Journal of Autism and Developmental Disorders

, Volume 44, Issue 11, pp 2971–2977 | Cite as

Brief Report: An Open-Label Study of the Neurosteroid Pregnenolone in Adults with Autism Spectrum Disorder

  • Lawrence K. FungEmail author
  • Robin A. Libove
  • Jennifer Phillips
  • Francois Haddad
  • Antonio Y. Hardan
Brief Report


The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.5 ± 5.8 years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.4 ± 7.4 at baseline to 11.2 ± 7.0 at 12 weeks (p = 0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p = 0.046) and total Short Sensory Profile score (p = 0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.


Autism spectrum disorder Pregnenolone Neurosteroids Irritability Open-label trial 



This study was supported by a grant from the Escher Family Fund at the Silicon Valley Community Foundation to AYH and Mosbacher Fund to LKF. LKF is a recipient of the Ruth L. Kirschstein Individual Postdoctoral National Research Service Award. The authors would like to thank Pure Encapsulations (Sudbury, MA, USA) for donating the pregnenolone capsules.

Conflict of interest

Over the last 3 years, Dr. A.Y. Hardan has received research support and honorarium for consulting from the following companies: Bristol-Myers Squibb, Roche, Forest, and IntegraGen. Drs. L. K. Fung, J. Phillips, F. Haddad and Ms. R. A. Libove did not report any conflict.


