THC + CBD for Opioid Use Disorder and Chronic Pain

Overseen By Julia V. Meyerovich, M.S.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must be taking: Methadone

Must not be taking: Benzodiazepines, Other opioids

Disqualifiers: Cannabis use disorder, Liver dysfunction, Neurological conditions, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 3 weeks

147 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you can only participate if you are on a stable dose of certain medications for at least three months. If you take medications that affect pain, like NSAIDs or certain antidepressants, you need to be on a consistent dose.

What data supports the effectiveness of the drug THC + CBD for Opioid Use Disorder and Chronic Pain?

Research suggests that THC and CBD together can help manage chronic pain and may reduce the need for opioids, as they have been shown to enhance pain relief and have a good safety profile compared to opioids. Additionally, many patients report improvement in pain symptoms when using cannabis-based treatments, indicating potential effectiveness. ^{1 2 3 4 5}

Is the combination of THC and CBD safe for humans?

The combination of THC and CBD is generally considered safe for humans, with most side effects being mild, such as sleepiness, dizziness, and dry mouth, which often decrease over time. It has a good safety profile compared to opioids, with low potential for dependence and abuse, but should be used cautiously in people with depression, psychosis, or suicidal tendencies. ^{1 2 4 6 7}

How does the THC + CBD drug differ from other treatments for opioid use disorder and chronic pain?

The THC + CBD drug is unique because it combines two components, THC and CBD, which work together to enhance pain relief while reducing some side effects. Unlike opioids, it has a lower risk of dependence and abuse, and it can also help reduce opioid usage and prevent tolerance and withdrawal symptoms. ^{1 4 7 8 9}

What is the purpose of this trial?

The primary objective of this phase 2 study is to investigate the therapeutic potential of orally administered combined delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in relieving both pain and cue-induced opioid craving in people with co-occurring opioid use disorder (OUD) and chronic pain who are undergoing methadone therapy.

Research Team

Joao P. De Aquino, M.D.

Principal Investigator

Yale University

Eligibility Criteria

This trial is for individuals with both opioid use disorder (OUD) and chronic pain who are currently on methadone therapy. It aims to see if THC and CBD can help reduce their pain and cravings for opioids.

Inclusion Criteria

Provision of signed and dated informed consent form

For females of reproductive potential: use of highly effective contraception and agreement to use during study participation and for additional 2 weeks after last test session

I am willing and able to follow all study requirements.

Exclusion Criteria

Currently lactating

Allergy or serious adverse reaction to Butylated Hydroxytoluene (BHT)

Allergy or serious adverse reaction to cannabis or its constituent cannabinoid

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive single doses of THC and CBD in a double-blind, placebo-controlled, crossover design across three test sessions

3 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including cardiovascular effects and adverse events

1 week

1 visit (in-person)

Treatment Details

Interventions

• Combined THC and CBD

Trial Overview The study tests the effects of two different doses of combined THC and CBD (600mg, 300mg) against a placebo, which has no active ingredients, to determine if they can alleviate symptoms of OUD and chronic pain.

Participant Groups

Group I: Dronabinol 5mg Active Control 3 Interventions

Participants will be randomized to which dronabinol (or placebo) dose they receive. The fixed dose they receive will be administered across all three test sessions. Therefore, participants may receive a single capsule of 5 mg Dronabinol across all three test sessions

Group II: Dronabinol 10mg Active Control 3 Interventions

Participants will be randomized to which dronabinol (or placebo) dose they receive. The fixed dose they receive will be administered across all three test sessions. Therefore, participants may receive a single capsule of 10 mg Dronabinol across all three test sessions

Group III: Placebo 0mg Placebo Group 3 Interventions

Participants will be randomized to which dronabinol (or placebo) dose they receive. The fixed dose they receive will be administered across all three test sessions. Therefore, participants may receive a single capsule of 0 mg Dronabinol across all three test sessions

Combined THC and CBD is already approved in Canada, United States, European Union for the following indications:

Approved in Canada as Medical Cannabis for:

• Chronic pain
• Nausea and vomiting associated with chemotherapy
• Spasticity associated with multiple sclerosis

Approved in United States as Cannabis for:

• Seizures associated with Lennox-Gastaut syndrome and Dravet syndrome
• Nausea and vomiting associated with chemotherapy
• Spasticity associated with multiple sclerosis

Approved in European Union as Medical Cannabis for:

• Spasticity associated with multiple sclerosis
• Nausea and vomiting associated with chemotherapy

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+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Findings from Research

Combination THC/CBD medicines are effective for chronic pain, particularly neuropathic and inflammatory pain, and have a good safety profile compared to opioids, with low potential for dependence.

CBD-only medications show substantial effectiveness for stress and moderate effectiveness for anxiety and insomnia, but should be used cautiously in patients with a history of depression or psychosis, as they may exacerbate these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tetrahydrocannabinol and cannabidiol medicines for chronic pain and mental health conditions. Henson, JD., Vitetta, L., Hall, S.[2022]

In a study of 2,112 adult patients with chronic pain, 92.5% reported improvement in their primary symptoms after using cannabis-based oral formulations, indicating high efficacy as an adjuvant treatment.

