Abstract
Oral N-acetylcysteine (NAC) has shown efficacy for debilitating habit-driven and neuropsychiatric disorders in small, mostly adult studies. We retrospectively evaluated the therapeutic use and safety of oral NAC in 93 children from the Children’s Hospital of Philadelphia (CHOP). This study supports the use of oral NAC for habit-driven skin, hair, and nail abnormalities in pediatric patients.
Introduction:
N-acetylcysteine (NAC) improves habit-driven pediatric dermatologic and neuropsychiatric disorders, such as trichotillosis, nail biting, and skin picking. NAC is a precursor of cysteine and glutathione with effects on the cystine-glutamate exchange system. It is thought to decrease impulsivity and craving, thus inhibiting unwanted behaviors.1,2 Biochemically, NAC likely increases extracellular levels of glutamate in the nucleus accumbens, with a re-balance blocking compulsive behaviors. It is also hypothesized that cysteine provided by NAC increases cellular production of glutathione, causing several outcomes, such as decreasing compulsive behaviors.3 While NAC is commonly used for acetaminophen toxicity, there is scant data for the utility of oral NAC in pediatric neuropsychiatric conditions.4 Therefore, we evaluated the safety and efficacy of NAC.
Methods:
This was a retrospective single-center study of individuals receiving NAC for dermatologic or psychiatric/neurobehavioral indications that was determined as exempt by the Children’s Hospital of Philadelphia Institutional Review Board. Chart review was performed. Outcomes of NAC-users were recorded on a 6-point Likert scale (worse, somewhat worse, neutral, somewhat better, significantly better, or clear) and checked independently by two authors (JRT, DZ). Logistic regression was used to associate clinical conditions and demographic variables with the outcome. See supporting information for additional details.
Results:
Query of CHOP’s Arcus platform5 identified 1,189 pediatric patients’ charts referencing use of NAC in the last 10 years. Patients using oral NAC for metabolic disorders or acetaminophen poisoning (647), and with unclear use (“unclear if took”) were excluded, as were patients without outcome data, leaving 93 patients. Seven patients (8%) were completely clear of their habit-driven activities, 42 (45%) were significantly better, 19 (20%) were somewhat better, and 26 (27%) experienced no effect. None had somewhat worse or worse outcomes. There were no differences between those with and without available outcome data based on ethnicity or race, comorbidity profiles, current medications, age, or weight (all p > 0.05; Table 1).
Table 1.
Demographic characteristics of the analysis cohort.
| Variable | Overall Cohort (n = 187) | Available Outcome Data (n = 93) | No Available Outcome Data (n = 94) | P- value |
|---|---|---|---|---|
| Age, mean (SD), [range] | 12.0 (3.3), [2.5 – 17] | 12.0 (3.2), [5 – 17] | 12.0 (3.4), [2.5 – 17] | 0.955 |
| Female Sex (n, %) | 97 (52%) | 39 (42%) | 51 (54%) | 0.124 |
| Race (n, %) | 0.082 | |||
| White | 143 (77%) | 75 (81%) | 68 (72%) | |
| Black or African American | 21 (11%) | 7 (8%) | 14 (15%) | |
| Asian | 9 (5%) | 6 (6%) | 3 (3%) | |
| Indian | 4 (2%) | 3 (3%) | 1 (1%) | |
| Other | 10 (5%) | 2 (2%) | 8 (9%) | |
| Hispanic/Latino Ethnicity (n, %) | 8 (4%) | 5 (5%) | 3 (3%) | 0.706 |
| Weight (kg), mean (SD), [range] | 49.7 (21.8), [12.5 – 120] | 50.6 (22.2), [13 – 120] | 48.8 (21.5), [12.5 – 117.3] | 0.603 |
| Duration (months), median [range] | 15.0 [0.25 – 144.0] | 15.0 [0.25 – 144.0] | 12.0 [0.5 – 122.0] | 0.749 |
| Primary Prescribing Services | 0.194 | |||
| Dermatology | 97 (52%) | 48 (52%) | 49 (52%) | |
| Neurology | 32 (17%) | 15 (16%) | 17 (18%) | |
| Behavioral Health | 25 (13%) | 11 (12%) | 14 (15%) | |
| Pediatrics | 9 (5%) | 5 (5%) | 4 (4%) | |
| Child Development | 10 (5%) | 9 (10%) | 1 (1%) | |
| Other | 8 (4%) | 5 (5%) | 3 (3%) | |
| Missing/Unclear | 6 (3%) | 0 (0%) | 6 (6%) | |
Sixteen behavioral issues, including skin picking, nail biting, hair pulling or twirling, and aggressive behavior associated with other psychological disorders, were evaluated. The odds of being significantly better or clear on NAC were not statistically associated with any conditions considered, including when adjusting for age and sex (all p > 0.05; Table 2).
