Alcohol's immediate effects on brain PDE4B imaging

Acute Effects of Alcohol on PET Imaging of Phosphodiesterase-4B (PDE4B)

This will see if a controlled intravenous dose of alcohol increases PET tracer binding to PDE4B in healthy adults who drink socially.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 21 Years to 70 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Drugs / interventions: radiation
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT07027839 on ClinicalTrials.gov

What this trial studies

Healthy adult social drinkers enrolled in NIAAA natural history protocols will undergo PET imaging with the radioligand [18F]PF-06445974 to measure PDE4B binding. Participants will have baseline and post-ethanol PET scans using a within-subject design, with intravenous ethanol administered to reach a target breath alcohol concentration of 0.08 g% before the post-ethanol scan; some participants who already have baseline data will undergo only the post-ethanol scan. MRI will be performed for anatomical reference and participants may complete up to four clinic visits and three imaging sessions. The primary outcome is change in whole-brain PDE4B binding (VT) with secondary analyses of regional binding changes.

Who should consider this trial

Good fit: Ideal candidates are healthy adults 21–70 years old who drink socially, do not meet criteria for alcohol or other substance use disorders, and are enrolled in the NIAAA Natural History Protocol (14-AA-0181).

Not a fit: People with a history of alcohol use disorder or other substance use disorders, current non-drinkers, or those not enrolled in the required NIAAA protocol would not be eligible and are unlikely to benefit from participation.

Why it matters

Potential benefit: If alcohol acutely increases PDE4B binding, the result could identify PDE4B as a treatment-relevant brain target and help guide new therapies for alcohol use disorder.

How similar studies have performed: PET approaches have successfully measured other brain enzymes and receptors, but human PET imaging of PDE4B with [18F]PF-06445974 is novel and has limited prior human data.

Eligibility criteria

* INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet the following criteria:

1. Be enrolled in protocol 14-AA-0181, NIAAA Natural History Protocol.
2. Age 21 - 70 years.
3. Willingness to complete the study including MRI tests.
4. Be in good general health as evidenced by medical history and physical examination.
5. Participants must have had their radial artery pulse checked for the presence of adequate ulnar collateral flow and the absence of any metal or foreign objects in both wrists.
6. Able to provide informed consent.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. History of AUD or SUD. Participants may currently use cannabis recreationally but cannot meet criteria for cannabis use disorder, or present for study visits with positive urine drug screen for THC.
2. Current non-drinkers (alcohol-naive individuals or no use of alcohol in the past year), or individuals with no experience drinking 5 or more drinks on one occasion in their lifetime.
3. Current or prior history of alcohol-induced flushing reactions, including rapid reddening of the face, rapid heart rate and breathing, and nausea after 1 or 2 drinks.
4. Clinically significant abnormalities on EKG or laboratory tests: CBC and acute care panel (Na, K, Cl, CO2, creatinine, glucose, urea nitrogen), liver function tests (GGT, AST, ALT, bilirubin).
5. Participants who have taken an antipsychotic or antidepressant medication within two weeks prior to the PET scan #1, with longer washout times of 1 month for antidepressants with longer half-lives such as fluoxetine. In addition, they will be withdrawn if they begin these medications during the two PET scans.
6. Medication exclusion for alcohol:

6a. Use of prescription or OTC medication known to interact with alcohol 2 weeks prior to screening or screening update visit. These include but may not be limited to: isosorbide; nitroglycerine; benzodiazepines; warfarin; anti-depressants such as amitriptyline, clomipramine and nefazodone; anti-diabetes medications such as glyburide, metformin and tolbutamide; H2-antagonists for heartburn such as famotidine, cimetidine and ranitidine; muscle relaxants; anti-epileptics including phenytoin and phenobarbital; codeine and opioid analgesics including Darvocet, Percocet and hydrocodone.

6b. Regular (more than once a week) or prescribed use of antihistamines, pain medicines, and anti-inflammatories such as aspirin, ibuprofen, acetaminophen, celecoxib, and naproxen, and unable to refrain from these medications for 48 hours prior to study visits

6c. Use of medications known to inhibit or induce enzymes that metabolize alcohol for 4 weeks prior to screening or screening update visit. These include chlorzoxazone, isoniazid, metronidazole, and disulfiram.

7\) HIV infection.

8\) Pregnancy or breast feeding.

9\) Have recent exposure to radiation related to research (e.g., PET from other research) that, when combined with this study, would be above the allowable limits.

10\) Have an inability to lie flat and/or lie still on the camera bed for two hours, including claustrophobia, overweight greater than the maximum for the scanner, and uncontrollable behavioral symptoms, which will be screened by an interview with the participant during the screening visit.

11\) Are unable to have an MRI scan (e.g., because of pacemakers or other implanted electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, shrapnel fragments, or metal fragments in the eye

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Robert B Innis, M.D. — National Institute of Mental Health (NIMH)
• Study coordinator: Tara N Turon, C.R.N.P.

Conditions Alcohol Use Disorder; PET Imaging; Phosphodiesterase-4B