The majority of patients experienced minimal side effects, with 71.7% reporting none, and the most common mild side effects, such as somnolence and dizziness, tended to decrease over time, suggesting that these formulations are safe for chronic pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sex-Dependent Prescription Patterns and Clinical Outcomes Associated With the Use of Two Oral Cannabis Formulations in the Multimodal Management of Chronic Pain Patients in Colombia. Moreno-Sanz, G., Madiedo, A., Hernandez, P., et al.[2022]

This study will evaluate the effectiveness of cannabis in reducing opioid use and managing chronic non-cancer pain in 250 adults currently taking prescription opioids, as part of a comprehensive behavioral pain management program.

Participants will be randomly assigned to either use cannabis or abstain for 6 months, with primary outcomes focusing on changes in opioid dosage and pain interference, while also monitoring for any adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised, pragmatic, waitlist controlled trial of cannabis added to prescription opioid support on opioid dose reduction and pain in adults with chronic non-cancer pain: study protocol. Jashinski, J., Grossman, E., Quaye, A., et al.[2023]

The novel combination cannabinoid medication (1:1 THC/CBD) was well tolerated in a phase I study involving 9 patients with chronic non-cancer pain, with most adverse events being mild, such as euphoric mood and headache.

While there were no significant changes in pain severity, improvements in pain interference, mood, and some sleep parameters were noted, suggesting potential benefits that warrant further investigation in a larger randomized controlled trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Safety, and Tolerability of a Medicinal Cannabis Formulation in Patients with Chronic Non-cancer Pain on Long-Term High Dose Opioid Analgesia: A Pilot Study. Bonomo, Y., Norman, A., Collins, L., et al.[2022]

Medical cannabis and cannabinoids are increasingly recognized for their efficacy in managing chronic pain, with various preparations available that differ in their THC:CBD ratios.

Despite the popularity of the 'entourage effect' theory, systematic studies have not supported the idea that other cannabis plant constituents enhance pain treatment, and there is a lack of well-conducted comparisons between different cannabis products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Cannabis, Cannabidiol and Other Cannabinoids in Chronic Pain. The Perspective of Physicians. Köstenberger, M., Nahler, G., Jones, TM., et al.[2023]

In a mouse model of neuropathic pain, both THC and CBD were effective in reducing pain when administered orally, but THC also caused side effects at similar doses, indicating a limited therapeutic window.

The combination of THC and CBD did not enhance pain relief compared to THC alone when taken orally, but it did increase the risk of side effects, suggesting that CBD may offer a safer alternative for treating neuropathic pain despite its lower efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral efficacy of Δ(9)-tetrahydrocannabinol and cannabidiol in a mouse neuropathic pain model. Mitchell, VA., Harley, J., Casey, SL., et al.[2021]

In a study of 100 chronic pain patients using medical cannabis, 93% reported a decrease or cessation of opioid use after starting cannabis, indicating its potential efficacy in reducing reliance on opioids.

However, 10% of participants, particularly younger individuals, met the criteria for cannabis use disorder, highlighting the need for careful evaluation of risk factors like age and depression before prescribing medical cannabis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk and benefit of cannabis prescription for chronic non-cancer pain. Zloczower, O., Brill, S., Zeitak, Y., et al.[2022]

In a study of 800 patients with severe chronic pain, the oromucosal spray containing THC and CBD resulted in a significant average symptom relief improvement of 39% after 12 weeks, with particularly strong effects observed in patients with neuropathic pain.

The treatment was generally well-tolerated, with 19.9% of patients reporting mild side effects, such as increased appetite and changes in taste, and only 4% discontinuing due to adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and tolerability of THC:CBD oromucosal spray as add-on measure in patients with severe chronic pain: analysis of 12-week open-label real-world data provided by the German Pain e-Registry. Ueberall, MA., Essner, U., Mueller-Schwefe, GH.[2020]

Medical cannabis can effectively reduce chronic pain and, when used alongside prescription opiates, can lead to lower opiate usage and fewer side effects for patients.

Cannabinoids may help prevent tolerance and withdrawal symptoms from opiates, and they could also assist in treating problematic substance use, suggesting that better access to medical cannabis could mitigate the harms associated with opioid addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain. Lucas, P.[2012]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Tetrahydrocannabinol and cannabidiol medicines for chronic pain and mental health conditions. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Sex-Dependent Prescription Patterns and Clinical Outcomes Associated With the Use of Two Oral Cannabis Formulations in the Multimodal Management of Chronic Pain Patients in Colombia. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Randomised, pragmatic, waitlist controlled trial of cannabis added to prescription opioid support on opioid dose reduction and pain in adults with chronic non-cancer pain: study protocol. [2023]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Safety, and Tolerability of a Medicinal Cannabis Formulation in Patients with Chronic Non-cancer Pain on Long-Term High Dose Opioid Analgesia: A Pilot Study. [2022]

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

The Role of Cannabis, Cannabidiol and Other Cannabinoids in Chronic Pain. The Perspective of Physicians. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Oral efficacy of Δ(9)-tetrahydrocannabinol and cannabidiol in a mouse neuropathic pain model. [2021]

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

Risk and benefit of cannabis prescription for chronic non-cancer pain. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Effectiveness and tolerability of THC:CBD oromucosal spray as add-on measure in patients with severe chronic pain: analysis of 12-week open-label real-world data provided by the German Pain e-Registry. [2020]

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

Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain. [2012]