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The promise and pitfalls of intranasally administering psychopharmacological agents for the treatment of psychiatric disorders

Molecular Psychiatry volume 21, pages 29–38 (2016)Cite this article

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Abstract

Accumulating research demonstrates the potential of intranasal delivery of psychopharmacological agents to treat a range of psychiatric disorders and symptoms. It is believed that intranasal administration offers both direct and indirect pathways to deliver psychopharmacological agents to the central nervous system. This administration route provides a unique opportunity to repurpose both old drugs for new uses and improve currently approved drugs that are indicated for other administration routes. Despite this promise, however, the physiology of intranasal delivery and related assumptions behind the bypassing of the blood brain barrier is seldom considered in detail in clinical trials and translational research. In this review, we describe the current state of the art in intranasal psychopharmacological agent delivery research and current challenges using this administration route, and discuss important aspects of nose-to-brain delivery that may improve the efficacy of these new therapies in future research. We also highlight current gaps in the literature and suggest how research can directly examine the assumptions of nose-to-brain delivery of psychopharmacological agents in humans.

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References

  1. Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS et al. Grand challenges in global mental health. Nature 2011; 475: 27–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bloom DE, Cafiero E, Jané-Llopis E, Abrahams-Gessel S, Bloom LR, Fathima S et al. The Global Economic Burden of Non-communicable Diseases. Geneva: World Economic Forum 2011.

  3. Miller G . Is pharma running out of brainy ideas. Science 2010; 329: 502–504.

    Article  CAS  PubMed  Google Scholar 

  4. Abbott A . Novartis to shut brain research facility. Nature 2011; 480: 161–162.

    Article  CAS  PubMed  Google Scholar 

  5. Insel T, Voon V, Nye J, Brown VJ, Altevogt B, Bullmore E et al. Innovative solutions to novel drug development in mental health. Neurosci Biobehav Rev 2013; 37: 2438–2444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pangalos MN, Schechter LE, Hurko O . Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 2007; 6: 521–532.

    Article  CAS  PubMed  Google Scholar 

  7. Hyman SE . Revolution stalled. Sci Transl Med 2012; 4: 155cm111–155cm111.

    Article  Google Scholar 

  8. Chong CR, Sullivan DJ . New uses for old drugs. Nature 2007; 448: 645–646.

    Article  CAS  PubMed  Google Scholar 

  9. DiMasi JA, Hansen RW, Grabowski HG . The price of innovation: new estimates of drug development costs. J Health Econ 2003; 22: 151–185.

    Article  PubMed  Google Scholar 

  10. Quintana DS, Alvares GA, Hickie IB, Guastella AJ . Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. Neurosci Biobehav Rev 2015; 49: 182–192.

    Article  CAS  PubMed  Google Scholar 

  11. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH II . Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004; 127: 481–496.

    Article  CAS  PubMed  Google Scholar 

  12. Thorne RG, Emory CR, Ala TA, Frey WH II . Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res 1995; 692: 278–282.

    Article  CAS  PubMed  Google Scholar 

  13. Balin BJ, Broadwell RD, Salcman M, El-Kalliny M . Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J Comp Neurol 1986; 251: 260–280.

    Article  CAS  PubMed  Google Scholar 

  14. Djupesland PG, Skretting A, Winderen M, Holand T . Breath actuated device improves delivery to target sites beyond the nasal valve. Laryngoscope 2006; 116: 466–472.

    Article  PubMed  Google Scholar 

  15. Pardridge WM . CNS drug design based on principles of blood-brain barrier transport. J Neurochem 1998; 70: 1781–1792.

    Article  CAS  PubMed  Google Scholar 

  16. Yamamoto A, Iseki T, Ochi-Sugiyama M, Okada N, Fujita T, Muranishi S . Absorption of water-soluble compounds with different molecular weights and [Asu1.7]-eel calcitonin from various mucosal administration sites. J Control Release 2001; 76: 363–374.

    Article  CAS  PubMed  Google Scholar 

  17. Guastella AJ, Hickie IB, McGuinness MM, Otis M, Woods EA, Disinger HM et al. Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology 2013; 38: 612–625.

