Vitamin D for Opioid Use Disorder

Overseen By Gustavo Angarita, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must be taking: Buprenorphine

Must not be taking: Methadone, Psychotropics

Disqualifiers: Substance dependence, Psychiatric disorder, others

Stay on Your Current Meds You can continue your current medications while participating

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 2 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how vitamin D, specifically calcitriol, might assist individuals with Opioid Use Disorder (OUD). Researchers are investigating calcitriol's effects on brain activity linked to OUD using PET scans. Participants will receive both calcitriol and a placebo in random order to compare effects. Individuals stable on buprenorphine treatment for OUD might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to explore its potential benefits.

Will I have to stop taking my current medications?

The trial requires participants to stop using any prescription or over-the-counter medications, vitamins, and herbal supplements that could negatively interact with calcitriol or affect the study results, within 2 weeks before each test day. However, participants must continue their buprenorphine treatment for Opioid Use Disorder.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that calcitriol, a type of vitamin D, is usually safe for people to take. Studies have found that the most common side effects are mild and may include temporary increases in calcium levels in the blood, known as hypercalcemia. This can sometimes cause symptoms like nausea or increased thirst, but these effects are short-lived.

The FDA has already approved calcitriol for other uses, indicating its general safety. However, individuals allergic to calcitriol or its ingredients should avoid it.

This trial examines how calcitriol affects people with opioid use disorder, but previous studies on its safety in humans provide reassuring information. Participants should discuss any concerns with the research team to make an informed choice. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about calcitriol for opioid use disorder (OUD) because it introduces a novel approach by utilizing a form of vitamin D. Unlike standard treatments for OUD, which often include medications like methadone or buprenorphine that work by targeting opioid receptors to manage withdrawal and cravings, calcitriol may influence the brain's dopamine system in a way that could modify the rewarding effects of opioids. This unique mechanism could potentially offer a complementary or alternative strategy to current options, providing new hope for individuals struggling with OUD.

What evidence suggests that calcitriol might be an effective treatment for Opioid Use Disorder?

Research shows that vitamin D, such as calcitriol, might help treat opioid use disorder (OUD). Studies have found that a lack of vitamin D can increase sensitivity to the pleasurable effects of opioids, potentially worsening addiction. In lab studies, animals with low vitamin D levels showed a stronger liking for morphine, suggesting that adequate vitamin D could reduce this preference. Although direct evidence from human studies remains limited, these findings suggest that calcitriol might help by addressing vitamin D deficiencies linked to increased opioid sensitivity. In this trial, participants will receive both active calcitriol and a placebo control, with the order of these interventions randomized, to explore how calcitriol could support people with OUD. ^{6 7 8 9 10}

Who Is on the Research Team?

Marc Potenza, MD, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults with Opioid Use Disorder (OUD) and healthy individuals. Participants must be willing to undergo PET scans. Specific criteria for inclusion or exclusion are not detailed, but typically involve factors like age, health status, and the severity of OUD.

Inclusion Criteria

Voluntary, written, informed consent

Meets the criteria for OUD, as determined by the Structured Clinical Interview for DSM-5 (SCID)

Lab results without clinically relevant findings (e.g., renal function, electrolytes, and vitamin D levels)

Exclusion Criteria

Morbid obesity i.e., BMI over 35 (more prone to lower vitamin D levels)

Serum levels of 25(OH)D3 below 12 ng/ml

I have kidney problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Subjects receive a baseline MRI and initial assessments

1 day

1 visit (in-person)

Treatment

Subjects receive either calcitriol or placebo, followed by PHNO injection and PET Scan

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Calcitriol

Trial Overview The study is testing whether calcitriol can affect dopamine receptors in people with OUD compared to healthy controls. It involves a double-blind setup where neither participants nor researchers know who's getting calcitriol or placebo during two PET scan sessions using [11C]-PHNO.

How Is the Trial Designed?

Group I: Calcitriol Active Control 3 Interventions

Subjects with OUD will receive a baseline MRI. On the night before and day of testing, subjects with OUD will receive two doses of calcitriol (3.0mcg total), followed by PHNO injection and PET Scan for the calcitriol condition. All subjects will complete the study with both active calcitriol and a placebo control and the order these interventions are received will be randomized.

