Dopamine Signaling Study for Opioid Use Disorder

Overseen By Nora Volkow, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Must be taking: Opioid agonists, Naltrexone

Must not be taking: Antidepressants, Antipsychotics, Stimulants, Benzodiazepines

Disqualifiers: Psychiatric disorders, Major medical problems, others

Compensation: Varies

Number of Visits: 6

360 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: The chemical messenger dopamine carries signals between brain cells. It may affect addiction. Heavy use of pain medicines called opioids may decrease the amount of dopamine available to the brain. Researchers want to study if decreased dopamine decreases self-control and increases impulsiveness. Objective: To learn more about how opiate use disorder affects dopamine in the brain. Eligibility: Adults 18-80 years old who are moderate or severe opiate users Healthy volunteers the same age Design: Participants will first be screened under another protocol. They will: * Have a physical exam * Answer questions about their medical, psychiatric, and alcohol and drug use history * Take an MRI screening questionnaire * Give blood and urine samples * Have their breath tested for alcohol Participants will have up to 3 study visits. They will have 2-3 positron emission tomography (PET) scans. A radioactive chemical will be injected for the scans. Participants will lie on a bed that slides in and out of the donut-shaped scanner. A cap or plastic mask may be placed on the head. Vital signs will be taken before and after the PET scans. Participants will get capsules of placebo or the study drug. They will rate how they feel before, during and after. Participants will have their breath and urine tested each day. Participants will have magnetic resonance imaging (MRI) scans. They will lie on a table that slides into a cylinder in a strong magnetic field. They may do tasks on a computer screen while inside the scanner. Participants will have tests of memory, attention, and thinking. Participants will wear an activity monitor for one week....

Will I have to stop taking my current medications?

The trial requires that participants not be on certain medications, such as methadone, buprenorphine, or naltrexone, for more than three weeks if they are in the MAT- OUD group. Participants in the MAT+ OUD and Naltrexone OUD groups must continue their current opioid treatment. Some medications, like stimulants, may need to be paused on specific test days.

What data supports the effectiveness of the drug for opioid use disorder?

Research shows that the drug [11C]raclopride, which is part of the treatment, has been used in studies to measure dopamine receptor activity in the brain. This is important because dopamine signaling is linked to addiction behaviors, suggesting that understanding and potentially modifying this signaling could help in treating disorders like opioid use disorder. ^{1 2 3 4 5}

Is [11C]raclopride safe for humans?

Studies involving [11C]raclopride, a compound used in brain imaging, have been conducted on healthy volunteers and have not reported any significant safety concerns. It is primarily used to study dopamine receptors in the brain and has been tested in various conditions without indicating harmful effects. ^{1 2 3 4 6}

How is the drug [11C]raclopride unique in treating opioid use disorder?

[11C]raclopride is unique because it is used in imaging studies to measure dopamine receptor activity in the brain, which can help understand the role of dopamine in opioid use disorder. Unlike typical treatments that directly target opioid receptors, this drug helps visualize and study brain activity related to dopamine, potentially leading to more personalized treatment approaches. ^{1 2 3 7 8}

Research Team

Nora Volkow, M.D.

Principal Investigator

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Eligibility Criteria

Adults aged 18-65 with moderate to severe opioid use disorder (OUD) who haven't used opioids regularly for at least 3 months, or those on opioid agonist therapy. Healthy volunteers of the same age range can also participate. Exclusions include major medical issues, certain psychiatric disorders, pregnancy, and inability to lie flat or have an MRI.

Inclusion Criteria

Only individuals who have a certain medical condition can participate in this study.

You can read and understand information about the study and agree to participate by signing a form.

You have been diagnosed with Opiate Use Disorder.

Exclusion Criteria

I am a healthy volunteer without major medical issues or specific conditions listed.

You have a history of certain mental health disorders that require antipsychotic medications, or are currently receiving treatment for opioid addiction using specific medications. Additionally, you may be excluded if you have significant medical issues, have been exposed to radiation, are pregnant or breastfeeding, have certain eye conditions or difficulty lying flat, or are unable to communicate in English. Study investigators and staff are also not eligible to participate.

Additional exclusion criteria for MAT+ / MAT- / Naltrexone OUD participants: Participation in a court ordered residential treatment program

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

PET Scans

Participants undergo 2-3 PET scans to assess dopamine receptor availability and striatal dopamine release

3 visits

3 visits (in-person)

MRI and Neuropsychological Testing

Participants undergo MRI scans and neuropsychological tests to assess brain function and cognitive performance

2 visits

2 visits (in-person)

Follow-up

Participants are monitored for recovery and changes in brain function after treatment

6 months

Treatment Details

Interventions

• [11C]NNC-112
• [11C]raclopride

Trial Overview The study is examining how opioid addiction affects dopamine in the brain using PET scans with radioactive chemicals and MRIs. Participants will receive either a placebo or a drug alongside [11C]raclopride or [11C]NNC-112 to measure brain activity related to self-control and impulsiveness.

Participant Groups

Group I: [11C]raclopride plus drug Active Control 2 Interventions

Methylphenidate 60 mg. po will be given 60 minutes prior to \[11C\]raclopride scan to measure striatal dopamine release. MRI scan to follow end of PET scan. Subject blind as to drug administration.

Group II: [11C]raclopride plus placebo Placebo Group 2 Interventions

Placebo (po) will be given 60 minutes prior to \[11C\]raclopride scan to measure baseline dopamine D2 receptors. MRI scan to follow end of PET scan. Subject blind as to drug administration.