    Article  CAS  PubMed  Google Scholar 

  18. Miller JL, Ashford JW, Archer SM, Rudy AC, Wermeling DP . Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study. Pharmacotherapy 2008; 28: 875–882.

    Article  CAS  PubMed  Google Scholar 

  19. Meredith ME, Salameh TS, Banks WA . Intranasal delivery of proteins and peptides in the treatment of neurodegenerative diseases. AAPS J 2015; 17: 780–787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Miyake MM, Bleier BS . The blood-brain barrier and nasal drug delivery to the central nervous system. Am J Rhinol Allergy 2015; 29: 124–127.

    Article  PubMed  Google Scholar 

  21. Kaminsky BM, Bostwick JR, Guthrie SK . Alternate routes of administration of antidepressant and antipsychotic medications. Ann Pharmacother 2015; 49: 808–817.

    Article  CAS  PubMed  Google Scholar 

  22. Jiang Y, Li Y, Liu X . Intranasal delivery: circumventing the iron curtain to treat neurological disorders. Expert Opin Drug Deliv 2015; 12: 1717–1725.

    Article  CAS  PubMed  Google Scholar 

  23. Andrade C . Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. J Clin Psychiatry 2015; 76: e628–e631.

    Article  PubMed  Google Scholar 

  24. Flexner S . The mode of infection in epidemic poliomyelitis. J Am Med Assoc 1912; 59: 1371–1372.

    Article  Google Scholar 

  25. Clark PF, Fraser FR, Amoss HL . The relation to the blood of the virus of epidemic poliomyelitis. J Exp Med 1914; 19: 223–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Findlay G, Clarke L . Infection with neurotropic yellow fever virus following instillation into the nares and conjunctival sac. J Pathol Bacteriol 1935; 40: 55–64.

    Article  Google Scholar 

  27. Slavin HB, Berry GP . Studies on herpetic infection in mice: II. The pathways of invasion of the central nervous system after intranasal instillation of virus in suckling mice. J Exp Med 1943; 78: 315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Perlman S, Barnett E, Jacobsen G . Mouse hepatitis virus and herpes simplex virus move along different CNS pathways. In: Laude H, Vautherot J-F (eds). Coronaviruses, vol. 342. Springer, New York, 1993, pp 313–318.

    Google Scholar 

  29. Mathison S, Nagilla R, Kompella UB . Nasal route for direct delivery of solutes to the central nervous system: fact or fiction? J Drug Target 1998; 5: 415–441.

    Article  CAS  PubMed  Google Scholar 

  30. Sharma S, Mukkur T, Benson HA, Chen Y . Pharmaceutical aspects of intranasal delivery of vaccines using particulate systems. J Pharm Sci 2009; 98: 812–843.

    Article  CAS  PubMed  Google Scholar 

  31. Henriksson J, Tallkvist J, Tjälve H . Uptake of nickel into the brain via olfactory neurons in rats. Toxicol Lett 1997; 91: 153–162.

    Article  CAS  PubMed  Google Scholar 

  32. Chen X, Fawcett J, Rahman Y, Ala T, Frey I . Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimers Dis 1998; 1: 35–44.

    Article  CAS  PubMed  Google Scholar 

  33. Ross T, Martinez P, Renner J, Thorne R, Hanson L, Frey W II . Intranasal administration of interferon beta bypasses the blood–brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J Neuroimmunol 2004; 151: 66–77.

    Article  CAS  PubMed  Google Scholar 

  34. Shipley M . Transport of molecules from nose to brain: transneuronal anterograde and retrograde labeling in the rat olfactory system by wheat germ agglutinin-horseradish peroxidase applied to the nasal epithelium. Brain Res Bull 1985; 15: 129–142.

    Article  CAS  PubMed  Google Scholar 

  35. Doty RL, Bromley SM . Cranial nerve I: olfactory nerve, chapter 7. In: Goetz CG (ed) Textbook of Clinical Neurology (3rd edn). W.B. Saunders: Philadelphia, 2007 pp 99–112.

    Book  Google Scholar 

  36. Roth G . Sensory systems: the coupling between brain and environment. The Long Evolution of Brains and Minds. Springer, Dordrecht, The Netherlands, 2013, pp 165–192.

