Nasal oxytocin for the treatment of psychiatric disorders and pain: achieving meaningful brain concentrations

Translational Psychiatry ARTICLE www.nature.com/tp OPEN Nasal oxytocin for the treatment of psychiatric disorders and pain: achieving meaningful brain concentrations ✉ David C. Yeomans1 , Leah R. Hanson2, Dean S. Carson3,4, Brendan J. Tunstall 7 Daniel Jacobs and William H. FreyII 2 5 , Mary R. Lee6, Alexander Z. Tzabazis1, © The Author(s) 2021 There is evidence of the therapeutic potential of intranasal oxytocin for the treatment of pain and various psychiatric disorders, however, there is scant evidence that oxytocin reaches the brain. We quantified the concentration and distribution pattern of [125I]radiolabeled oxytocin in the brains and peripheral tissues of rats after intranasal delivery using gamma counting and autoradiography, respectively. Radiolabel was detected in high concentrations in the trigeminal and olfactory nerves as well as in brain regions along their trajectories. Considerable concentrations were observed in the blood, however, relatively low levels of radiolabel were measured in peripheral tissues. The addition of a mucoadhesive did not enhance brain concentrations. These results provide support for intranasal OT reaching the brain via the olfactory and trigeminal neural pathways. These findings will inform the design and interpretation of clinical studies with intranasal oxytocin. Translational Psychiatry (2021)11:388 ; https://doi.org/10.1038/s41398-021-01511-7 INTRODUCTION A growing body of research highlights the potential for the neuropeptide oxytocin (OT) in the treatment of a wide range of central nervous system (CNS) disorders, spanning autism to chronic pain [1, 2]. Oral delivery of peptide therapeutics leads to limited absorption due in part to degradation in the gut, injections are not favored for chronic daily use, and both delivery methods typically result in limited CNS penetration for large molecules like OT (molecular weight = 1007.19 Da) [3]. In order to circumvent the restrictions of the blood–brain barrier (BBB), many clinical researchers have utilized the noninvasive intranasal delivery route in the hopes of enhancing OT brain penetration by bypassing the BBB [4]. Intranasal delivery of large molecular weight drugs and proteins resulted in substantial brain penetration via transport along the perivascular space of blood vessels associated with olfactory and trigeminal nerves [5]. Thorne et al. [6] reported that intranasal, but not intravenous, delivery of radioiodinated insulin-like growth factorI (7.65 kDa) rapidly (<30 min) resulted in significant brain penetration along extracellular olfactory and trigeminal nerve pathways. Similar results were found in nonhuman primates (cynomolgus monkeys) after intranasal administration of interferon-β1b (20 kDa) with the highest concentration of radioiodinated IFN-β1b found in the olfactory bulb as well as the basal ganglia [7]. Intranasal, compared with intravenous, administration of hypocretin (3.5 kDa) resulted in significantly greater tissue-to-blood concentrations in all brain regions measured over 2 h while blood concentrations were tenfold lower [8]. Thus, there is strong evidence supporting brain penetrance and limited systemic exposure after intranasal administration of therapeutic peptides. Regarding OT, a number of recent studies have measured both blood and CSF OT concentrations following intranasal delivery of OT to nonhuman primates and demonstrated dose-dependent effects in blood OT concentration and activation of brain regions in humans [9, 10]. Lee et al. [11] administered intranasal, labeled (deuterated) OT (80 IU) to rhesus macaques and measured, by mass spectrometry, plasma and CSF concentrations of administered OT in the CSF and plasma. There were significant elevations of labeled OT in CSF and plasma over the 60-min sampling period after intranasal administration. These results built on previous studies in rhesus macaques where unlabeled OT was administered intranasally and significant elevations in CSF OT concentrations were observed after 40 [12] and 120 [13] min. In humans, Striepens et al. also reported significant elevation of CSF OT delivered intranasally after 75 min [14]. Thus, there is good evidence to support the delivery of OT to the CNS of nonhuman primates and humans after intranasal administration, although, it is important to note that the CSF recovery of the delivered OT dose in such studies is on the order of 0.001% [15, 16]. One possibility not tested in these aforementioned studies is that intranasal OT delivery bypasses the BBB and results in significantly greater elevations of administered OT in brain parenchyma compared to CSF. Importantly, many studies that test the ability of OT to cross the BBB use CSF as a surrogate for determining distribution within the CNS and do not test for delivery to the brain parenchyma itself. It is important to note that CSF drug concentration is not always a good proxy for brain concentration for drugs administered intranasally. For example, Dhuria et al. [8] reported that the concentration of hypocretin in trigeminal nerves and olfactory 1 Department of Anaesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, USA. 2Department of Neuroscience, HealthPartners Institute, Minneapolis, MN, USA. 3Trigemina, Inc., Moraga, CA, USA. 4Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA, USA. 5Department of Pharmacology, Addiction Science, and Toxicology, The University of Tennessee Health Science Center, Memphis, TN, USA. 6Veterans Affairs Medical Center, Washington, DC, USA. 7Department of Surgery, Permanente Medical Group, Santa Clara, CA, USA. ✉email: Received: 3 May 2021 Revised: 1 June 2021 Accepted: 21 June 2021 D.C. Yeomans et al. 1234567890();,: 2 bulbs was much higher than the hypocretin concentration in cisternal CSF 30 min after intranasal delivery compared to intravenous delivery. As regards OT, administration of intranasal OT resulted in a significant increase in OT concentrations in microdialysates taken from both the amygdala and hippocampus, however, there were no changes in ventricular CSF OT concentrations [17]. More recently, intranasal OT administered to OT-null mice resulted in a similar elevation in central OT concentrations in microdialysates, suggesting that the elevation is due solely to exogenous OT [18]. Measuring brain concentrations after intranasal administration of labeled OT, Lee et al. [19] reported that deuterated OT administered intranasally to rhesus macaques was quantified 2 h after administration in brain tissue collected from regions along the trajectory of the trigeminal and olfactory nerves, demonstrating that intranasal OT achieves brain penetration. Interestingly, IV administration of OT did not generate detectable brain concentrations of OT at this time point, consistent with OT’s rapid degradation in the bloodstream. This suggests that intranasal OT’s penetration of brain tissue might (...truncated)