An Exploratory Trial of Transdermal Nicotine for Aggression and Irritability in Adults with Autism Spectrum Disorder

Abstract

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.

The Role of Nicotinic Receptors in the Attenuation of Autism‐Related Behaviors in a Murine BTBR T + tf/J Autistic Model

“…Therefore, the current findings support the hypothesis of previous results that nicotine, by activating nAChRs, increases cholinergic tone, producing positive modulation of social deficits and repetitive behavior abnormalities in BTBR mice. The current study broadens the knowledge of previous findings [Perry et al, 2001;Lee et al, 2002;Martin-Ruiz et al, 2004;Ray et al, 2005;Gotti, Riganti, Vailati, & Clementi, 2006;Wang et al, 2015;Wang et al, 2016] to support exploring the effects of selective nAChR subtypes and/or PAMs for specific subtypes of nicotinic receptors in the BTBR autisticlike mouse model and possibly biomarkers and therapy for ASD [Yoshimura et al, 2017;Lewis et al, 2018;Van Schalkwyk et al, 2015;Ogawa, Tatsumi, Fujio, Katayama, & Magata, 2006;Horti, Gao, Kuwabara, & Dannals, 2010], but there are as yet a few data regarding nicotine behavioral effects in other autistic-like rodent models.…”

“…Nicotine has demonstrated efficacy and safety in children with Tourette's disorder [Sanberg et al, 1997;Silver et al , 2001b, and reduced inattention, hyperactivity, and irritability in other chronic disorders beginning in childhood, such as Down syndrome [Seidl, Tiefenthaler, Hauser, & Lubec, 2000;Bernert, Sustrova, Sovcikova, Seidl, & Lubec, 2001], or in the modulation of aggressive behaviors in autism [for review, see Lewis & Picciotto, 2020]. Transdermal nicotine for aggression and irritability in adults with ASD has been examined [Van Schalkwyk et al, 2015;Lewis et al, 2018]. Interestingly, a case report describing the treatment of a 9-year-old boy with ASD using varenicline, a smoking cessation drug that is an α4β2 nAChR partial agonist, reported improvements in numerous domains [Arnold, Anand, & Aman, 2013].…”

Treatment of Aggression in Adults with Autism Spectrum Disorder: A Review

“…In the Lewis and colleagues 124 study, transdermal nicotine at a dose of 7 mg daily over one week in 5 adult subjects with ASD was associated with a decrease in mean ABC-I 30 scores from baseline compared to the placebo group, but the difference was not statistically significant. While the study was judged to be at low risk of bias regarding deviation from intended interventions and missing outcome data, it was assessed to be at moderate risk of bias regarding the randomization process, measurement of outcome, and selection of reported results.…”

“…Demographic and other information for the samples in each study (including mean age, sex distribution, intellectual functioning, and verbal/nonverbal status) are included in the table. These trials explored the efficacy of vigorous aerobic exercise, 120 fluvoxamine, 121 risperidone, 48 , 122 vibroacoustic music, 123 transdermal nicotine, 124 and dextromethorphan/quinidine. 125 …”

“…In addition, all but one of the studies 48 were assessed to be at moderate risk of bias arising from the randomization process (due to no information being provided on allocation-sequence concealment). Five of the 7 studies 120 , 122 – 125 were judged to be at moderate risk of bias with regard to measurement of outcome; 3 of these studies 122 , 124 , 125 employed crossover designs, in which rater blinding may have been compromised due to subjects receiving the study drug at predictable stages, and side effects/response possibly being obvious to single raters. The other 2 of the 7 studies 48 , 121 were judged to be at low risk of bias with regard to measurement of outcome because in each study outcome assessors were blinded (i.e., unaware of the drug assignment).…”