    Book  Google Scholar 

  37. Kalogjera L, Dzepina D . Management of smell dysfunction. Curr Allergy Asthma Rep 2012; 12: 154–162.

    Article  Google Scholar 

  38. Doty RL . The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol 2008; 63: 7–15.

    Article  PubMed  Google Scholar 

  39. Li Y, Field PM, Raisman G . Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres. Glia 2005; 52: 245–251.

    Article  PubMed  Google Scholar 

  40. Kristensson K, Olsson Y . Uptake of exogenous proteins in mouse olfactory cells. Acta Neuropathol (Berl) 1971; 19: 145–154.

    Article  CAS  Google Scholar 

  41. Dhuria SV, Hanson LR, Frey WH II . Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 2009; 99: 1654–1673.

    Article  CAS  Google Scholar 

  42. Wolburg H, Wolburg-Buchholz K, Sam H, Horvát S, Deli MA, Mack AF . Epithelial and endothelial barriers in the olfactory region of the nasal cavity of the rat. Histochem Cell Biol 2008; 130: 127–140.

    Article  CAS  PubMed  Google Scholar 

  43. Dahlin M, Bergman U, Jansson B, Björk E, Brittebo E . Transfer of dopamine in the olfactory pathway following nasal administration in mice. Pharm Res 2000; 17: 737–742.

    Article  CAS  PubMed  Google Scholar 

  44. Anand Kumar T, David G, Kumar K, Umberkoman B, Krishnamoorthy M . A new approach to fertility regulation by interfering with neuroendocrine pathways. In: Anand Kumar TC (ed). Neuroendocrine Regulation of Fertility. Karger: Basel, 1976; 314–322.

    Google Scholar 

  45. Alcalá-Barraza SR, Lee MS, Hanson LR, McDonald AA, Frey WH, McLoon LK . Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS. J Drug Target 2010; 18: 179–190.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Chow HHS, Chen Z, Matsuura GT . Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats. J Pharm Sci 1999; 88: 754–758.

    Article  CAS  PubMed  Google Scholar 

  47. Anderson M, Tambe P, Sammons H, Mulla H, Cole R, Choonara I . Pharmacokinetics of buccal and intranasal lorazepam in healthy adult volunteers. Eur J Clin Pharmacol 2012; 68: 155–159.

    Article  CAS  PubMed  Google Scholar 

  48. Kumar M, Misra A, Babbar A, Mishra A, Mishra P, Pathak K . Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm 2008; 358: 285–291.

    Article  CAS  PubMed  Google Scholar 

  49. Grant I, Nimmo W, Clements J . Pharmacokinetics and analgesic effects of i.m. and oral ketamine. Br J Anaesth 1981; 53: 805–810.

    Article  CAS  PubMed  Google Scholar 

  50. Wallum B, Taborsky G Jr, Porte D Jr, Figlewicz D, Jacobson L, Beard J et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 1987; 64: 190–194.

    Article  CAS  PubMed  Google Scholar 

  51. Foster K, Roberts M . Experimental methods for studying drug uptake in the head and brain. Curr Drug Metab 2000; 1: 333–356.

    Article  CAS  PubMed  Google Scholar 

  52. Hansch C, Clayton JM . Lipophilic character and biological activity of drugs II: the parabolic case. J Pharm Sci 1973; 62: 1–21.

    Article  CAS  PubMed  Google Scholar 

  53. Banks WA, Kastin AJ . Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res Bull 1985; 15: 287–292.

    Article  CAS  PubMed  Google Scholar 

  54. Smith AL, Freeman SM, Voll RJ, Young LJ, Goodman MM . Investigation of an F-18 oxytocin receptor selective ligand via PET imaging. Bioorg Med Chem Lett 2013; 23: 5415–5420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Smith AL, Freeman SM, Voll RJ, Young LJ, Goodman MM . Carbon-11N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors. Bioorg Med Chem Lett 2013; 23: 902–906.

    Article  CAS  PubMed  Google Scholar 

  56. Bartlett JA, van der Voort Maarschalk K . Understanding the oral mucosal absorption and resulting clinical pharmacokinetics of asenapine. AAPS PharmSciTech 2012; 13: 1110–1115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. DeSesso JM . The relevance to humans of animal models for inhalation studies of cancer in the nose and upper airways. Qual Assur 1993; 2: 213–231.

