Genetics and Cannabinoid Response for Cannabis Use Disorder

Overseen By Christina Luddy, BS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Disqualifiers: Major medical conditions, cannabis naïve, pregnancy, others

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 day

215 Participants Needed

Trial Summary

What is the purpose of this trial?

Cannabis is widely used worldwide and is associated with negative outcomes including cannabis use disorder (CanUD), psychosis, and cognitive impairment amongst others. Given the legalization of "recreational" and "medical" cannabis globally, the increasing availability of cannabis, the higher potency of cannabis, the availability of highly potent cannabinoid products, the commercialization of cannabis, and the rising rates of cannabis use, it is critical to understand how genetic factors influence 1) an individual's vulnerability for addiction and psychosis, 2) the response to cannabinoids, 3) the response to novel treatments for CanUD. CanUD is strongly genetically influenced; the investigators published the first CanUD genomewide association study (GWAS) with genomewide-significant results; however, the precise nature of the contribution of genetic factors in the development of CanUD is still not clear. Cannabis exposure has also been linked to a number of psychosis outcomes including schizophrenia (SCZ). SCZ is highly heritable and population-based and genetics studies both support a bidirectional genetic relationship between SCZ and CanUD. However, the precise contribution of genetic factors in the development of psychosis outcomes related to cannabis are not clear.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

Is Delta-9-THC generally safe for human use?

Research suggests that Delta-9-THC, when used in a controlled and monitored setting, has a reasonable safety profile for medical purposes, with most adverse effects being mild to moderate. However, it can cause some acute effects like increased heart rate, low blood pressure when standing, and mental effects such as anxiety or paranoia, so monitoring is important. ^{1 2 3 4 5}

How is the drug Delta-9-THC unique in treating cannabis use disorder?

Delta-9-THC (Dronabinol) is unique because it directly targets the same cannabinoid receptors in the brain that are affected by cannabis, potentially helping to reduce withdrawal symptoms and cravings. This approach is different from other treatments that may not directly interact with these specific receptors. ^{6 7 8 9 10}

Research Team

Deepak D'Souza, MD

Principal Investigator

Yale University

Eligibility Criteria

This trial is for people aged 18-60 who have used cannabis and may struggle with addiction (CanUD) or have experienced psychosis. It's not for those with major health issues, no history of cannabis use, or pregnant individuals.

Inclusion Criteria

I am between 18 and 60 years old.

Exclusion Criteria

Positive pregnancy test

I do not have any major or unstable health conditions.

Cannabis naïve individuals

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

1 visit (in-person)

Assessment

Participants are assessed using various scales including PANSS, VAS, CADSS, and CogState Battery at multiple time points after drug infusion

6 hours

1 visit (in-person)

Follow-up

Participants are monitored for any delayed effects or adverse reactions post-treatment

1-2 weeks

Treatment Details

Interventions

• Delta-9-THC

Trial Overview Researchers are testing the effects of Delta-9-THC (the active component in cannabis) against a placebo to understand how genetics influence addiction, response to cannabinoids, and potential treatments for CanUD.

Participant Groups

Group I: Delta-9-THC Active Control 2 Interventions

Active delta-9-THC (0.036 mg/kg) administered intravenously over 20 minutes.

Group II: Placebo Placebo Group 2 Interventions

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

Delta-9-THC is already approved in United States, Canada for the following indications:

Approved in United States as Marinol for:

• HIV/AIDS-induced anorexia
• chemotherapy-induced nausea and vomiting

Approved in United States as Syndros for:

• HIV/AIDS-induced anorexia
• chemotherapy-induced nausea and vomiting

Approved in Canada as REDUVO for:

• HIV/AIDS-induced anorexia
• chemotherapy-induced nausea and vomiting

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

A study involving 431 individuals with chronic non-cancer pain found that using a standardized herbal cannabis product for one year did not increase the risk of serious adverse events compared to non-users, suggesting a reasonable safety profile for medical cannabis.

However, cannabis users experienced a higher rate of non-serious adverse events, mostly mild to moderate, indicating that while cannabis may be safe for serious complications, it can still lead to some side effects that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). Ware, MA., Wang, T., Shapiro, S., et al.[2022]

The metabolism of THC is significantly influenced by genetic variations in the CYP2C9 enzyme, with individuals carrying the CYP2C9*3 variant showing reduced exposure to the active metabolite THC-COOH, which may have therapeutic implications.