Group III: [11C]NNC-112 Placebo Group 1 Intervention

\[11C\]NNC-112 PET scan obtained without any drug intervention to measure dopamine D1 receptors. Blind N/A

Who Is Running the Clinical Trial?

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Lead Sponsor

Trials

865

Recruited

1,091,000+

Findings from Research

The study involving three healthy male volunteers showed that the effective dose of [11C]raclopride for dopamine D2 receptor imaging is 6.7 microSv/MBq, which is considered acceptable for repeated clinical PET imaging studies.

The biodistribution results indicated that the primary clearance routes for [11C]raclopride were renal and intestinal, with significant activity observed in the gall-bladder, kidneys, and liver, suggesting these organs receive the highest radiation doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biodistribution and radiation dosimetry of [11C]raclopride in healthy volunteers. Ribeiro, MJ., Ricard, M., Bourgeois, S., et al.[2018]

The PET signal from the ventral striatum can accurately predict individual treatment responses in cocaine dependence with an 82% success rate, indicating its potential as a biomarker for treatment outcomes.

Combining the PET signal with early treatment response data, such as clinic attendance, can significantly enhance predictive accuracy to 96%, suggesting that a multimodal approach may be the most effective for personalizing treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multimodal predictive modeling of individual treatment outcome in cocaine dependence with combined neuroimaging and behavioral predictors. Luo, SX., Martinez, D., Carpenter, KM., et al.[2021]

The study demonstrated very good long-term test-retest reliability of [(11)C]raclopride binding in the striatum and thalamus, with intraclass correlation coefficients (ICCs) ranging from 0.82 to 0.92, indicating that this method can consistently measure D2/3 receptor availability over time.

Cortical areas showed good to moderate reproducibility, suggesting that while striatal measurements are highly reliable, further investigation is needed to confirm the reliability of extrastriatal D2/3 binding using [(11)C]raclopride PET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term test-retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [(11)C]raclopride and high-resolution PET. Alakurtti, K., Johansson, JJ., Joutsa, J., et al.[2018]

A study using PET imaging with [(11)C]NPA and [(11)C]raclopride found no significant differences in the binding of D(2/3 HIGH) receptors between 10 recently abstinent cocaine abusers and matched healthy controls, suggesting that cocaine dependence does not alter the availability of these receptors in the striatum.

The findings indicate that the status of D(2/3 HIGH) receptors, which are important for dopamine signaling, remains similar in cocaine abusers compared to healthy individuals, challenging previous assumptions about receptor changes in addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging of dopamine D2/3 agonist binding in cocaine dependence: a [11C]NPA positron emission tomography study. Narendran, R., Martinez, D., Mason, NS., et al.[2021]

In a study involving 15 cocaine-dependent individuals and 15 healthy controls, PET scans revealed that cocaine-dependent subjects had higher levels of D3 receptors in the substantia nigra, which were linked to impulsiveness and risky decision-making behaviors.

Unlike the expected D2 receptor deficiency, the findings suggest that cocaine dependence may be associated with increased D3 receptor levels, indicating a potential new target for addiction treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO. Payer, DE., Behzadi, A., Kish, SJ., et al.[2021]

This study is the first to provide in vivo evidence that morphine affects dopamine transmission in the ventral striatum, as shown by a significant decrease in [11C]raclopride binding in healthy participants.

While morphine produced strong subjective and physiological effects, these effects did not correlate straightforwardly with the observed dopamine release, indicating a complex relationship between opioid effects and dopamine activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Striatal Dopamine Release in Response to Morphine: A [11C]Raclopride Positron Emission Tomography Study in Healthy Men. Spagnolo, PA., Kimes, A., Schwandt, ML., et al.[2021]

This report provides essential guidance on the chemistry and biochemistry of PET radioligands for imaging dopamine receptors, focusing on methods to prepare D1 and D2 receptor ligands labeled with positron-emitting isotopes.

Highlighted ligands, such as 11C-labelled SCH23390 and raclopride, have proven effective in clinical PET investigations, making this report a valuable resource for new research groups in the field of dopaminergic neurotransmission imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PET radioligands for dopamine receptors and re-uptake sites: chemistry and biochemistry. Mazière, B., Coenen, HH., Halldin, C., et al.[2019]

Using PET imaging with the radiotracer 11C-raclopride, researchers demonstrated that GABAergic neuron activity can significantly inhibit dopamine release in the striatum, as shown in studies with adult female baboons.

Both gamma-vinyl-GABA (GVG) and lorazepam increased 11C-raclopride binding, indicating that these drugs enhance GABAergic transmission and allow for measurable changes in dopamine levels, highlighting the potential of PET to assess drug mechanisms in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. Dewey, SL., Smith, GS., Logan, J., et al.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Biodistribution and radiation dosimetry of [11C]raclopride in healthy volunteers. [2018]

2. Ireland pubmed.ncbi.nlm.nih.gov

Multimodal predictive modeling of individual treatment outcome in cocaine dependence with combined neuroimaging and behavioral predictors. [2021]

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

Long-term test-retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [(11)C]raclopride and high-resolution PET. [2018]

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

Imaging of dopamine D2/3 agonist binding in cocaine dependence: a [11C]NPA positron emission tomography study. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO. [2021]

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

Striatal Dopamine Release in Response to Morphine: A [11C]Raclopride Positron Emission Tomography Study in Healthy Men. [2021]

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

PET radioligands for dopamine receptors and re-uptake sites: chemistry and biochemistry. [2019]

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

GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. [2019]