    CAS  PubMed  Google Scholar 

  58. Frauman AG, Cooper ME, Parsons BJ, Jerums G, Louis WJ . Long-term use of intranasal insulin in insulin-dependent diabetic patients. Diabetes Care 1987; 10: 573–578.

    Article  CAS  PubMed  Google Scholar 

  59. Cacciotti-Saija C, Langdon R, Ward PB, Hickie IB, Scott E, Naismith SL et al. A double-blind randomized controlled trial of oxytocin nasal spray and social cognition training for young people with early psychosis. Schizophr Bull 2015; 41: 483–493.

    Article  PubMed  Google Scholar 

  60. Guastella AJ, Gray KM, Rinehart NJ, Alvares GA, Tonge BJ, Hickie IB et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J Child Psychol Psychiatry 2015; 56: 444–452.

    Article  PubMed  Google Scholar 

  61. Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014; 76: 970–976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Carr DB, Goudas LC, Denman WT, Brookoff D, Staats PS, Brennen L et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain 2004; 108: 17–27.

    Article  CAS  PubMed  Google Scholar 

  63. Barton ED, Colwell CB, Wolfe T, Fosnocht D, Gravitz C, Bryan T et al. Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting. J Emerg Med 2005; 29: 265–271.

    Article  PubMed  Google Scholar 

  64. Jansson B, Björk E . Visualization of in vivo olfactory uptake and transfer using fluorescein dextran. J Drug Target 2002; 10: 379–386.

    Article  CAS  PubMed  Google Scholar 

  65. Baker H, Spencer RF . Transneuronal transport of peroxidase-conjugated wheat germ agglutinin (WGA-HRP) from the olfactory epithelium to the brain of the adult rat. Exp Brain Res 1986; 63: 461–473.

    Article  CAS  PubMed  Google Scholar 

  66. Nonaka N, Farr SA, Kageyama H, Shioda S, Banks WA . Delivery of galanin-like peptide to the brain: targeting with intranasal delivery and cyclodextrins. J Pharmacol Exp Ther 2008; 325: 513–519.

    Article  CAS  PubMed  Google Scholar 

  67. Danielyan L, Schäfer R, von Ameln-Mayerhofer A, Bernhard F, Verleysdonk S, Buadze M et al. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res 2011; 14: 3–16.

    Article  CAS  PubMed  Google Scholar 

  68. Lai M, Topp E . Solid-state chemical stability of proteins and peptides. J Pharm Sci 1999; 88: 489–500.

    Article  CAS  PubMed  Google Scholar 

  69. Waterhouse RN . Determination of lipophilicity and its use as a predictor of blood–brain barrier penetration of molecular imaging agents. Mol Imaging Biol 2003; 5: 376–389.

    Article  PubMed  Google Scholar 

  70. Pardridge WM . Drug and gene delivery to the brain: the vascular route. Neuron 2002; 36: 555–558.

    Article  CAS  PubMed  Google Scholar 

  71. Adjei A, Sundberg D, Miller J, Chun A . Bioavailability of leuprolide acetate following nasal and inhalation delivery to rats and healthy humans. Pharm Res 1992; 9: 244–249.

    Article  CAS  PubMed  Google Scholar 

  72. Proctor DF . The upper airways. I. Nasal physiology and defense of the lungs. Am Rev Respir Dis 1977; 115: 97–129.

    CAS  PubMed  Google Scholar 

  73. Weiss L . Cell and Tissue Biology: A Textbook of Histology. Lippincott Williams & Wilkins, 1988.

    Google Scholar 

  74. Schweitzer VG . Osteolytic sinusitis and pneumomediastinum: deceptive otolaryngologic complications of cocaine abuse. Laryngoscope 1986; 96: 206–210.

    CAS  PubMed  Google Scholar 

  75. Jones N . The nose and paranasal sinuses physiology and anatomy. Adv Drug Deliv Rev 2001; 51: 5–19.

    Article  CAS  PubMed  Google Scholar 

  76. Wexler DB, Davidson TM . The nasal valve: a review of the anatomy, imaging, and physiology. Am J Rhinol 2004; 18: 143–150.