Group II: Placebo Placebo Group 3 Interventions

Subjects with OUD will receive a baseline MRI. On the night before and day of testing, subjects with OUD will receive two doses of an inactive placebo, followed by PHNO injection and PET Scan for the placebo condition. All subjects will complete the study with both active calcitriol and a placebo control and the order these interventions are received will be randomized.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

Cholecalciferol (vitamin D3) and its metabolites can be effectively used to treat conditions like azotaemic osteodystrophy with lower doses than previously required, thanks to a better understanding of vitamin D metabolism.

In patients undergoing repetitive haemodialysis, some may develop a resistant osteomalacic syndrome that does not respond to standard vitamin D treatment, potentially due to aluminium intoxication from dialysis fluid.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology and therapeutic use of vitamin D and its analogues. Pierides, AM.[2018]

Alfacalcidol has been effectively used since 1981 as a prodrug for calcitriol to treat conditions like hypocalcemia, chronic renal failure, hypoparathyroidism, and osteoporosis, demonstrating its long-standing efficacy in managing these disorders.

Doxercalciferol, introduced in 1999, serves as a prodrug for treating secondary hyperparathyroidism, highlighting the ongoing development and application of vitamin D derivatives in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new look at the most successful prodrugs for active vitamin D (D hormone): alfacalcidol and doxercalciferol. Kubodera, N.[2021]

In a study of 150 elderly Chinese women with osteopenia or osteoporosis, treatment with Rocaltrol (calcitriol) plus Caltrate D resulted in a significant increase in bone mineral density (BMD) at the lumbar spine compared to Caltrate D alone after 12 months.

Both treatment groups showed improvements in muscle strength and balance, with no severe adverse events reported, indicating that the combination therapy is safe and effective for enhancing bone health in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of calcitriol and/or Caltrate D in elderly Chinese women with low bone mass. Xia, WB., Zhang, ZL., Wang, HF., et al.[2022]

In a clinical trial involving 622 women with postmenopausal osteoporosis, calcitriol significantly reduced the rate of new vertebral fractures by three times compared to those receiving only calcium after three years of treatment.

Calcitriol is generally well tolerated with infrequent mild hypercalcemia, but its use requires careful monitoring due to its narrow therapeutic window, making it a viable option for treating mild to moderate postmenopausal osteoporosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Calcitriol. A review of its use in the treatment of postmenopausal osteoporosis and its potential in corticosteroid-induced osteoporosis. Dechant, KL., Goa, KL.[2018]

A 3-year study showed that eldecalcitol effectively improves bone mineral density and reduces fracture rates in osteoporosis patients without causing excessively low bone turnover, even in those with initially low turnover markers.

Eldecalcitol treatment normalizes bone turnover levels without further suppression, indicating a safety profile that minimizes the risk of deteriorating bone quality over the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eldecalcitol normalizes bone turnover markers regardless of their pre-treatment levels. Shiraki, M., Saito, H., Matsumoto, T.[2017]

Natural vitamin D products like cholecalciferol and calcifediol are effective for correcting vitamin D deficiency in patients with normal renal function and chronic kidney disease (CKD), with calcifediol being more rapid and effective, but all forms carry a risk of hypercalcemia, especially at higher doses.

Calcitriol is the most potent form for inhibiting parathyroid activity in renal patients but poses a significant risk of hypercalcemia; newer analogs like paricalcitol offer effective treatment for secondary hyperparathyroidism with a lower risk of elevated calcium levels, highlighting the need for careful selection based on individual patient needs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin D metabolites and/or analogs: which D for which patient? Mazzaferro, S., Goldsmith, D., Larsson, TE., et al.[2022]

1 alpha-hydroxycholecalciferol and 1 alpha, 25-dihydroxycholecalciferol are effective vitamin D3 agents that improve clinical symptoms of osteoporosis and osteomalacia within 1-2 months, with bone regeneration observable in 6-12 months.

