Cannabis Abstinence for Cannabis Use Disorder

Overseen By Stylianos Mysirlidis, B.S.

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Yale University

Must not be taking: Psychotropic medications

Disqualifiers: Substance use disorder, Psychiatric disorder, Neurological illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore the effects of stopping cannabis use on brain function and chemistry in people with cannabis use disorder. Researchers will study brain activity and cognitive function (how well the brain works) using special imaging techniques, including [18F]FPEB with PET (a type of brain imaging). Participants in two groups—those with cannabis use disorder and healthy individuals—will undergo testing before and after a period of cannabis abstinence. Ideal candidates for the study include those diagnosed with cannabis use disorder who are willing to attempt abstinence.

As an Early Phase 1 trial, this research focuses on understanding how stopping cannabis use affects the brain, offering participants a unique opportunity to contribute to groundbreaking insights.

Do I have to stop taking my current medications for the trial?

Yes, you must stop taking any psychotropic or potentially psychoactive prescription medications to participate in this trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that certain supportive methods, such as motivational talks and reward-based programs, are generally safe for individuals trying to quit cannabis. These methods have helped adults with cannabis use disorder (CUD) stop or reduce their cannabis use. However, about 12-17% of cannabis users may experience withdrawal symptoms when quitting. These symptoms can include irritability, sleep disturbances, and anxiety, but they are not considered dangerous. Prospective trial participants should understand what to expect, which can help ease concerns about the process. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how cannabis abstinence, combined with motivational enhancement and contingency management, could impact cannabis use disorder (CUD). Unlike traditional treatments that often involve medication, this approach focuses on behavioral strategies to encourage abstinence, which could offer a drug-free alternative for individuals with CUD. By using advanced neuroimaging and cognitive testing, the trial aims to uncover how abstinence affects brain function and cognition. This could lead to a better understanding of CUD and more effective, non-pharmacological treatment options.

What evidence suggests that cannabis abstinence might be an effective treatment for cannabis use disorder?

This trial will compare cannabis abstinence in participants with cannabis use disorder (CUD) to healthy controls. Research has shown that reducing cannabis use can significantly benefit individuals with CUD. For instance, using cannabis about half as often and cutting the amount by about 75% correlates with improved health outcomes, according to doctors. Completely stopping cannabis use can also help identify patients more likely to succeed long-term. In this trial, participants with CUD will receive motivational enhancement and contingency management during a 4-week abstinence period. Overall, these findings suggest that reducing or stopping cannabis use can effectively aid those dealing with CUD. ^{1 5 6 7 8}

Who Is on the Research Team?

Stephen R Baldassarri, M.D.

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults with Cannabis Use Disorder (CUD) who have used cannabis more than 20 times but don't have other substance use disorders or major psychiatric conditions. They must be physically healthy, not pregnant or breastfeeding, and have an IQ over 80. Healthy controls (HC) with no recent cannabis use can also participate.

Inclusion Criteria

Urine toxicology evidence of cannabinoid use

Your scores on the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) demonstrate a full scale and verbal IQ of 80 or greater.

HC and CUD Group:

Exclusion Criteria

Other substance use disorder within 1 year, except for nicotine

Pregnancy or breastfeeding (women).

I have a history of seizures or epilepsy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo neuroimaging, cognitive testing, and EEG at baseline

1 day

1 visit (in-person)

Abstinence and Follow-up

CUD participants undergo motivational enhancement and contingency management during a 4-week abstinence period, followed by neuroimaging, cognitive testing, and EEG

4 weeks

1 visit (in-person) at the end of 4 weeks

Follow-up

Participants are monitored for changes in mGluR5 availability, neural oscillations, and cognitive function

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• [18F]FPEB with PET
• Cannabis abstinence

Trial Overview The study investigates how stopping cannabis affects brain chemistry, brain waves, and thinking in people with CUD using PET scans to measure a specific receptor and EEG to monitor brain activity. It compares these findings between regular cannabis users and non-users.

How Is the Trial Designed?

Group I: Healthy control Experimental Treatment 1 Intervention

Healthy control participants undergo neuroimaging, cognitive testing, and EEG at baseline.

Group II: Cannabis use disorder Experimental Treatment 2 Interventions

CUD participants participants undergo neuroimaging, cognitive testing, and EEG at baseline and following cannabis abstinence at 4 weeks follow-up. Participants will receive motivational enhancement and contingency management during the 4-week abstinence period.

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

Adolescent exposure to high levels of THC from cannabis can lead to long-term cognitive and social performance issues in adulthood, highlighting a critical vulnerability during neurodevelopment.

Cannabidiol (CBD) shows promise as a therapeutic agent for treating neuropsychiatric disorders, particularly when used as an early intervention during adolescence to mitigate the negative effects of THC exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phytocannabinoids and schizophrenia: Focus on adolescence as a critical window of enhanced vulnerability and opportunity for treatment. Stark, T., Di Martino, S., Drago, F., et al.[2022]

A single oral dose of 750 mg of cannabidiol (CBD) showed significantly increased exposure when taken with a high-fat/calorie meal, with a 3.8-fold increase in overall exposure (AUC0-∞) and a 5.2-fold increase in maximum concentration (Cmax) compared to fasting.

