An Exploratory Trial of Transdermal Nicotine for Aggression and Irritability in Adults with Autism Spectrum Disorder
Nicotinic acetylcholine receptors (nAChRs), particularly the α7 nAChR, are implicated in the pathophysiology of both autism spectrum disorder (ASD) and aggressive behavior. We explored the feasibility, tolerability, and preliminary efficacy of targeting nAChRs using transdermal nicotine to reduce aggressive symptoms in adults with ASD. Eight subjects were randomized in a double-blind crossover trial of 7 mg transdermal nicotine or placebo, each for 1 week. All participants tolerated nicotine treatment well. Five subjects contributed data to the primary outcome, Aberrant Behavior Checklist-Irritability (ABC-I) subscale change from baseline, which was improved by nicotine compared to placebo. Sleep ratings were also improved by nicotine and correlated with ABC-I improvement. These findings support further investigation of nAChR agonists for aggression and sleep in ASD.
KeywordsNicotine Nicotinic acetylcholine receptor Autism spectrum disorder Aggression Irritability Adult Sleep
This work was supported by Autism Speaks grant #9699 (ASL), National Institutes of Health grants R01DA14241 and R01MH077681 (MRP), R25MH071584, T32MH019961, and T32MH14276 (ASL), and the Child Study Center Associates and the AACAP Pilot Award for General Psychiatry Residents (GIvS). We thank Lawrence Price, Roger Jou, Michael Bloch, and Philip Smith for constructive feedback on this study and Jeffrey Eilbott for technical assistance.
ASL and GIvS conceived of the study, participated in its design, coordination, and data collection, and drafted the manuscript; MOL participated in the coordination of the study and performed data collection; FRV, MRP, and DGS participated in the design of the study and interpretation of the results. All authors read and approved the final manuscript.
This work was supported by Autism Speaks grant #9699, National Institutes of Health grants R01DA14241, R01MH077681, R25MH071584, T32MH019961, and T32MH14276, and the Yale Child Study Center Associates and the AACAP Pilot Award for General Psychiatry Residents.
Compliance with Ethical Standards
Conflict of interest
The authors declare no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- Allen, M. H., Debanne, M., Lazignac, C., Adam, E., Dickinson, L. M., & Damsa, C. (2011). Effect of nicotine replacement therapy on agitation in smokers with schizophrenia: A double-blind, randomized, placebo-controlled study. American Journal of Psychiatry, 168, 395–399. https://doi.org/10.1176/appi.ajp.2010.10040569.CrossRefPubMedGoogle Scholar
- Arnold, L. E., Aman, M. G., Hollway, J., Hurt, E., Bates, B., Li, X., et al. (2012). Placebo-controlled pilot trial of mecamylamine for treatment of autism spectrum disorders. Journal of child and Adolescent Psychopharmacology, 22, 198–205. https://doi.org/10.1089/cap.2011.0056.CrossRefPubMedPubMedCentralGoogle Scholar
- Carmel, H., & Sheitman, B. B. (2007). Adjunctive transdermal nicotine reduced behavioral agitation in severe dementia. The American Journal of Geriatric Psychiatry, 15, 449. https://doi.org/10.1097/01.JGP.0000235688.05709.e2.CrossRefPubMedGoogle Scholar
- Constantino, J. N., & Gruber, C. P. (2012). Social responsiveness scale: SRS-2 (2nd ed.). Torrance: Western Psychological Services.Google Scholar
- Cubells, J. F., DeOreo, E. H., Harvey, P. D., Garlow, S. J., Garber, K., Adam, M. P., et al. (2011). Pharmaco-genetically guided treatment of recurrent rage outbursts in an adult male with 15q13.3 deletion syndrome. American Journal of Medical Genetics Part A, 155A, 805–810. https://doi.org/10.1002/ajmg.a.33917.CrossRefPubMedGoogle Scholar
- Erickson, C. A., Veenstra-Vanderweele, J. M., Melmed, R. D., McCracken, J. T., Ginsberg, L. D., Sikich, L., et al. (2014). STX209 (arbaclofen) for autism spectrum disorders: An 8-week open-label study. Journal of Autism and Developmental Disorders, 44, 958–964. https://doi.org/10.1007/s10803-013-1963-z.CrossRefPubMedGoogle Scholar
- Hill, A. P., Zuckerman, K. E., Hagen, A. D., Kriz, D. J., Duvall, S. W., Van Santen, J., et al. (2014). Aggressive behavior problems in children with autism spectrum disorders: Prevalence and correlates in a large clinical sample. Research in Autism Spectrum Disorders, 8, 1121–1133. https://doi.org/10.1016/j.rasd.2014.05.006.CrossRefPubMedPubMedCentralGoogle Scholar
