Dopamine Signaling Study for Opioid Use Disorder

Overseen By Nora D Volkow Adler, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how opioid use affects dopamine in the brain. Dopamine, a chemical that helps send signals in the brain, might influence addiction and self-control. The trial uses scans and tests with imaging agents [11C]NNC-112 and [11C]raclopride to observe dopamine changes in individuals with opioid use disorder compared to healthy individuals. Those who have used opioids regularly for three or more years, whether currently active or not, and healthy volunteers with no opioid use may qualify for this study. As an Early Phase 1 trial, this research aims to understand how opioid use affects brain chemistry, offering participants a chance to contribute to groundbreaking insights.

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.

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

Previous studies have used [11C]raclopride in brain imaging to study dopamine, a chemical that aids communication between brain cells. Research has shown that [11C]raclopride is generally safe and well-tolerated in these imaging studies. This compound helps researchers understand dopamine function in the brain, especially in individuals using opioids. No serious side effects have been consistently reported in the studies.

[11C]NNC-112 is similar, serving as another compound for brain imaging to examine dopamine activity. Although less specific data exists on [11C]NNC-112 compared to [11C]raclopride, compounds like this are usually safe in controlled clinical settings.

The trial also includes methylphenidate, a medication for attention deficit hyperactivity disorder (ADHD). Methylphenidate is well-known and generally safe, though it can sometimes cause mild side effects like trouble sleeping or feeling jittery.

Overall, the treatments in this study are primarily used for brain imaging and to understand dopamine function. They have been used in previous research with few safety concerns. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for opioid use disorder because they use advanced imaging agents, [11C]NNC-112 and [11C]raclopride, to explore dopamine receptor activity in the brain. Unlike current treatments like methadone or buprenorphine, which primarily focus on alleviating withdrawal symptoms and reducing cravings, these imaging agents help to better understand the brain's dopamine signaling pathways. This could lead to insights into how dopamine influences addiction and potentially pave the way for new therapeutic approaches that target these pathways directly.

What evidence suggests that this trial's treatments could be effective for opioid use disorder?

Research has shown that [11C]raclopride, which participants in this trial may receive, can detect changes in dopamine levels in the brain during PET scans. This is important because dopamine is a chemical that may influence addiction and self-control. Studies have found that morphine, an opioid, reduces [11C]raclopride binding in certain brain areas, suggesting that opioids might impact the brain's dopamine system. Understanding these changes can help researchers learn more about how opioid use disorder affects the brain. ^{1 4 6 7 8}

Who Is on the Research Team?

Nora D Volkow Adler, M.D.

Principal Investigator

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Are You a Good Fit for This Trial?

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.

I am 18-65, have a history of opioid abuse, and haven't used opioids or treatment meds in 3 months.

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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Each participant underwent 3 PET scans; one to measure D1 receptors ([11C]NNC119) and two to measure D2 receptors ([11C]raclopride) with and ...