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

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.

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-V psychiatric disorder (e.g., schizophrenia, bipolar disorder,
major depression, etc.) as determined by the Structured Clinical Interview for DSM-V
(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] Raclopride, or calcitriol

- Malabsorption syndromes (i.e. Celiac sprue)

- Serum corrected calcium > 10.5 mg/dl or phosphate > 4.2 mg/dl