THC is primarily cleared from the body through liver metabolism, and its clearance is dependent on liver blood flow rather than protein binding, indicating that the route of administration (IV or inhalation) does not significantly affect THC elimination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minimal Physiologically Based Pharmacokinetic Model of Intravenously and Orally Administered Delta-9-Tetrahydrocannabinol in Healthy Volunteers. Wolowich, WR., Greif, R., Kleine-Brueggeney, M., et al.[2020]

The safety of cannabis and cannabinoid medications is a significant concern, and while some safety information can be drawn from recreational use studies, medical and recreational users may experience different effects.

There is a pressing need for long-term safety monitoring of cannabinoid use in patients, as clinical experience is still developing, which will help inform both therapeutic decisions and public policy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety issues concerning the medical use of cannabis and cannabinoids. Ware, MA., Tawfik, VL.[2019]

Clinical studies on cannabis administration are essential for understanding its effects and developing treatments for cannabis dependence, with different methods of administration (smoking, oral, intravenous) each having unique safety and efficacy profiles.

Acute adverse effects from cannabis can include tachycardia, cognitive impairment, and anxiety, necessitating careful screening and monitoring of participants to ensure safety during research studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methods for clinical research involving cannabis administration. Gorelick, DA., Heishman, SJ.[2019]

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]

Cannabis use has a moderate heritability, meaning genetics play a significant role in individual differences in usage patterns, especially in more severe cases, as shown by twin studies.

Genome-wide association studies (GWAS) have identified several genetic variants linked to cannabis use, indicating a genetic overlap with other traits like substance use and mental health disorders, particularly schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The genetic aetiology of cannabis use: from twin models to genome-wide association studies and beyond. Verweij, KJH., Vink, JM., Abdellaoui, A., et al.[2023]

The heritability of cannabis use varies by different usage patterns, indicating that specific gene variants may influence factors like age of first use, overall usage, and the development of cannabis use disorder.

Identifying genetic risk factors associated with cannabis use can help understand the biological mechanisms behind it and may lead to new interventions and treatments for those struggling with cannabis dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High genes: Genetic underpinnings of cannabis use phenotypes. Thorpe, HHA., Talhat, MA., Khokhar, JY.[2021]

Heritable factors account for 50-70% of the variation in cannabis use and use disorders, indicating a significant genetic component to these behaviors.

Current research suggests that larger sample sizes are needed to identify specific genetic variants associated with cannabis involvement, which could lead to advancements in understanding and treating cannabis use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic and Environmental Factors Associated with Cannabis Involvement. Bogdan, R., Winstone, JM., Agrawal, A.[2023]

Genetic factors play a significant role in cannabinoid use and dependence, but current studies show low reproducibility and little overlap in identified candidate genes due to small sample sizes and varied populations.

Recent well-powered studies indicate that the genetic basis for cannabis use is similar to other substance use disorders, suggesting that larger, more focused studies could help identify additional genetic risk factors for cannabis dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Factors in Cannabinoid Use and Dependence. Mulligan, MK.[2019]

A large genome-wide association study involving 20,916 cases and 363,116 controls identified two significant genetic loci associated with cannabis use disorder, suggesting a strong genetic component to the disorder.

The study found that cannabis use disorder shares genetic liability with other mental health issues like ADHD and major depression, indicating that while cannabis use and cannabis use disorder are related, they have different genetic influences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A large-scale genome-wide association study meta-analysis of cannabis use disorder. Johnson, EC., Demontis, D., Thorgeirsson, TE., et al.[2023]

References

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

Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). [2022]

2. France pubmed.ncbi.nlm.nih.gov

Minimal Physiologically Based Pharmacokinetic Model of Intravenously and Orally Administered Delta-9-Tetrahydrocannabinol in Healthy Volunteers. [2020]

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

Safety issues concerning the medical use of cannabis and cannabinoids. [2019]

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

Methods for clinical research involving cannabis administration. [2019]

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

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

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

The genetic aetiology of cannabis use: from twin models to genome-wide association studies and beyond. [2023]

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

High genes: Genetic underpinnings of cannabis use phenotypes. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Genetic and Environmental Factors Associated with Cannabis Involvement. [2023]

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

Genetic Factors in Cannabinoid Use and Dependence. [2019]

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

A large-scale genome-wide association study meta-analysis of cannabis use disorder. [2023]