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

6 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will be the first in vivo human multimodal neuroimaging study exploring the relationship between mGluR5 availability (PET), neural oscillations (EEG), and cognitive function in people with CUD. The goal is to test the overall hypothesis that mGluR5 availability is higher in people with CUD compared with HC. In Aim 1, the investigators will determine differences in mGluR5 availability between people with CUD and HC in the fronto-limbic brain circuit. Aim 2 examines the associations between mGluR5 availability, CUD severity, neural oscillations, and cognitive function in CUD subjects. Aim 3 will determine how prolonged abstinence from chronic cannabis use affects mGluR5 availability, neural oscillations, and cognitive function in CUD subjects.

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.

What data supports the idea that Cannabis Abstinence for Cannabis Use Disorder is an effective treatment?

The available research shows that using Sativex, a combination of THC and CBD, can help reduce cannabis withdrawal symptoms and cravings. In a study with nine participants, Sativex was tested for its effects on withdrawal and cravings, suggesting it might be helpful for those trying to quit cannabis. Additionally, a pilot study with nabiximols, which is similar to Sativex, showed it could be safe and tolerable for people seeking treatment for cannabis dependence. These findings suggest that cannabis abstinence, supported by treatments like Sativex, can be effective for managing withdrawal and reducing cravings in cannabis use disorder. ^{1 2 3 4 5}

What safety data exists for cannabis abstinence treatments like Epidiolex and Sativex?

Safety data for cannabis abstinence treatments, such as Epidiolex and Sativex, indicate that Epidiolex (a formulation of cannabidiol or CBD) has very low abuse potential and is unlikely to produce physical dependence. Studies show that CBD does not maintain self-administration in animals, does not increase drug-lever responding, and does not produce withdrawal symptoms upon discontinuation. Additionally, a study on Sativex, which contains both THC and CBD, assessed its effects on cannabis withdrawal and cravings, suggesting its potential use in managing cannabis dependence. Overall, these treatments appear to be safe with a low risk of abuse. ^{1 5 6 7 8}

Is the drug used in the trial 'Cannabis Abstinence for Cannabis Use Disorder' a promising treatment?

Yes, the drug, which includes cannabidiol (CBD), shows promise as a treatment for cannabis use disorder. Studies suggest that CBD can help reduce cravings and withdrawal symptoms without causing dependence, making it a potentially effective option for those trying to quit cannabis. ^{1 3 4 5 9}

Research Team

Stephen R Baldassarri, M.D.

Principal Investigator

Yale University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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]

References

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

Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence. [2022]

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

Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: A pilot randomized clinical trial. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: CBD Cigarettes for Harm Reduction and Adjunctive Therapy in a Patient With Schizophrenia and Substance Use Disorder. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Trials of Cannabidiol for Substance Use Disorders: Outcome Measures, Surrogate Endpoints, and Biomarkers. [2021]

5. Ireland pubmed.ncbi.nlm.nih.gov

Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. [2023]

6. United States 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. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam. [2021]

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

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. [2019]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Phytocannabinoids and schizophrenia: Focus on adolescence as a critical window of enhanced vulnerability and opportunity for treatment. [2022]