Vitamin D for Opioid Use Disorder

Overseen By Adam Stryjewski, BA

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

24 Participants Needed

Trial Summary

What is the purpose of this trial?

The research team is investigating Opioid Use Disorder (OUD), a disorder characterized by dysregulated dopaminergic tone, to evaluate the mechanisms of adjunctive treatment with calcitriol. The investigators will recruit 12 subjects with OUD and 12 healthy subjects to participate in a double-blind, randomized study design where subjects will complete up to 2 Positron Emission Tomography (PET) scans using \[11C\]-PHNO. The investigators will compare subjects in differences between their own study days and in differences between healthy control subjects and subjects with OUD.

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.

What evidence supports the effectiveness of the drug calcitriol for opioid use disorder?

There is no direct evidence supporting the effectiveness of calcitriol for opioid use disorder. However, calcitriol has shown promise in treating osteoporosis by improving bone mineral density and reducing fracture rates, which suggests it may have beneficial effects on bone health. ^{1 2 3 4 5}

Is Vitamin D (Calcitriol) safe for human use?

Calcitriol, a form of Vitamin D, is generally well tolerated in humans. Clinical studies have shown that at recommended dosages, it rarely causes significant side effects, with mild hypercalcemia (high calcium levels in the blood) being the most common issue, which can be managed by adjusting the dosage. Long-term use in patients with osteoporosis has not shown significant kidney toxicity. ^{1 2 6 7 8}

How does vitamin D differ from other treatments for opioid use disorder?

Vitamin D, specifically in the form of calcitriol, is unique because it is primarily known for its role in bone health and calcium regulation, rather than directly targeting opioid addiction. This makes it different from standard opioid use disorder treatments, which typically involve medications like methadone or buprenorphine that directly affect opioid receptors in the brain. ^{1 6 8 9 10}

Research Team

Marc Potenza, MD, PhD

Principal Investigator

Yale University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

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

The efficacy and safety of calcitriol and/or Caltrate D in elderly Chinese women with low bone mass. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

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

3. Germany pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Eldecalcitol normalizes bone turnover markers regardless of their pre-treatment levels. [2017]

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

What is the optimal regimen for vitamin D? [2019]

6. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Vitamin D metabolites and/or analogs: which D for which patient? [2022]

7. Russia (Federation) 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]. [2016]

8. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of liquid calcitriol formulation in advanced solid tumor patients: comparison with caplet formulation. [2015]

9. New Zealand pubmed.ncbi.nlm.nih.gov

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

10. Switzerland pubmed.ncbi.nlm.nih.gov

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