Does T3 Cross the Blood-Brain Barrier?
Yes, triiodothyronine (T3) crosses the blood-brain barrier, but it requires specific membrane transporters—primarily MCT8 and OATP1C1—to enter the brain, as thyroid hormones cannot passively diffuse across cell membranes despite being lipophilic. 1, 2, 3
Transport Mechanisms Across the Blood-Brain Barrier
T3 penetrates the blood-brain barrier through active transport rather than passive diffusion, requiring specialized carrier proteins:
MCT8 (monocarboxylate transporter 8) is the primary transporter for T3 entry into brain neurons, with high specificity for thyroid hormones and rapid cellular uptake capability 2, 3, 4
OATP1C1 (organic anion transporting polypeptide 1C1) preferentially transports T4 (thyroxine) across the blood-brain barrier, though it can also transport T3 with lower affinity 2, 3, 5
Both transporters are essential for maintaining adequate thyroid hormone levels in the central nervous system, as demonstrated by severe neurological deficits in mice lacking both MCT8 and OATP1C1 4
Clinical Evidence from Genetic Disorders
The absolute requirement for these transporters is proven by human genetic diseases:
Mutations in MCT8 cause Allan-Herndon-Dudley syndrome (AHDS), characterized by severe psychomotor retardation and elevated serum T3 levels, demonstrating that T3 cannot adequately enter the brain without functional MCT8 2, 3, 4
Deficiency of OATP1C1 is linked to brain hypometabolism and progressive neurodegeneration, indicating its critical role in thyroid hormone delivery to the central nervous system 2
Mice lacking both MCT8 and OATP1C1 show dramatically reduced brain T3 and T4 content, delayed cerebellar development, reduced myelination, and pronounced locomotor abnormalities, confirming these transporters are the primary route for thyroid hormone brain entry 4
Pharmacological Implications
The FDA-approved drug label for intravenous liothyronine sodium (T3) explicitly states relevant transport properties:
"T3 is bound much less firmly to serum binding proteins and therefore penetrates into the cells much more rapidly than T4" 1
"Since liothyronine sodium (T3) is not firmly bound to serum protein, it is readily available to body tissues", including brain tissue once it crosses the blood-brain barrier via MCT8 1
A single intravenous dose of T3 produces detectable metabolic response in 2-4 hours and maximum therapeutic response within 2 days, reflecting its rapid tissue penetration once transported across barriers 1
Routes of Brain Entry
T3 can enter the brain through two distinct anatomical routes with different distribution patterns:
Transport across the blood-brain barrier (cerebral capillary endothelium) provides widespread distribution throughout brain parenchyma, with access to nuclear T3 receptors in neurons and glia 6
Transport across the choroid plexus into cerebrospinal fluid results in limited periventricular distribution, with preferential access to circumventricular organs but restricted penetration into deeper brain structures 6
The blood-brain barrier route appears more important for T3's genomic actions at nuclear receptors, while the choroid plexus route may serve specialized functions in periventricular regions 6
Critical Pitfalls to Avoid
Do not assume T3 freely crosses the blood-brain barrier simply because it is lipophilic—active transport via MCT8 is absolutely required for adequate brain delivery 2, 3, 4
Recognize that peripheral T3 levels do not reliably predict brain T3 concentrations when transporter function is impaired, as seen in AHDS where serum T3 is elevated but brain T3 is deficient 2, 4
Understand that T3 augmentation therapy for treatment-resistant depression relies on T3's ability to cross the blood-brain barrier via MCT8 to reach limbic system thyroid hormone receptors 7, 8