Vitamin D's Capacity to Increase Amphetamine-Induced Dopamine Release in Healthy Humans: A Clinical Translational [¹¹C]-PHNO Positron Emission Tomography Study

Background: Dopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D₂/D₃ receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans.

Methods: Healthy, vitamin D-sufficient adults (N = 18, 32.8 ± 6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving 4 total scans over 2 visits consisting of same-day preamphetamine and postamphetamine (0.3 mg/kg) [¹¹C]-PHNO positron emission tomography scanning to examine D₂/D₃ receptor availability (nondisplaceable binding potential [BP_ND]) following active calcitriol (1.5 μg night before experimental day and 1.5 μg morning of experimental day) or placebo at least 6 days apart. Parametric images of [¹¹C]-PHNO positron emission tomography BP_ND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra.

Results: For preamphetamine scans, there was a medication × region of interest interaction (F_4,153 = 2.59, p = .039) and a main effect of medication (F_1,153 = 4.88, p = .029) on BP_ND, with higher BP_ND values on calcitriol in the ventral striatum (t₁₅₃ = 2.89, p = .004) and dorsal putamen (t₁₅₃ = 2.15, p = .033). There was a main effect of medication on postamphetamine change in BP_ND (F_4,153 = 5.93, p = .016), with greater decreases in calcitriol in the ventral striatum (t₁₅₃ = 3.00, p = .003), substantia nigra (t₁₅₃ = 2.49, p = .014), and dorsal caudate (t₁₅₃ = 2.29, p = .023).

Conclusions: Results provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders that involve dysregulated dopamine function.