Both treatments are safe, showing no significant side effects or hypercalcemia at daily doses of 0.25-2 micrograms, and are equally effective in osteoporotic conditions, although Rocaltrol may be preferred for patients with liver issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparative evaluation of the effectiveness of vitamin D3 preparations (1-alpha-hydroxy- and 1-alpha,25-dihydroxycholecalciferol in various forms of osteoporosis and osteomalacia]. Zarubina, NA., Rozhinskaia, LIa., Bukhman, AI., et al.[2016]

Combining alfacalcidol, an active D-hormone analog, with bisphosphonates like alendronate may enhance treatment outcomes for osteoporosis due to their different mechanisms of action, leading to improved bone mineral density (BMD).

Clinical trials, including a 2-year study, showed that the combination of alendronate and alfacalcidol resulted in fewer falls, fractures, and reduced back pain compared to using either treatment alone, suggesting a promising approach for managing osteoporosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving the outcome of established therapies for osteoporosis by adding the active D-hormone analog alfacalcidol. Ringe, JD., Schacht, E.[2018]

The study analyzed the pharmacokinetics of a liquid formulation of calcitriol (1,25-D(3)) compared to a caplet formulation in cancer patients, finding no significant differences in maximum concentration (C(max)) and area under the curve (AUC) between the two forms.

Both formulations did not show dose-related increases in C(max) and AUC at doses above 13 micrograms, indicating that the liquid formulation does not provide a pharmacokinetic advantage over the caplet formulation for achieving systemic exposure associated with antitumor activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of liquid calcitriol formulation in advanced solid tumor patients: comparison with caplet formulation. Muindi, JR., Potter, DM., Peng, Y., et al.[2015]

Recent advancements in understanding renal osteodystrophy have led to the use of vitamin D metabolites like calcitriol and alfacalcidol, but issues like hyperphosphatemia and hypercalcemia remain problematic.

New vitamin D metabolites such as 22-oxacalcitriol, paricalcitol, and doxercalciferol show promise in reducing side effects while effectively controlling parathyroid hormone levels, but their comparative benefits to existing treatments are still uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the optimal regimen for vitamin D? Cunningham, J.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39431589/

Risk of Opioid Overdose Associated with Concomitant Use of ... Our findings suggest that concomitant use of methadone with simvastatin, atorvastatin, or lovastatin is not associated with the risk of opioid overdose.

2. sciencedirect.com sciencedirect.com/science/article/pii/S277239252400049X

Potential roles for vitamin D in preventing and treating ... These results suggest that deficiencies in VDR signaling may increase sensitivity to the rewarding effects of opioids.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04386811

Vitamin D as a Therapeutic Adjunct in the Stimulant ... The specific aim of this study is to determine whether acute calcitriol (vitaminD) administration (compared to placebo) enhances the neurocognitive effects of ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9927858/

The effect of vitamin D on morphine preference in rats D insufficiency aggravates opioid addiction and makes lab animals sensitive to morphine (Mor.) reward (Kemény et al., 2021). A previous research ...

5. cdc.gov cdc.gov/mmwr/volumes/73/wr/mm7325a1.htm

Treatment for Opioid Use Disorder: Population Estimates In 2022, 3.7% of US adults aged ≥18 years needed OUD treatment. Among these, only 25.1% received medications for OUD.

6. cdn.caymanchem.com cdn.caymanchem.com/cdn/msds/71820m.pdf

Safety Data Sheet This product is for research use - Not for human or veterinary diagnostic or therapeutic use. · Details of the supplier of the safety data sheet.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8195487/

Vitamin D deficiency exacerbates UV/endorphin and opioid ... Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose-dependent ...

8. stridespharmausa.com stridespharmausa.com/wp-content/uploads/2020/03/Calcitriol-Capsules-SDS-Sheet.doc

Calcitriol-Capsules-SDS-Sheet Use of Calcitriol in patients with known hypersensitivity of Calcitriol (or drugs of the same class) and any of the constituent excipient is contraindicated.

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/1998/21068lbl.pdf

Rocaltrol (calcitriol) is a synthetic vi - accessdata.fda.gov The most common safety issues are mild, transient episodes of hypercalcemia, hyperphosphatemia, and increases in the serum calcium times ...

10. imgcdn.mckesson.com imgcdn.mckesson.com/CumulusWeb/Click_and_learn/MSDS_9PERR_CALCITRIOL_OINT.pdf

MATERIAL SAFETY DATA SHEET Ingestion of this material may cause effects similar to those seen in clinical use including hypercalcemia. Inhalation: Aerosol generation from this product may ...