Lauren Elizabeth Absher

Background:  Autism spectrum disorder (ASD) is a complex neurodevelopmental condition marked by impairments in social communication, sensory dysregulation, and repetitive behaviors.⁷ Among the most challenging symptoms to manage is self-injurious behavior, which is highly prevalent and dangerous.⁶ Current pharmacological treatments for self-injurious behaviors in ASD are limited in efficacy and availability.⁶ Recent evidence shows that oxidative stress and immune dysfunction may be important pathways in the physiology of ASD and self-injurious behavior, suggesting potential pathways for pharmacological interventions.^1,2,3,4,5,6 N-acetylcysteine (NAC), a precursor to glutathione (GSH), has emerged as a potential treatment due to its ability to reduce oxidative stress.^1,4 This review explores the preclinical and clinical studies investigating NAC as a treatment for self-injurious behaviors in ASD.

Objective:  To evaluate the efficacy and mechanisms of NAC in treating self-injurious and autism related behaviors, particularly through its modulation of oxidative stress and inflammatory pathways.

Search Methods:  A literature search was conducted through PubMed to identify relevant articles published between 2017 and 2023. Keywords and MESH terms used included “autism”, “self-injury”, “self-injurious behavior”, and “N-acetylcysteine”. Studies involving NAC in animal and human models of ASD and self-injury were assessed.

Results:  Animal models of ASD – including valproic acid exposure, Shank3b deficiency, Slc13a4 haploinsufficiency, and administration of a barbering diet in C57BL/6J rats – demonstrated elevated oxidative stress and inflammatory markers correlated with autism-like behaviors and self-injurious behaviors.^1,2,3,4 NAC treatment improved social interactions, decreased repetitive or barbering behaviors, and normalized oxidative stress markers.^1,2,3,4 For example, NAC reversed autophagic deficiencies and Notch-1/Hes-1 pathway activation in valproic acid models, reduced pro-inflammatory cytokines in Shank3b(-/-) mice, and restored sulfate levels in Slc12a4(+/-) mice.^1,2,3 NAC also improved behavioral models in all studies, with NAC mice exhibiting increased sociability and decreased repetitive and barbering behaviors.^1,2,3,4  Clinically, NAC demonstrated therapeutic potential in children with ASD. One study reported reduced stereotypic behaviors when NAC was used in combination with risperidone.⁵ A case study showed complete resolution of self-injurious behaviors in a child with ASD following administration of NAC.⁶

Conclusion:  The literature shows a strong association between oxidative stress and autism like behaviors, including repetitive behaviors and barbering.^1,2,3,4 NAC appears to ameliorate these effects by increasing antioxidant capacity and reducing inflammation.^1,2,3,4 Both preclinical and early clinical studies show that NAC improves symptoms of ASD, including self-injurious behaviors.^1,2,3,4,5,6 While these studies show promising results, further randomized controlled human trials are necessary to determine the extent of the efficacy in humans, proper dosing, and long-term effects.

Works Cited:

1. Zhang YH, Wang T, Li YF, Deng YN, He XL, Wang LJ. N-acetylcysteine improves autism-like behavior by recovering autophagic deficiency and decreasing Notch-1/Hes-1 pathway activity. Exp Biol Med (Maywood). 2023;248(11):966-978. doi:10.1177/15353702231179924
2. Pangrazzi L, Cerilli E, Balasco L, et al. N-Acetylcysteine Counteracts Immune Dysfunction and Autism-Related Behaviors in the Shank3b Mouse Model of Autism Spectrum Disorder. Antioxidants (Basel). 2024;13(11):1390. Published 2024 Nov 14. doi:10.3390/antiox13111390
3. Zhang Z, Dawson PA, Piper M, Simmons DG. Postnatal N-acetylcysteine administration rescues impaired social behaviors and neurogenesis in Slc13a4 haploinsufficient mice. EBioMedicine. 2019;43:435-446. doi:10.1016/j.ebiom.2019.03.081
4. Vieira GLT, Lossie AC, Lay DC Jr, Radcliffe JS, Garner JP. Preventing, treating, and predicting barbering: A fundamental role for biomarkers of oxidative stress in a mouse model of Trichotillomania. PLoS One. 2017;12(4):e0175222. Published 2017 Apr 20. doi:10.1371/journal.pone.0175222
5. Çelebi F, Koyuncu A, Coşkun M. N-acetylcysteine may reduce repetitive behaviors in children with autism: A case series. Psychiatry and Clinical Psychopharmacology. 2017;27(2):185-188. doi:10.1080/24750573.2017.1309817
6. Marler S, Sanders KB, Veenstra-VanderWeele J. N-acetylcysteine as treatment for self-injurious behavior in a child with autism. J Child Adolesc Psychopharmacol. 2014;24(4):231–234. doi: 10.1089/cap.2013.0137
7. Summers J, Shahrami A, Cali S, D’Mello C, Kako M, Palikucin-Reljin A, Savage M, Shaw O, Lunsky Y. Self-Injury in Autism Spectrum Disorder and Intellectual Disability: Exploring the Role of Reactivity to Pain and Sensory Input. Brain Sciences. 2017; 7(11):140. https://doi.org/10.3390/brainsci7110140