- Hoppman-Chaney, N., Wain, K., Seger, P. R., Superneau, D. W., & Hodge, J. C. (2013). Identification of single gene deletions at 15q13.3: Further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype. Clinical Genetics, 83, 345–351. https://doi.org/10.1111/j.1399-0004.2012.01925.x.CrossRefPubMedGoogle Scholar
- McDougle, C. J., Scahill, L., Aman, M. G., McCracken, J. T., Tierney, E., Davies, M., et al. (2005). Risperidone for the core symptom domains of autism: Results from the study by the autism network of the research units on pediatric psychopharmacology. American Journal of Psychiatry, 162, 1142–1148. https://doi.org/10.1176/appi.ajp.162.6.1142.CrossRefPubMedGoogle Scholar
- Mikhail, F. M., Lose, E. J., Robin, N. H., Descartes, M. D., Rutledge, K. D., Rutledge, S. L., et al. (2011). Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders. American Journal of Medical Genetics Part A, 155A, 2386–2396. https://doi.org/10.1002/ajmg.a.34177.CrossRefPubMedGoogle Scholar
- Oginsky, M. F., Cui, N., Zhong, W., Johnson, C. M., & Jiang, C. (2014). Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome. American Journal of Physiology-Cell Physiology, 307, C508-20. https://doi.org/10.1152/ajpcell.00035.2014.CrossRefPubMedGoogle Scholar
- Olincy, A., Blakeley-Smith, A., Johnson, L., Kem, W. R., & Freedman, R. (2016). Brief report: Initial trial of alpha7-nicotinic receptor stimulation in two adult patients with autism spectrum disorder. Journal of Autism and Developmental Disorders, 46, 3812–3817. https://doi.org/10.1007/s10803-016-2890-6.CrossRefPubMedGoogle Scholar
- Picciotto, M. R., Addy, N. A., Mineur, Y. S., & Brunzell, D. H. (2008). It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Progress in Neurobiology, 84, 329–342. https://doi.org/10.1016/j.pneurobio.2007.12.005.CrossRefPubMedGoogle Scholar
- Picciotto, M. R., Lewis, A. S., van Schalkwyk, G. I., & Mineur, Y. S. (2015). Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2014.12.028.PubMedPubMedCentralGoogle Scholar
- Ray, M. A., Graham, A. J., Lee, M., Perry, R. H., Court, J. A., & Perry, E. K. (2005). Neuronal nicotinic acetylcholine receptor subunits in autism: An immunohistochemical investigation in the thalamus. Neurobiology of Disease, 19, 366–377. https://doi.org/10.1016/j.nbd.2005.01.017.CrossRefPubMedGoogle Scholar
- Spielberger, C. D. (1999). The state-trait anger expression inventory-2 (STAXI-2): Professional manual. Odessa, FL: Psychological Assessment Resources, Inc.Google Scholar
- Spielberger, C. D., Gorsuch, R. L., Lushene, R., Vagg, P. R., & Jacobs, G. A. (1983). Manual for the state-trait anxiety inventory. Palo Alto, CA: Consulting Psychologists Press.Google Scholar
- Sukhodolsky, D. G., Wyk, B. C. V., Eilbott, J. A., McCauley, S. A., Ibrahim, K., Crowley, M. J., et al. (2016). Neural mechanisms of cognitive-behavioral therapy for aggression in children and adolescents: Design of a randomized controlled trial within the national institute for mental health research domain criteria construct of frustrative non-reward. Journal of child and Adolescent Psychopharmacology, 26, 38–48. https://doi.org/10.1089/cap.2015.0164.CrossRefPubMedPubMedCentralGoogle Scholar
- Tsakanikos, E., Costello, H., Holt, G., Sturmey, P., & Bouras, N. (2007). Behaviour management problems as predictors of psychotropic medication and use of psychiatric services in adults with autism. Journal of Autism and Developmental Disorders, 37, 1080–1085. https://doi.org/10.1007/s10803-006-0248-1.CrossRefPubMedGoogle Scholar
- van Schalkwyk, G. I., Lewis, A. S., Beyer, C., Johnson, J., van Rensburg, S., & Bloch, M. H. (2017). Efficacy of antipsychotics for irritability and aggression in children: A meta-analysis. Expert Review of Neurotherapeutics, 17, 1045–1053. https://doi.org/10.1080/14737175.2017.1371012.CrossRefPubMedGoogle Scholar
- Van Schalkwyk, G. I., Lewis, A. S., Qayyum, Z., Koslosky, K., Picciotto, M. R., & Volkmar, F. R. (2015a). Reduction of aggressive episodes after repeated transdermal nicotine administration in a hospitalized adolescent with autism spectrum disorder. Journal of Autism and Developmental Disorders, 45, 3061–3066. https://doi.org/10.1007/s10803-015-2471-0.CrossRefPubMedPubMedCentralGoogle Scholar