Vitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD

NCT ID: NCT03103750

Last Updated: 2024-03-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-15
• Study Completion Date: 2023-01-17

Brief Summary

Specific Aim 1: As part of a within-subject, two-days, study design, to determine whether acute calcitriol (vs. placebo) pre-treatment is associated with greater amphetamine (Amp)-induced dopamine (DA) release in the caudate, putamen, ventral striatum (VST), and substantia nigra / ventral tegmental area (SN/VTA) of healthy human subjects.

Specific Aim 2: To determine whether acute calcitriol (vs. placebo) pre-treatment is associated with better performance on a test of attention (e.g., the Continuous Performance Task or CPT-IP), after treatment with amphetamine. Hypothesis: Investigators hypothesize that Subjects pre-treated with calcitriol will have faster reaction times/higher accuracy on the CPT-IP vs. subjects pre-treated with placebo, after treatment with amphetamine.

Detailed Description

Increases in the rates of childhood ADHD over the past two decades have lead to speculation that calcitriol deficiency (e.g., secondary to the increased use of sunscreen and/or increases in sedentary, indoor lifestyles in children) plays a causal/contributory role in the etiology of ADHD. To date, evidence of a direct link is lacking. One study showed higher maternal circulating Vitamin D levels in pregnancy are associated with lower risk of developing ADHD-like symptoms in childhood. On the other hand, another study did not replicate the above association, and a prospective study using umbilical cord samples stored at the time of birth reported no difference in serum vitamin D levels between ADHD group versus healthy controls. In terms of clinical trials, one randomized double blind study among adults with ADHD reported a beneficial effect of the intervention, measured with the Conners Adult ADHR rating scale, in comparison with placebo, but the intervention included the combination of vitamin D and several other micronutrients. An analysis of moderators of a positive response to ADHD behaviors did not reveal a significant predictive effect of vitamin D.

However, recent studies provide intriguing indirect evidence of an inverse relationship between solar intensity (SI) and/or altitude (a proxy for greater sun/UV light exposure) and regional rates of ADHD. One study examined three large datasets across 49 U.S. states for 2003 and 2007, and across 9 non-U.S. countries. This study examined the prevalence of ADHD and Solar Intensity (SI) maps. They found an inverse association between solar intensity and prevalence of ADHD. Another study examined two national survey datasets. They found an inverse relationship between altitude and prevalence of ADHD. Investigators hypothesize, as suggested by Huber, that a common denominator on the above studies is the increased vitamin D levels in those exposed to a higher solar intensity, which is known to increase with altitude.

Conditions

ADHD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Calcitriol then placebo

Healthy volunteers will receive a baseline MRI. On the night before and day of testing, subjects will receive two doses of calcitriol (3.0mcg total), followed by PHNO injection and PET Scan #1. After PET Scan #1, subjects will receive a Dexedrine dose, followed by PHNO injection and PET Scan #2. A minimum of six days later, subjects will receive two doses of placebo for the night before and day of testing, followed by a third PHNO injection and PET scan #3. After PET scan #3, subjects will receive another Dexedrine dose, followed by PHNO injection and PET scan #4.

Group Type: EXPERIMENTAL

Magnetic Resonance Imaging (MRI)

Intervention Type: PROCEDURE

Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis

PHNO

Intervention Type: DRUG

Used as a tracer for in vivo imaging.

calcitriol

Intervention Type: DIETARY_SUPPLEMENT

three 0.5 mcg capsules

Placebo oral capsule

Intervention Type: DRUG

three 0.5 mcg capsules

high-resolution research tomography

Intervention Type: PROCEDURE

A functional imaging technique that is used to observe metabolic processes in the body.

Dextro Amphetamine

Intervention Type: DRUG

Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg

Placebo then Calcitriol

Healthy volunteers will receive a baseline MRI. On the night before and day of testing, subjects will receive two doses of placebo, followed by PHNO injection and PET Scan #1. After PET Scan #1, subjects will receive a Dexedrine dose, followed by PHNO injection and PET Scan #2. A minimum of six days later, subjects will receive two doses of calcitriol (3.0mcg total) for the night before and day of testing, followed by a third PHNO injection and PET scan #3. After PET scan #3, subjects will receive another Dexedrine dose, followed by PHNO injection and PET scan #4.

