Hydrocortisone-enhanced PET Scans for Cocaine Use Disorder

Overseen By Rajesh Narendran, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Rajesh Narendran

Must not be taking: Psychotropics, Opiates, Sedatives, others

Disqualifiers: Psychiatric disorders, Opiate abuse, others

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

Compensation: Varies

Number of Visits: 2

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a specific brain receptor interacts with stress hormones in individuals with cocaine use disorder (CUD). Researchers aim to determine if these interactions can predict relapse. Participants will undergo PET scans, an imaging test, following a hydrocortisone challenge to assess the body's stress response. The trial seeks individuals with cocaine use disorder who have no other psychiatric or substance use issues. Healthy individuals without any past psychiatric disorders are also needed for comparison. As an Early Phase 1 trial, this research focuses on understanding the treatment's mechanism in people, offering participants a chance to contribute to groundbreaking insights into CUD.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any prescription medical or psychotropic medications to participate in this trial.

What prior data suggests that this method is safe for imaging cocaine use disorder?

Research has shown that [C-11]NOP-1A is safe for humans. Studies indicate it moves predictably through the body, which is promising. The drug's distribution within the body aligns with safe use.

Hydrocortisone, a steroid commonly used to reduce swelling, has been safely used in many treatments. Since this study is in its early stages, the main goal is to gather information on safety and tolerance. Researchers carefully monitor for any side effects.

Overall, evidence suggests that both [C-11]NOP-1A and hydrocortisone are well-tolerated in humans. However, as with any clinical trial, researchers closely monitor for any negative reactions. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using hydrocortisone-enhanced PET scans for cocaine use disorder because they offer a new way to understand how the brain is affected by addiction. Unlike current treatments that primarily focus on behavioral therapy or medications like disulfiram and naltrexone, this approach uses [C-11]NOP-1A to visualize specific brain receptors involved in craving and addiction. By enhancing PET scans with hydrocortisone, researchers hope to gain clearer images and insights into brain activity, potentially leading to more targeted and effective treatments in the future.

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

Research has shown that hydrocortisone can mimic some effects of cocaine on the brain, particularly in its impact on thinking and memory. People with cocaine addiction often exhibit higher levels of cortisol, a stress hormone linked to difficulties with learning and memory. Understanding these interactions might help predict who could relapse after treatment. Although this research remains in the early stages, findings suggest that hydrocortisone could play a significant role in studying cocaine addiction. Participants in this trial will undergo PET scans using [C-11]NOP-1A to explore these interactions further. ^{6 7 8 9 10}

Who Is on the Research Team?

Rajesh Narendran, MD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for men and women aged 18-55 with cocaine use disorder, without other psychiatric or addictive disorders. Participants must not be on medications, have severe illnesses, be pregnant/breastfeeding, have significant past radiation exposure, MRI-incompatible body metals, or recent abuse of various drugs including opiates and alcohol.

Inclusion Criteria

No present or past DSM-5 disorders for Healthy Controls (HC)

Nicotine use will be quantified and controlled between groups using the Fagerstrom Test for Nicotine Dependence (Heatherton et al., 1991)

Fulfil DSM-5 criteria for cocaine use disorder

Exclusion Criteria

I am not taking any prescription drugs or mental health medications.

No history of significant radioactivity exposure in past year from another research study or occupation that exceeds RDRC guidelines

I don't have severe illnesses like glaucoma, seizures, high blood pressure, or high cholesterol.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Imaging

Participants undergo baseline PET imaging with [11C]NOP-1A

1 day

1 visit (in-person)

Hydrocortisone Challenge

Participants receive an intravenous hydrocortisone challenge and undergo PET imaging to assess NOP receptor binding

1 day

1 visit (in-person)

Follow-up

Participants are monitored for relapse over a 12-week period

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• [C-11]NOP-1A
• Hydrocortisone

Trial Overview

The study tests how cortisol interacts with brain receptors in people with cocaine addiction compared to healthy controls using PET scans before and after hydrocortisone administration. It aims to see if these interactions can predict relapse in cocaine users.