  1. Aman, M. G., Singh, N. N., Stewart, A. W., & Field, C. J. (1985). Psychometric characteristics of the aberrant behavior checklist. American Journal of Mental Deficiency, 89, 492–502.PubMedGoogle Scholar
  2. APA. (2013). Diagnostic and statistical manual of mental disorders: DSM-5 (4th ed.). Washington, DC: American Psychiatric Association.Google Scholar
  3. Constantino, J. N., et al. (2003). Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. Journal of Autism and Developmental Disorders, 33, 427–433.PubMedCrossRefGoogle Scholar
  4. Ebisch, S. J., et al. (2011). Altered intrinsic functional connectivity of anterior and posterior insula regions in high-functioning participants with autism spectrum disorder. Human Brain Mapping, 32, 1013–1028. doi: 10.1002/hbm.21085.PubMedCrossRefGoogle Scholar
  5. Fatemi, S. H., Reutiman, T. J., Folsom, T. D., Rooney, R. J., Patel, D. H., & Thuras, P. D. (2010). mRNA and protein levels for GABAAalpha4, alpha5, beta1 and GABABR1 receptors are altered in brains from subjects with autism. Journal of Autism and Developmental Disorders, 40, 743–750. doi: 10.1007/s10803-009-0924-z.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Fatemi, S. H., Reutiman, T. J., Folsom, T. D., Rustan, O. G., Rooney, R. J., & Thuras, P. D. (2014). Downregulation of GABA receptor protein subunits alpha6, beta2, delta, epsilon, gamma2, theta, and rho2 in superior frontal cortex of subjects with autism. Journal of Autism and Developmental Disorders,. doi: 10.1007/s10803-014-2078-x.PubMedGoogle Scholar
  7. Fido, A., & Al-Saad, S. (2008). Olanzapine in the treatment of behavioral problems associated with autism: an open-label trial in Kuwait. Medical Principles and Practice, 17, 415–418. doi: 10.1159/000141508.PubMedCrossRefGoogle Scholar
  8. Gai, X., et al. (2012). Rare structural variation of synapse and neurotransmission genes in autism. Molecular Psychiatry, 17, 402–411. doi: 10.1038/mp.2011.10.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Gogolla, N., Leblanc, J. J., Quast, K. B., Sudhof, T. C., Fagiolini, M., & Hensch, T. K. (2009). Common circuit defect of excitatory-inhibitory balance in mouse models of autism. Journal of Neurodevelopment Disorders, 1, 172–181. doi: 10.1007/s11689-009-9023-x.CrossRefGoogle Scholar
  10. Hosie, A. M., Wilkins, M. E., da Silva, H. M., & Smart, T. G. (2006). Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature, 444, 486–489.PubMedCrossRefGoogle Scholar
  11. Kandel, E. R., Schwartz, J. H., Jessell, T. M., Siegelbaum, S. A., & Hudspeth, A. J. (2013). Principles of Neural Science (5th ed.). McGraw Hill Companies: New York.Google Scholar
  12. Kemner, C., Willemsen-Swinkels, S. H., de Jonge, M., Tuynman-Qua, H., & van Engeland, H. (2002). Open-label study of olanzapine in children with pervasive developmental disorder. Journal of Clinical Psychopharmacology, 22, 455–460.PubMedCrossRefGoogle Scholar
  13. Kostakis, E., et al. (2013). The neuroactive steroid pregnenolone sulfate stimulates trafficking of functional N-methyl D-aspartate receptors to the cell surface via a noncanonical, G protein, and Ca2 + -dependent mechanism. Molecular Pharmacology, 84, 261–274. doi: 10.1124/mol.113.085696.PubMedCrossRefPubMedCentralGoogle Scholar
  14. Lord, C., Rutter, M., & Le Couteur, A. (1994). Autism diagnostic interview-revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders, 24, 659–685.PubMedCrossRefGoogle Scholar
  15. Lord, C., et al. (2000). The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30, 205–223.PubMedCrossRefGoogle Scholar
  16. Majewska, M. D., Harrison, N. L., Schwartz, R. D., Barker, J. L., & Paul, S. M. (1986). Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science, 232, 1004–1007.PubMedCrossRefGoogle Scholar
  17. Marx, C. E., et al. (2009). Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology, 34, 1885–1903. doi: 10.1038/npp.2009.26.PubMedCrossRefPubMedCentralGoogle Scholar
  18. McDougle, C. J., et al. (1997). Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective open-label study. Journal of the American Academy of Child and Adolescent Psychiatry, 36, 685–693. doi: 10.1097/00004583-199705000-00020.PubMedCrossRefGoogle Scholar
  19. Mendez, M. A., et al. (2012). The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [(11)C]Ro15-4513 positron emission tomography study. Neuropharmacology,. doi: 10.1016/j.neuropharm.2012.04.008.PubMedGoogle Scholar
  20. Naylor, J., et al. (2010). Pregnenolone sulphate- and cholesterol-regulated TRPM3 channels coupled to vascular smooth muscle secretion and contraction. Circulation Research, 106, 1507–1515. doi: 10.1161/CIRCRESAHA.110.219329.PubMedCrossRefPubMedCentralGoogle Scholar
  21. Oblak, A., Gibbs, T. T., & Blatt, G. J. (2009). Decreased GABA(A) receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism. Autism Research, 2, 205–219. doi: 10.1002/aur.88.PubMedCrossRefPubMedCentralGoogle Scholar
  22. O’Roak, B. J., et al. (2011). Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genetics, 43, 585–589. doi: 10.1038/ng.835.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Osuji, I. J., Vera-Bolanos, E., Carmody, T. J., & Brown, E. S. (2010). Pregnenolone for cognition and mood in dual diagnosis patients. Psychiatry Research, 178, 309–312. doi: 10.1016/j.psychres.2009.09.006.PubMedCrossRefGoogle Scholar
  24. Ritsner, M. S., et al. (2010). Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial. Journal of Clinical Psychiatry, 71, 1351–1362. doi: 10.4088/JCP.09m05031yel.PubMedCrossRefGoogle Scholar
  25. Rubenstein, J. L., & Merzenich, M. M. (2003). Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes, Brain and Behavior, 2, 255–267.CrossRefGoogle Scholar
  26. Siever, L. J. (2008). Neurobiology of aggression and violence. American Journal of Psychiatry, 165, 429–442. doi: 10.1176/appi.ajp.2008.07111774.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Solomon, M., et al. (2013). The development of the neural substrates of cognitive control in adolescents with autism spectrum disorders. Biological Psychiatry,. doi: 10.1016/j.biopsych.2013.08.036.Google Scholar
  28. Sparrow, S., Balla, D. A., & Cinchetti, D. (2005). Vineland Adaptive Behavior Scales. Bloomington: IN, Pearson Education Inc.Google Scholar
  29. Sripada, R. K., Marx, C. E., King, A. P., Rampton, J. C., Ho, S. S., & Liberzon, I. (2013). Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits. Biological Psychiatry, 73, 1045–1053. doi: 10.1016/j.biopsych.2012.12.008.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Stigler, K. A., Mullett, J. E., Erickson, C. A., Posey, D. J., & McDougle, C. J. (2012). Paliperidone for irritability in adolescents and young adults with autistic disorder. Psychopharmacology (Berl), 223, 237–245. doi: 10.1007/s00213-012-2711-3.CrossRefGoogle Scholar
  31. Stigler, K. A., et al. (2009). Aripiprazole in pervasive developmental disorder not otherwise specified and Asperger’s disorder: a 14-week, prospective, open-label study. Journal of Child and Adolescent Psychopharmacology, 19, 265–274. doi: 10.1089/cap.2008.093.PubMedCrossRefPubMedCentralGoogle Scholar
  32. Tomchek, S. D., & Dunn, W. (2007). Sensory processing in children with and without autism: a comparative study using the short sensory profile. The American Journal of Occupational Therapy: Official Publication of the American Occupational Therapy Association, 61, 190–200.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Lawrence K. Fung
    • 1
    Email author
  • Robin A. Libove
    • 1
  • Jennifer Phillips
    • 1
  • Francois Haddad
    • 2
  • Antonio Y. Hardan
    • 1
  1. 1.Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral SciencesStanford UniversityStanfordUSA
  2. 2.Division of Cardiovascular Medicine, Department of MedicineStanford UniversityStanfordUSA

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