evidence suggests that this trial's treatments could be effective for age-related cognitive decline?

Research has shown that delta-9-THC might help with memory and learning problems associated with aging. Studies in mice have found that small amounts of THC can improve learning and memory in older mice. In some cases, even very tiny doses of THC reversed memory issues related to aging. These results suggest that THC might help with similar problems in older humans. However, most of this evidence comes from animal studies, so researchers are still learning about its effects on people. In this trial, participants will receive either a placebo or varying doses of delta-9-THC to evaluate its impact on age-related cognitive decline. ^{6 7 8 9 10}

Who Is on the Research Team?

Deepak C D'Souza, MD

Principal Investigator

Yale University School of Medicine; VA Connecticut Healthcare System

Ashley Schnakenberg Martin, PhD

Principal Investigator

Yale University School of Medicine; VA Connecticut Healthcare System

Are You a Good Fit for This Trial?

This trial is for adults over 21 years old who may be experiencing age-related cognitive decline or mild cognitive impairment. Participants should not have any conditions that could interfere with the study, such as current substance abuse or certain medical conditions.

Inclusion Criteria

No family history of psychosis

At least one lifetime use of cannabis and/or THC in the past ten years

Negative urine screen for illicit substance use

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either active delta-9-THC or placebo intravenously over 20 minutes

1 day

2 drug administration sessions per test day

Follow-up

Participants are monitored for cognitive, subjective, and cardiovascular effects of THC

1 day

Multiple assessments throughout the day

What Are the Treatments Tested in This Trial?

Interventions

• Delta-9-THC

Trial Overview The study is testing the effects of Delta-9-THC compared to a placebo on older adults' cognition, mood, and cardiovascular health. It also examines how aging affects THC metabolism and information processing in the brain.

How Is the Trial Designed?

Group I: Delta-9-THC Very Low Dose Active Control 1 Intervention

Active delta-9-THC administered intravenously over 20 minutes.

Group II: Delta-9-THC Medium Dose Active Control 1 Intervention

Active delta-9-THC administered intravenously over 20 minutes.

Group III: Placebo Placebo Group 1 Intervention

Control: Small amount of alcohol administered intravenously (quarter teaspoon), with no delta-9-THC, over 20 minutes.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

In a study involving 10 dementia patients, THC was found to be rapidly absorbed with dose-linear pharmacokinetics, showing significant interindividual variability in how patients responded to the drug.

Only a few adverse events were related to THC, indicating that it may be safe for use in dementia patients, although further research is needed to explore the effects and efficacy of higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, pharmacodynamics, and pharmacokinetics of multiple oral doses of delta-9-tetrahydrocannabinol in older persons with dementia. Ahmed, AI., van den Elsen, GA., Colbers, A., et al.[2022]

In a phase 1 trial involving 12 healthy older adults (average age 72), the THC-based drug Namisol(®) was found to be safe and well tolerated, with drowsiness and dry mouth being the most common side effects.

Higher doses of THC (6.5mg) led to more adverse events compared to lower doses (3mg and 5mg), indicating that while THC is generally safe, careful dosing is important for older individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: a randomized controlled trial. Ahmed, AI., van den Elsen, GA., Colbers, A., et al.[2014]

Chronic exposure to vaporized cannabis high in Δ9-THC provided effective pain relief without developing tolerance, but did not improve anxiety or cognitive function, indicating its potential as an analgesic for older adults.

In contrast, chronic use of CBD enhanced brain network connectivity, effects that persisted even after stopping the drug, suggesting it may have long-term benefits for brain health, although its behavioral implications are still unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of inhaled cannabis high in Δ9-THC or CBD on the aging brain: A translational MRI and behavioral study. Sadaka, AH., Canuel, J., Febo, M., et al.[2023]

A survey of delta-8-THC consumers revealed that over half (51%) use it to treat various health conditions, with anxiety and stress being the most common, suggesting potential therapeutic benefits.

Participants reported favorably comparing delta-8-THC to delta-9-THC and pharmaceutical drugs, indicating it may have similar efficacy with potentially fewer adverse effects, although knowledge about safe dosages and medical integration remains low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consumer Experiences with Delta-8-THC: Medical Use, Pharmaceutical Substitution, and Comparisons with Delta-9-THC. Kruger, DJ., Kruger, JS.[2023]

Delta(9)-tetrahydrocannabinol (Delta(9)-THC) has well-documented therapeutic benefits, including reducing nausea from chemotherapy, increasing appetite, alleviating pain, and relieving symptoms of multiple sclerosis, supported by extensive research over the past 30 years.

While Delta(9)-THC can impair cognitive functions such as memory and perception, and may induce negative psychological effects like panic and hallucinations, the long-term impacts are still unknown, leading to a proposal by WHO to reschedule it as a low-risk substance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The good and the bad effects of (-) trans-delta-9-tetrahydrocannabinol (Delta 9-THC) on humans. Carlini, EA.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8435893/

Efficacy of Δ9 -Tetrahydrocannabinol (THC) Alone or in ... The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.

2. nature.com nature.com/articles/s41598-022-27146-2

tetrahydrocannabinol (THC) treatment stabilizes dendritic ... We have shown that a low dose chronic THC treatment improves learning abilities in old whereas impairs learning abilities in young mice.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0197458017303214

Reversal of age-related cognitive impairments in mice by ... This study was designed to test our hypothesis that an ultra-low dose of delta-9 tetrahydrocannabinol (THC) reverses age-dependent cognitive impairments in old ...

4. liebertpub.com liebertpub.com/doi/10.1177/25785125251394916

Cannabis, Aging and Cognition: An Urgent Need for ... In contrast to young mice, chronic low-dose THC improved spine density and reversed age-related cognitive decline in memory and learning tasks ...

5. biorxiv.org biorxiv.org/content/10.1101/2021.08.22.457252.full

An ultra-low dose of Δ9-tetrahydrocannabinol improves ... The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mice model of AD after disease onset.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7259587/

A Systematic Review of the Neurocognitive Effects ... Recent in vivo and in vitro studies have shown that chronic low doses of THC paradoxically reverse age-related cognitive dysfunction in old mice, promote ...

7. frontiersin.org frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.718850/full

Efficacy of Δ 9 -Tetrahydrocannabinol (THC) Alone or in ... The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.

8. movementdisorders.onlinelibrary.wiley.com movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29447

Cognitive Safety Data from a Randomized, Double‐Blind ... Data suggest this CBD/THC drug has a small detrimental effect on cognition following acute/short-term use in PD.

9. sciencedirect.com sciencedirect.com/science/article/pii/S0149763421000178

tetrahydrocannabinol (Δ 9 -THC)-induced driving and ... Most driving-related skills are predicted to recover within ∼5-hs (and almost all within ∼7-hs) of inhaling 20 mg Δ 9 -THC.

10. liebertpub.com liebertpub.com/doi/full/10.1177/25785125251394916

Cannabis, Aging and Cognition: An Urgent Need for ... In contrast to young mice, chronic low-dose THC improved spine density and reversed age-related cognitive decline in memory and learning tasks ...