CBD was well-tolerated with no severe adverse events reported, indicating its safety in healthy adults, while its absorption was also enhanced by low-fat meals, whole milk, and alcohol, albeit to a lesser extent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects. Crockett, J., Critchley, D., Tayo, B., et al.[2021]

In a pilot study involving 40 cannabis-dependent participants, nabiximols (a combination of THC and CBD) was well tolerated with no serious adverse events, indicating it is a safe option for treatment.

While nabiximols did not significantly improve abstinence rates compared to placebo, it did help reduce cannabis craving and allowed for a notable reduction in cannabis use in both treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial. Trigo, JM., Soliman, A., Quilty, LC., et al.[2023]

In a study of 47 patients with refractory epilepsy, highly purified cannabidiol (CBD) was found to be effective in reducing seizure frequency, regardless of whether it was used with clobazam (CLB) or not.

Patients taking CBD alongside CLB had a significantly higher responder rate (more than 50% reduction in seizures) at the point of best seizure control within the first year, indicating that combining these treatments may enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam. Savage, TE., Sourbron, J., Bruno, PL., et al.[2021]

A review of 207 studies identified only 3 randomized clinical trials (RCTs) specifically focused on using cannabidiol (CBD) for cannabis use disorder, highlighting a significant gap in research for CBD's efficacy in treating substance use disorders.

Ongoing trials are enhancing outcome measures by incorporating peripheral biomarkers from the endocannabinoid system, which may help predict how well individuals respond to CBD treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Trials of Cannabidiol for Substance Use Disorders: Outcome Measures, Surrogate Endpoints, and Biomarkers. Morel, A., Lebard, P., Dereux, A., et al.[2021]

Cannabidiol (CBD), specifically in its oral formulation Epidiolex, has been shown to have very low abuse potential and is unlikely to cause physical dependence, as demonstrated by studies in rats and nonhuman primates that showed no significant self-administration or withdrawal signs after chronic treatment.

The pharmacokinetic studies confirmed that the doses used in the experiments resulted in therapeutically relevant plasma levels, supporting the safety and efficacy of CBD for treating seizures in severe forms of epilepsy without the risks associated with addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence. Gray, RA., Heal, DJ., Maguire, DR., et al.[2022]

A clinical case study of a male patient with schizophrenia and substance use disorders showed that using CBD cigarettes with low THC content (<1%) helped reduce his cravings for high-THC cannabis and led to a cessation of cocaine use.

After 8 years of frequent hospitalizations due to psychotic relapses and substance use, the patient has not been hospitalized since starting the CBD treatment, suggesting that CBD may be a promising adjunctive therapy for cannabis use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: CBD Cigarettes for Harm Reduction and Adjunctive Therapy in a Patient With Schizophrenia and Substance Use Disorder. Meyer, M., Walter, M., Borgwardt, S., et al.[2021]

In a proof of concept study involving nine cannabis-dependent participants over 8 weeks, high fixed doses of Sativex significantly reduced cannabis withdrawal symptoms during abstinence compared to placebo, indicating its potential efficacy in managing withdrawal.

Self-titrated doses of Sativex were less effective than high fixed doses, and while Sativex reduced the 'high' experienced by participants, it did not significantly impact cravings for cannabis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. Trigo, JM., Lagzdins, D., Rehm, J., et al.[2023]

In a study of 139 participants with treatment-resistant epilepsy, the use of highly purified cannabidiol (CBD; Epidiolex®) led to significant reductions in adverse events, seizure severity, and seizure frequency over 12 weeks, with improvements sustained for up to 48 weeks.

The study demonstrated that CBD was well-tolerated, with a decrease in adverse events from 40.8 to 33.2 and a reduction in seizure severity scores from 80.7 to 39.2, indicating its efficacy as a treatment option for epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Szaflarski, JP., Bebin, EM., Cutter, G., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11910397/

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

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12272737/

Cannabis use reduction is associated with improved ... Reductions in cannabis use (~50% reduction in use days and ~75% reduction in amount) were associated with clinician-assessed improvement and ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2949875923000693

Monitoring adherence and abstinence of cannabis use ... Research has shown adherence and abstinence indicators to be useful for identifying subgroups of patients with different prognoses regarding long-term success.

4. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/add.70084

Effectiveness and safety of psychosocial interventions for ... Aim To evaluate the effectiveness, safety and cost-effectiveness of psychosocial interventions for cannabis use disorder (CUD).

5. jci.org jci.org/articles/view/172887

Cannabis use disorder: from neurobiology to treatment Trials have shown that individually both MET and CBT lead to modest improvements in cannabis-related outcomes (including reduced frequency and ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0376871622003192

Review Identifying risk-thresholds for the association ... A limited risk of CUD as a potential outcome of cannabis use exists even at infrequent levels of use, but significantly increases as frequency of use increases.

7. link.springer.com link.springer.com/article/10.1007/s00406-024-01829-5

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

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8655458/

Cannabis use and cannabis use Disorder - PMC Data predominantly from North America estimate the prevalence of cannabis withdrawal syndrome in the general population of cannabis users at 12–17%.