How Is the Trial Designed?

Group I: PET Experimental Treatment 3 Interventions

\[C-11\]NOP-1A

Who Is Running the Clinical Trial?

Rajesh Narendran

Lead Sponsor

Trials

4

Recruited

180+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

In a study of 12 patients with cocaine dependence, an acute cocaine challenge significantly increased levels of adrenocorticotropic hormone (ACTH) by 261% and cortisol by 73%, indicating strong activation of the hypothalamic-pituitary-adrenal (HPA) axis.

There was a significant positive correlation between the increases in ACTH and cortisol levels and the severity of depressive symptoms, particularly in vegetative symptoms, suggesting that the HPA axis may play a role in the mood disturbances associated with cocaine use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depressive symptomatology and cocaine-induced pituitary-adrenal axis activation in individuals with cocaine dependence. Elman, I., Breiter, HC., Gollub, RL., et al.[2019]

In a study involving 12 cocaine-dependent individuals, cortisol administration led to significant increases in growth hormone (GH), indicating enhanced dopaminergic activity, while cocaine resulted in decreased prolactin levels, suggesting different effects on the dopaminergic system.

The contrasting neuroendocrine responses to cortisol and cocaine highlight important differences in their mechanisms of action, with cortisol potentially facilitating dopaminergic activity while cocaine appears to suppress it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cortisol and cocaine on plasma prolactin and growth hormone levels in cocaine-dependent volunteers. Elman, I., Lukas, SE.[2013]

Cocaine administration (0.8 mg/kg) significantly increased the amplitude of pulsatile adrenocorticotropic hormone (ACTH) and cortisol release in male rhesus monkeys that exhibited behavioral stimulation, indicating a link between HPA axis activation and behavioral response.

However, not all monkeys responded similarly; those classified as low responders showed decreased ACTH peak amplitude and no change in cortisol release, suggesting individual differences in response to cocaine that were not related to plasma cocaine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cocaine on pulsatile activity of hypothalamic-pituitary-adrenal axis in male rhesus monkeys: neuroendocrine and behavioral correlates. Sarnyai, Z., Mello, NK., Mendelson, JH., et al.[2018]

Suppressing corticosterone secretion through adrenalectomy decreased the locomotor response to both cocaine and morphine in animals, indicating that basal corticosterone levels play a crucial role in drug sensitivity.

Restoring diurnal levels of corticosterone fully reversed the effects of adrenalectomy on cocaine response, while a complete circadian fluctuation of corticosterone was necessary to restore the response to morphine, highlighting the importance of hormonal timing in drug effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corticosterone circadian secretion differentially facilitates dopamine-mediated psychomotor effect of cocaine and morphine. Marinelli, M., Piazza, PV., Deroche, V., et al.[2019]

Cocaine addicts exhibited significantly higher levels of plasma ACTH, cortisol, and beta-endorphin compared to normal controls, indicating alterations in their hypothalamic-pituitary-adrenal (HPA) axis at the time of admission.

After 15 days of abstinence, cocaine addicts showed normalized levels of these hormones, suggesting that abstinence can lead to recovery of HPA axis function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diurnal variations in plasma ACTH, cortisol and beta-endorphin levels in cocaine addicts. Vescovi, PP., Coiro, V., Volpi, R., et al.[2018]

In a study of 14 abstinent cocaine-dependent individuals and 13 control participants, higher morning salivary cortisol levels were found in cocaine users, indicating altered HPA axis function that may relate to addiction.

The study suggests that salivary cortisol levels could serve as a biomarker for predicting craving and cognitive performance, particularly in verbal memory, highlighting potential avenues for treatment and assessment in cocaine addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salivary Cortisol Levels Are Associated with Craving and Cognitive Performance in Cocaine-Abstinent Subjects: A Pilot Study. Sampedro-Piquero, P., Vicario, S., Pérez-Rivas, A., et al.[2020]

In a study involving 27 patients with cocaine dependence and 16 healthy controls, no significant differences in hippocampal or total brain volumes were found, suggesting that chronic cocaine use may not lead to structural brain damage in these areas.