    Article  PubMed  Google Scholar 

  77. Bridger G, Proctor D . Maximum nasal inspiratory flow and nasal resistance. Ann Otol Rhinol Laryngol 1970; 79: 481–488.

    Article  CAS  PubMed  Google Scholar 

  78. Aggarwal R, Cardozo A, Homer J . The assessment of topical nasal drug distribution. Clin Otolaryngol Allied Sci 2004; 29: 201–205.

    Article  CAS  PubMed  Google Scholar 

  79. Uddströmer M . On the physiology of the nasal respiration. Acta Otolaryngol (Stockh) 1940; 28: 15–59.

    Article  Google Scholar 

  80. Mink PJ . Le nez comme voie respiratoire. Presse Otolaryng Belge 1903; 2: 481–496.

    Google Scholar 

  81. Mygind N, Dahl R . Anatomy, physiology and function of the nasal cavities in health and disease. Adv Drug Deliv Rev 1998; 29: 3–12.

    Article  CAS  PubMed  Google Scholar 

  82. Merkus P, Ebbens FA, Muller B, Fokkens WJ . Influence of anatomy and head position on intranasal drug deposition. Eur Arch Otorhinolaryngol 2006; 263: 827–832.

    Article  PubMed  Google Scholar 

  83. Djupesland PG, Mahmoud RA, Messina JC . Accessing the brain: the nose may know the way. J Cereb Blood Flow Metab 2013; 33: 793–794.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Quintana DS, Westlye LT, Rustan ØG, Tesli N, Poppy CL, Smevik H et al. Low dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized 4-way crossover trial with nasal cavity dimension assessment. Transl Psychiatry 2015; 5: 1–9.

    Article  CAS  Google Scholar 

  85. Sato K, Endo S, Tomita H . Sensitivity of three loci on the tongue and soft palate to four basic tastes in smokers and non-smokers. Acta Otolaryngol (Stockh) 2002; 122: 74–82.

    Article  Google Scholar 

  86. Homer J, Raine C . An endoscopic photographic comparison of nasal drug delivery by aqueous spray. Clin Otolaryngol Allied Sci 1998; 23: 560–563.

    Article  CAS  PubMed  Google Scholar 

  87. Perez AP, Mundiña-Weilenmann C, Romero EL, Morilla MJ . Increased brain radioactivity by intranasal 32 P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels. Int J Nanomed 2012; 7: 1373.

    CAS  Google Scholar 

  88. Kanazawa T . Brain delivery of small interfering ribonucleic acid and drugs through intranasal administration with nano-sized polymer micelles. Medl Devices (Auckl) 2015; 8: 57.

    CAS  Google Scholar 

  89. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012; 69: 29–38.

    Article  PubMed  Google Scholar 

  90. Hoekman JD, Ho RJ . Enhanced analgesic responses after preferential delivery of morphine and fentanyl to the olfactory epithelium in rats. Anesth Analg 2011; 113: 641.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Djupesland PG, Skretting A . Nasal deposition and clearance in man: comparison of a bidirectional powder device and a traditional liquid spray pump. J Aerosol Med Pulm Drug Deliv 2012; 25: 280–289.

    Article  CAS  PubMed  Google Scholar 

  92. Blanks AM, Thornton S . The role of oxytocin in parturition. BJOG 2003; 110: 46–51.

    Article  CAS  PubMed  Google Scholar 

  93. Fuchs A-R, Fuchs F, Husslein P, Soloff MS, Fernstrom MJ . Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor. Science 1982; 215: 1396–1398.

    Article  CAS  PubMed  Google Scholar 

  94. Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry 2007; 61: 498–503.

    Article  CAS  PubMed  Google Scholar 

  95. Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 2003; 28: 193–198.

    Article  CAS  PubMed  Google Scholar 

  96. Nishimori K, Young LJ, Guo Q, Wang Z, Insel TR, Matzuk MM . Oxytocin is required for nursing but is not essential for parturition or reproductive behavior. Proc Natl Acad Sci USA 1996; 93: 11699–11704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ruis H, Rolland R, Doesburg W, Broeders G, Corbey R . Oxytocin enhances onset of lactation among mothers delivering prematurely. BMJ 1981; 283: 340–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. McEwen BB . Brain–fluid barriers: relevance for theoretical controversies regarding vasopressin and oxytocin memory research. Adv Pharmacol 2004; 50: 531–592.

