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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how genetics influence responses to delta-9-THC, a compound in cannabis, and its potential to treat cannabis use disorder (CanUD). Researchers aim to understand why some individuals are more susceptible to addiction and psychosis from cannabis use. Participants will receive either a placebo or varying doses of delta-9-THC to observe their physical and mental reactions. Frequent cannabis users experiencing related issues might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, providing participants an opportunity to contribute to groundbreaking insights.

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

Research has shown that delta-9-THC, the active ingredient tested in this trial, has been studied for its effects and safety in people. Some studies indicate that THC use can lead to issues like psychosis, a mental disorder where someone loses touch with reality. High doses of THC might increase the chance of these effects. However, this trial uses very low to medium doses of THC, which might be safer than higher doses.

Another study examined THC's impact on driving and found that it can impair driving skills at various doses, indicating that even lower doses can affect the body and mind. Overall, THC can cause some side effects, but the risk depends on the dose and usage.

As this is an early-stage trial, the main goal is to understand safety and how well people tolerate the treatment. Researchers are closely monitoring for any side effects or problems. If there are concerns about joining a trial, discussing them with a healthcare provider is advisable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for cannabis use disorder, which often involve behavioral therapy and medications like naltrexone or bupropion, the investigational treatment uses delta-9-THC, a compound from cannabis itself. This approach is unique because it leverages a very low or medium dose of delta-9-THC, administered intravenously, to potentially modulate the body’s response to cannabis and reduce dependency. Researchers are excited about this treatment because it targets the endocannabinoid system directly, offering a novel mechanism compared to traditional methods. This innovative approach could pave the way for a more targeted and effective solution for those struggling with cannabis use disorder.

What evidence suggests that Delta-9-THC might be an effective treatment for cannabis use disorder?

This trial will compare different doses of delta-9-THC to a placebo to evaluate its effectiveness for cannabis use disorder (CanUD). Research suggests that delta-9-THC, a key ingredient in cannabis, might aid in managing CanUD. Studies have shown that dronabinol, a synthetic version of THC, can ease withdrawal symptoms and cravings when someone stops using cannabis. Nabiximols, which contains both THC and CBD, has also been found to help reduce these symptoms. Although these studies indicate possible benefits, more research is needed to confirm the effectiveness of delta-9-THC specifically for treating CanUD. ^{4 6 7 8 9}

Who Is on the Research Team?

Deepak D'Souza, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

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.

Exclusion Criteria

Positive pregnancy test

I do not have any major or unstable health conditions.

Cannabis naïve individuals

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

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

What Are the Treatments Tested in This Trial?

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.

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.

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

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High-Concentration Delta-9-Tetrahydrocannabinol ... Data extraction: Outcomes included anxiety, depression, psychosis or schizophrenia, and cannabis use disorder (CUD). Results were ...

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Effectiveness of cannabis use and cannabis use disorder ... This data synthesis examined the effectiveness of behavioural and pharmacological approaches for cannabis treatment.

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Efficacy of cannabidiol alone or in combination with Δ‐9‐ ... Nabiximols, which contains CBD and THC, demonstrated positive effects on cannabis withdrawal and craving symptoms. Evidence supporting the ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0149763421005273

Cannabinoids for the treatment of cannabis use disorder Dronabinol decreased withdrawal symptoms compared to placebo during cannabis abstinence. Dronabinol decreased ratings of cannabis craving compared to placebo.

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Cannabis Use Disorder - StatPearls - NCBI Bookshelf Cannabis use can cause intoxication, withdrawal, and biopsychosocial issues. A range of disorders are associated, including psychosis, sleep disorders, ...

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NCT07176208 | Clinical Study to Evaluate the Effects of ... The results of this study will address current knowledge gaps on the effects of oral Δ9-THC on driving impairment across a clinically relevant dose range.

8. samhsa.gov samhsa.gov/substance-use/learn/marijuana/risks

Know the Effects, Risks and Side Effects of Marijuana Research shows that people who use marijuana are more likely to have relationship problems, worse educational outcomes, lower career achievement, and reduced ...

9. ajph.aphapublications.org ajph.aphapublications.org/doi/full/10.2105/AJPH.2024.307823

Current Cannabis Use in the United States: Implications for ... In the long term, this includes increased cardiovascular and pulmonary disease risk; pregnancy and neonatal outcomes such as premature birth, ...