Group Type: EXPERIMENTAL

Magnetic Resonance Imaging (MRI)

Intervention Type: PROCEDURE

Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis

PHNO

Intervention Type: DRUG

Used as a tracer for in vivo imaging.

calcitriol

Intervention Type: DIETARY_SUPPLEMENT

three 0.5 mcg capsules

Placebo oral capsule

Intervention Type: DRUG

three 0.5 mcg capsules

high-resolution research tomography

Intervention Type: PROCEDURE

A functional imaging technique that is used to observe metabolic processes in the body.

Dextro Amphetamine

Intervention Type: DRUG

Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg

Interventions

Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis

Intervention Type: PROCEDURE

PHNO

Used as a tracer for in vivo imaging.

Intervention Type: DRUG

calcitriol

three 0.5 mcg capsules

Intervention Type: DIETARY_SUPPLEMENT

Placebo oral capsule

three 0.5 mcg capsules

Intervention Type: DRUG

high-resolution research tomography

A functional imaging technique that is used to observe metabolic processes in the body.

Intervention Type: PROCEDURE

Dextro Amphetamine

Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg

Intervention Type: DRUG

Other Intervention Names

PET scan; Dexedrine

Eligibility Criteria

Inclusion Criteria

• Age 18-50 years
• Voluntary, written, informed consent
• Physically healthy by medical history, physical, neurological, ECG, and laboratory examinations
• For females, non-lactating, with a negative serum or urine pregnancy test
• Lab results without clinically relevant findings (e.g. renal function, electrolytes, and vitamin D levels)
• English speaking

Exclusion Criteria

• Medical contraindication to Dexedrine administration (e.g., history of cardiac problems, seizures, glaucoma, hypertension, hyperthyroidism, etc.)
• Medical contraindication to calcitriol administration (e.g., history of hypersensitivity to calcitriol or any component of the formulation, hypercalcemia or vitamin D toxicity)
• History of substance dependence (e.g., alcohol, opiates, sedative hypnotics), except for nicotine
• A primary major DSM-5 psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depression, etc.) as determined by the Structured Clinical Interview for DSM-5 (SCID)
• A history of significant medical (e.g., cardiovascular, diabetic/metabolic) or neurological (e.g., cerebrovascular accidents, seizure, traumatic brain injury) illness
• Positive answers on the cardiac history questionnaire that may place the subject at higher risk, as determined by an internal medicine specialist or cardiologist's review of both the questionnaire responses and screening ECG
• Current use of psychotropic and/or potentially psychoactive prescription medications
• For females, laboratory (β-HCG) or physical evidence of pregnancy/lactation 9) MRI-incompatible implants and other contraindications for MRI (i.e., aneurysm clip, metal fragments, internal electrical devices such as a cochlear implant, spinal cord stimulator or pacemaker)
• History of claustrophobia or feeling of inability to lie still on his/her back for the PET or MRI scans
• History of any bleeding disorder or current anticoagulant therapy
• Donation or loss of 550 mL of blood or more (including plasmapheresis) or receipt of a transfusion of any blood product within 8 weeks prior to the first test day.
• Use of any prescription medications and/or over-the-counter medications, vitamins and/or herbal supplements which could have a negative clinical interaction with calcitriol/Dexedrine or which could confound scientific results of the study, within 2 weeks prior to each test day (e.g., thiazide diuretics, Mg based antiacids, digoxin, etc,.).
• Serum levels of 25(OH)D3 below 20 ng/ml.
• Obesity i.e. BMI over 30 (more prone to lower vitamin D levels)
• Subjects with history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over Radioactive Drug Research Committee (RDRC) limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year.
• Subjects with current, past or anticipated exposure to radiation in the work place
• History of kidney stones within the past 5 years
• Any degree of renal failure
• History of parathyroid disorder (hyper or hypoparathyroidism)
• History of osteoporosis or any pathologic fractures
• Vitamin D supplementation in any form in the past 3 months
• Known hypersensitivity to Dexedrine, [11C]PHNO, or calcitriol
• Malabsorption syndromes (i.e. Celiac sprue)
• Serum corrected calcium > 10.5 mg/dl or phosphate > 4.2 mg/dl

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Brain & Behavior Research Foundation

OTHER

Sponsor Role: collaborator

National Center for Complementary and Integrative Health (NCCIH)

NIH

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marc Potenza, PhD, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

Connecticut Mental Health Center

New Haven, Connecticut, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

M# 25288

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

1R01AT010508-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2000020604

Identifier Type: -

Identifier Source: org_study_id