    Article  PubMed  Google Scholar 

  99. Fisher A, Brown K, Davis S, Parr G, Smith D . The effect of molecular size on the nasal absorption of water-soluble compounds in the albino rat. J Pharm Pharmacol 1987; 39: 357–362.

    Article  CAS  PubMed  Google Scholar 

  100. Neumann ID, Landgraf R . Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 2012; 35: 649–659.

    Article  CAS  PubMed  Google Scholar 

  101. Neumann ID, Maloumby R, Beiderbeck DI, Lukas M, Landgraf R . Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology 2013; 38: 1985–1993.

    Article  CAS  PubMed  Google Scholar 

  102. Striepens N, Kendrick KM, Hanking V, Landgraf R, Wüllner U, Maier W et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep 2013; 3: 3440.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Nelson E, Panksepp J . Oxytocin mediates acquisition of maternally associated odor preferences in preweanling rat pups. Behav Neurosci 1996; 110: 583.

    Article  CAS  PubMed  Google Scholar 

  104. Popik P, Vetulani J, Van Ree JM . Low doses of oxytocin facilitate social recognition in rats. Psychopharmacology (Berl) 1992; 106: 71–74.

    Article  CAS  Google Scholar 

  105. Eckstein M, Becker B, Scheele D, Scholz C, Preckel K, Schlaepfer TE et al. Oxytocin facilitates the extinction of conditioned fear in humans. Biol Psychiatry 2014; 78: 194–202.

    Article  CAS  PubMed  Google Scholar 

  106. Groppe SE, Gossen A, Rademacher L, Hahn A, Westphal L, Gründer G et al. Oxytocin influences processing of socially relevant cues in the ventral tegmental area of the human brain. Biol Psychiatry 2013; 74: 172–179.

    Article  CAS  PubMed  Google Scholar 

  107. Striepens N, Scheele D, Kendrick KM, Becker B, Schäfer L, Schwalba K et al. Oxytocin facilitates protective responses to aversive social stimuli in males. Proc Natl Acad Sci USA 2012; 109: 18144–18149.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Dadds MR, MacDonald E, Cauchi A, Williams K, Levy F, Brennan J . Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. J Autism Dev Disord 2014; 44: 521–531.

    Article  PubMed  Google Scholar 

  109. Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010; 67: 692–694.

    Article  CAS  PubMed  Google Scholar 

  110. Anagnostou E, Soorya L, Chaplin W, Bartz J, Halpern D, Wasserman S et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 2012; 3: 16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Andari E, Duhamel J-R, Zalla T, Herbrecht E, Leboyer M, Sirigu A . Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 2010; 107: 4389–4394.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Fang A, Hoge EA, Heinrichs M, Hofmann SG . Attachment style moderates the effects of oxytocin on social behaviors and cognitions during social rejection applying a research domain criteria framework to social anxiety. Clin Psychol Sci 2014; 2: 740–747.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Guastella AJ, Ward PB, Hickie IB, Shahrestani S, Hodge MAR, Scott EM et al. A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia. Schizophr Res 2015.

  114. Lee MR, Wehring HJ, McMahon RP, Linthicum J, Cascella N, Liu F et al. Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: results from a randomized double blind placebo controlled pilot study. Schizophr Res 2013; 145: 110–115.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Davis MC, Lee J, Horan WP, Clarke AD, McGee MR, Green MF et al. Effects of single dose intranasal oxytocin on social cognition in schizophrenia. Schizophr Res 2013; 147: 393–397.

    Article  PubMed  Google Scholar 

  116. McRae-Clark AL, Baker NL, Moran-Santa Maria M, Brady KT . Effect of oxytocin on craving and stress response in marijuana-dependent individuals: a pilot study. Psychopharmacology (Berl) 2013; 228: 623–631.