Additionally, levels of ACTH and cortisol, both at baseline and after stimulation, were similar between cocaine-dependent individuals and healthy subjects, indicating that cocaine dependence may not alter the hypothalamic-pituitary-adrenal (HPA) axis response in the short term after abstinence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative medial temporal lobe brain morphology and hypothalamic-pituitary-adrenal axis function in cocaine dependence: a preliminary report. Jacobsen, LK., Giedd, JN., Kreek, MJ., et al.[2019]

In a study involving 8 men with concurrent cocaine and opioid dependence, a single intravenous dose of cocaine (30 mg) significantly increased various measures of adrenocorticotropic hormone (ACTH) secretion, indicating a strong physiological response to cocaine.

The findings suggest that cocaine may stimulate the release of corticotropin-releasing factor, which enhances the amplitude of ACTH pulses without changing their frequency, highlighting a specific mechanism of action related to hormone regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cocaine effects on pulsatile secretion of ACTH in men. Teoh, SK., Sarnyai, Z., Mendelson, JH., et al.[2018]

In a study involving 12 cocaine-dependent individuals, metyrapone was found to be well tolerated and did not worsen the physiological effects of cocaine, indicating its safety for potential outpatient use.

Metyrapone did not significantly change the subjective effects of cocaine, suggesting that while it may help in reducing stress-induced relapse, it does not interfere with the immediate drug experience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metyrapone and cocaine: a double-blind, placebo-controlled drug interaction study. Winhusen, T., Somoza, E., Harrer, JM., et al.[2013]

Citations

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pubmed.ncbi.nlm.nih.gov

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This study investigated the effects of acute cocaine administration on cognition, and whether these can be modeled using exogenous hydrocortisone.

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pmc.ncbi.nlm.nih.gov

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Elevated cortisol and learning and memory deficits in ...

These findings are the first to demonstrate that learning and memory deficits in CD individuals are associated with enhanced cortisol and with cocaine use ...

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Predictors of cocaine use disorder treatment outcomes

Younger age, more years of cocaine use, and craving levels were significant predictors of relapse and treatment dropout.

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frontiersin.org

frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.836771/full

BDNF and Cortisol in the Diagnosis of Cocaine-Induced ...

Results suggest a different pathogenesis for CUD-induced-MDD with higher levels of cortisol and BDNF compared with CUD-primary-MDD.

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accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/nda/2021/213876Orig1s000MedR.pdf

213876Orig1s000 CLINICAL REVIEW(S) - accessdata.fda.gov

... efficacy and safety of Hydrocortisone granules for the proposed indication based on the established bioequivalence of Hydrocortisone ...

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pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/31055968/

Nociceptin Receptors Upregulated in Cocaine Use Disorder ...

Results: A significant increase in [11C]NOP-1A VT was observed in the cocaine use disorder group compared with the healthy control group. This ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7039303/

Nociceptin receptors are upregulated in cocaine use disorder

In this [11C]NOP-1A PET study, we found that: (1) cocaine abuse in humans is associated with a generalized ~10% increase in binding to NOP in brain regions ...

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sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0090955624101171

Occupancy of Nociceptin/Orphanin FQ Peptide Receptors ...

In humans, [11C]NOP-1A is safe, with favorable kinetics and reproducibility (Lohith et al., 2012, 2014), and exhibits a distribution volume (VT) consistent with ...

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clinicaltrials.gov/study/NCT03448016

NCT03448016 | [C-11]NOP-1A and Alcohol Use Disorder

These trials gather additional information about a drug's safety, efficacy, or optimal use. ... disorder, manic episode, drug and alcohol use disorder in first- ...

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NOP-1A: Uses, Interactions, Mechanism of Action

Improve decision support & research outcomes with our structured adverse effects data. See a data sample. Toxicity. Not Available. Pathways: Not Available ...