Delta-9-THC for Age-related Cognitive Decline

(THC-Aging Trial)

Overseen By Deepak C D'Souza

Age: 18 - 65

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

Trial Summary

What is the purpose of this trial?

The primary objective of this study is to determine if increasing age confers greater vulnerability to the acute A) cognitive (e.g., memory, attention, psychomotor function), B) subjective (e.g., anxiogenic and rewarding effects), and C) cardiovascular (heart rate and blood pressure), effects of THC in adults \> 21 years old. The secondary aims of the study are to explore age-related acute effects of THC on electrophysiological indices of information processing (e.g., auditory steady-state response (ASSR), oddball paradigm \[P300\], and resting state cortical noise) and to determine age-related differences in the metabolism of THC. It is hypothesized that increasing age will confer greater vulnerability to THC-induced cognitive impairments, anxiogenic effects, and cardiovascular effects but are less vulnerability to its rewarding effects. Increasing age will confer greater vulnerability to THC-induced deficits in electrophysiological indices of information processing including.

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.

What data supports the effectiveness of the drug Delta-9-THC for age-related cognitive decline?

Research on mice has shown that very low doses of Delta-9-THC can improve memory and learning in older mice, making them perform like younger mice. Additionally, studies suggest that cannabinoids, like THC, may help reduce symptoms related to dementia and Alzheimer's disease in older people. ^{1 2 3 4 5}

Is Delta-9-THC safe for humans?

Delta-9-THC has been shown to be generally safe and well-tolerated in humans, including older adults, though it can cause side effects like drowsiness and dry mouth. It may also affect memory, perception, and mental tasks, but long-term effects are not well-known. The European Food Safety Authority has set a safe intake level for THC in food, indicating it does not pose a substantial risk to public health. ^{6 7 8 9 10}

How does the drug Delta-9-THC differ from other treatments for age-related cognitive decline?

Delta-9-THC is unique because it uses an extremely low dose that improves cognitive function in aging without causing the typical psychoactive effects associated with cannabis. This low dose increases levels of Sirtuin1, an enzyme linked to brain protection and adaptability, and enhances brain structure and function, making it a novel approach compared to other treatments. ^{1 3 11 12 13}

Research Team

Deepak C D'Souza, MD

Principal Investigator

Yale University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Delta-9-THC Active Control 1 Intervention

Active delta-9-THC (0.03 mg/kg) administered intravenously over 20 minutes.

Group II: 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+

Findings from Research

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]

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Safety, pharmacodynamics, and pharmacokinetics of multiple oral doses of delta-9-tetrahydrocannabinol in older persons with dementia. [2022]

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

Cannabinoids in late-onset Alzheimer's disease. [2015]

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

Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of medical cannabinoids in older subjects: a systematic review. [2018]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia: An-Open Label, Add-On, Pilot Study. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: a randomized controlled trial. [2014]

7. England pubmed.ncbi.nlm.nih.gov

A broader view on deriving a reference dose for THC traces in foods. [2022]

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

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

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

The effect of delta 9-tetrahydrocannabinol on the extinction of an adverse associative memory. [2019]

10. England pubmed.ncbi.nlm.nih.gov

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

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

Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors. [2018]

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

A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice. [2018]

13. Switzerland 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. [2023]