    Article  CAS  Google Scholar 

  117. MacDonald K, MacDonald TM, Brüne M, Lamb K, Wilson MP, Golshan S et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinology 2013; 38: 2831–2843.

    Article  CAS  PubMed  Google Scholar 

  118. Muin DA, Wolzt M, Marculescu R, Rezaei SS, Salama M, Fuchs C et al. Effect of long-term intranasal oxytocin on sexual dysfunction in premenopausal and postmenopausal women: a randomized trial. Fertil Steril 2015; 104: 715–723.

    Article  CAS  PubMed  Google Scholar 

  119. Einfeld SL, Smith E, McGregor IS, Steinbeck K, Taffe J, Rice LJ et al. A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome. Am J Med Genet A 2014; 164: 2232–2239.

    Article  CAS  Google Scholar 

  120. Cacciotti-Saija C, Langdon R, Ward PB, Hickie IB, Scott EM, Naismith SL et al. A double-blind randomized controlled trial of oxytocin nasal spray and social cognition training for young people with early psychosis. Schizophr Bull 2014; 41: 483–493.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Bakermans-Kranenburg M, Van Ijzendoorn M . Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl Psychiatry 2013; 3: e258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wigton R, Jocham Radua PA, Averbeck B, Meyer-Lindenberg A, McGuire P, Shergill SS et al. Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies. J Psychiatry Neurosci 2015; 40: E1.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Adolphs R . The neurobiology of social cognition. Curr Opin Neurobiol 2001; 11: 231–239.

    Article  CAS  PubMed  Google Scholar 

  124. Rilling JK, DeMarco AC, Hackett PD, Thompson R, Ditzen B, Patel R et al. Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology 2012; 37: 447–461.

    Article  CAS  PubMed  Google Scholar 

  125. Paloyelis Y, Doyle OM, Zelaya FO, Maltezos S, Williams SC, Fotopoulou A et al. A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans. Biol Psychiatry 2014.

  126. Boccia ML, Petrusz P, Suzuki K, Marson L, Pedersen CA . Immunohistochemical localization of oxytocin receptors in human brain. Neuroscience 2013; 253: 155–164.

    Article  CAS  PubMed  Google Scholar 

  127. Dal Monte O, Noble PL, Turchi J, Cummins A, Averbeck BB . CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS One 2014; 9: e103677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Chang SW, Barter JW, Ebitz RB, Watson KK, Platt ML . Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). Proc Natl Acad Sci USA 2012; 109: 959–964.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Kendrick K, Keverne E, Hinton M, Goode J . Cerebrospinal fluid and plasma concentrations of oxytocin and vasopressin during parturition and vaginocervical stimulation in the sheep. Brain Res Bull 1991; 26: 803–807.

    Article  CAS  PubMed  Google Scholar 

  130. Leng G, Ludwig M . Intranasal oxytocin: myths and delusions. Biol Psychiatry 2015.

  131. Quintana DS, Woolley JD . Intranasal oxytocin mechanisms can be better understood but its effects on social cognition and behavior are not to be sniffed at. Biol Psychiatry 2015 in press.

  132. Goldman RD . Intranasal drug delivery for children with acute illness. Curr Drug Ther 2006; 1: 127–130.

    Article  CAS  Google Scholar 

  133. Howes M . Ketamine for paediatric sedation/analgesia in the emergency department. Emerg Med J 2004; 21: 275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Barceloux DG . KetamineMedical Toxicology of Drug Abuse. John Wiley & Sons, Inc, 2012 pp 110–119.

    Book  Google Scholar 

  135. Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos 2003; 24: 37–43.

    Article  CAS  PubMed  Google Scholar 

  136. Malinovsky J, Servin F, Cozian A, Lepage J, Pinaud M . Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth 1996; 77: 203–207.

    Article  CAS  PubMed  Google Scholar 

  137. Sanacora G, Treccani G, Popoli M . Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 2012; 62: 63–77.

    Article  CAS  PubMed  Google Scholar 

  138. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2014; 170: 1134–1142.

    Article  Google Scholar 

  139. Horacek J, Brunovsky M, Novak T, Tislerova B, Palenicek T, Bubenikova-Valesova V et al. Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect. Psychol Med 2010; 40: 1443–1451.

    Article  CAS  PubMed  Google Scholar 

  140. Zarate CA Jr, Brutsche N, Laje G, Luckenbaugh DA, Venkata SLV, Ramamoorthy A et al. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry 2012; 72: 331–338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kaube H, Herzog J, Käufer T, Dichgans M, Diener H . Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000; 55: 139–141.

    Article  CAS  PubMed  Google Scholar 

  142. Wolfe T, Barton E . Nasal drug delivery in EMS: reducing needlestick risk. JEMS 2003; 28: 52–63.

    PubMed  Google Scholar 

  143. Barton ED, Ramos J, Colwell C, Benson J, Baily J, Dunn W . Intranasal administration of naloxone by paramedics. Prehosp Emerg Care 2002; 6: 54–58.

    Article  PubMed  Google Scholar 

  144. Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–962.

    Article  CAS  PubMed  Google Scholar 

  145. Modi ME, Connor-Stroud F, Landgraf R, Young LJ, Parr LA . Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 2014; 45: 49–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bethlehem RAI, van Honk J, Auyeung B, Baron-Cohen S . Oxytocin, brain physiology, and functional connectivity: a review of intranasal oxytocin fMRI studies. Psychoneuroendocrinology 2013; 38: 962–974.

    Article  CAS  PubMed  Google Scholar 

  147. Quintana DS, Kemp AH, Alvares GA, Guastella AJ . A role for autonomic cardiac control in the effects of oxytocin on social behavior and psychiatric illness. Front Neurosci 2013; 7: 48.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Dadds MR, MacDonald E, Cauchi A, Williams K, Levy F, Brennan J . Nasal oxytocin for social deficits in childhood autism: A randomized controlled trial. J Autism Dev Disord 2014; 44: 521–531.

    Article  PubMed  Google Scholar 

  149. Eckstein M, Becker B, Scheele D, Scholz C, Preckel K, Schlaepfer TE et al. Oxytocin facilitates the extinction of conditioned fear in humans. Biol Psychiatry 2014; 78: 194–202.

    Article  CAS  PubMed  Google Scholar 

  150. Guastella AJ, Mitchell PB, Mathews F . Oxytocin enhances the encoding of positive social memories in humans. Biol Psychiatry 2008; 64: 256–258.

    Article  CAS  PubMed  Google Scholar 

  151. Guastella AJ, Howard AL, Dadds MR, Mitchell P, Carson DS . A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder. Psychoneuroendocrinology 2009; 34: 917–923.

    Article  CAS  PubMed  Google Scholar 

  152. McIntyre RS, Soczynska JK, Woldeyohannes HO, Miranda A, Vaccarino A, MacQueen G et al. A randomized, double‐blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. Bipolar Disord 2012; 14: 697–706.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Mental Health and Addiction, NORMENT, KG Jebsen Centre for Psychosis Research, University of Oslo, and Oslo University Hospital, Oslo, Norway

    D S Quintana, L T Westlye & O A Andreassen

  2. Brain and Mind Center, Central Clinical School, University of Sydney, Sydney, NSW, Australia

    A J Guastella

  3. Department of Psychology, University of Oslo, Oslo, Norway

    L T Westlye

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  1. D S Quintana
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  2. A J Guastella
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  3. L T Westlye
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  4. O A Andreassen
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Correspondence to D S Quintana.

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Competing interests

Daniel S Quintana, Lars T Westlye and Ole A Andreassen are investigators in a project studying oxytocin’s effects after intranasal delivery partnered by OptiNose AS (Oslo, Norway) and funded by a BIA grant (219483) from the Research Council of Norway. Adam J Guastella is an investigator in a project investigating oxytocin’s effects partnered by OptiNose AS and funded by a Linkage Grant from the Australian Research Council (LP150101307). The funders and partner had no influence in the ideas contained in the manuscript and no role in the writing of the manuscript.

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Quintana, D., Guastella, A., Westlye, L. et al. The promise and pitfalls of intranasally administering psychopharmacological agents for the treatment of psychiatric disorders. Mol Psychiatry 21, 29–38 (2016). https://doi.org/10.1038/mp.2015.166

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  • DOI: https://doi.org/10.1038/mp.2015.166

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