Table 2.
Unadjusted and adjusted odds ratios (OR) of having a significantly better or clear outcome versus a neutral or somewhat better outcome based on the clinical condition, comorbid medications used by patients, or demographic variables. Adjusted models include age and sex.
| Condition | Count (%) with Condition (N = 93) | Unadjusted OR (95% CI) | P-value | Adjusted OR (95% CI) | P- value |
|---|---|---|---|---|---|
| Clinical Conditions | |||||
| Acne | 13 (14%) | 1.06 (0.32, 3.54) | 0.928 | 1.60 (0.44, 6.02) | 0.476 |
| ADHD | 37 (40%) | 0.91 (0.40, 2.11) | 0.834 | 0.73 (0.37, 14.22) | 0.482 |
| Aggressive Behavior | 7 (8%) | 1.21 (0.25, 6.47) | 0.806 | 1.19 (0.23, 6.60) | 0.835 |
| Allergies | 14 (15%) | 1.76 (0.55, 6.15) | 0.350 | 1.71 (0.53, 6.08) | 0.383 |
| Anxiety | 37 (40%) | 0.64 (0.27, 1.47) | 0.291 | 0.56 (0.23, 1.32) | 0.188 |
| ASD | 27 (29%) | 1.18 (0.48, 2.93) | 0.723 | 0.89 (0.33, 2.37) | 0.815 |
| Asthma | 17 (18%) | 1.01 (0.35, 2.96) | 0.982 | 1.19 (0.40, 3.64) | 0.749 |
| Depression | 10 (11%) | 0.89 (0.23, 3.41) | 0.857 | 1.05 (0.26, 4.20) | 0.943 |
| Learning Disorder | 28 (30%) | 0.86 (0.35, 2.09) | 0.733 | 0.72 (0.28, 1.82) | 0.490 |
| OCD | 6 (6%) | 4.89 (0.75, 95.68) | 0.155 | 5.02 (0.73, 100.38) | 0.155 |
| Comorbid Medications Used by Patients | |||||
| ADHD Stimulants | 28 (30%) | 0.86 (0.35, 2.09) | 0.733 | 0.78 (0.31, 1.93) | 0.585 |
| Antidepressants | 33 (35%) | 0.64 (0.27, 1.49) | 0.301 | 0.59 (0.24, 1.42) | 0.240 |
| Antipsychotics | 12 (13%) | 1.30 (0.38, 4.71) | 0.675 | 0.92 (0.25, 3.56) | 0.905 |
| Demographic Variables | |||||
| Sex | |||||
| Female | 54 (58%) | [Reference] | [Reference] | ||
| Male | 39 (42%) | 1.86 (0.81, 4.35) | 0.148 | 1.76 (0.76, 4.17) | 0.189 |
| Age Group | |||||
| 2–7 years | 11 (12%) | [Reference] | [Reference] | ||
| 7–12 years | 38 (41%) | 0.71 (0.16, 2.74) | 0.622 | 0.73 (0.17, 2.89) | 0.660 |
| 12–18 years | 44 (47%) | 0.52 (0.12, 1.98) | 0.350 | 0.58 (0.13, 2.26) | 0.440 |
| Weight | |||||
| Weight < 45 kg | 44 (49%) | [Reference] | [Reference] | ||
| Weight > 45 kg | 46 (51%) | 1.30 (0.57, 3.00) | 0.536 | 2.51 (0.81, 8.33) | 0.119 |
| Race | |||||
| White Race | 75 (81%) | [Reference] | [Reference] | ||
| Other Race | 18 (19%) | 0.66 (0.23, 1.86) | 0.437 | 0.65 (0.22, 1.87) | 0.431 |
The average duration of treatment differed between outcome groups. Patients with a significantly better or clear outcome had a significantly longer duration, 34.8 (SD = 31.9) months compared to an average of 15.3 (SD = 20.5) months for patients with neutral or somewhat better outcome (p < 0.001). There were no differences between outcome groups for weight (p = 0.999) or age (p = 0.320).
Considerations influencing adherence included medication taste (7 patients, 8%), pill size (5 patients, 5%), cost (1 patient), and mild gastrointestinal upset (1 patient). Dose ranged from 400–3000 mg in divided doses. The most-commonly recommended dose was 600 mg BID. There were 11 patients (12%) who took low dose NAC (<600 mg BID) and 82 (88%) who took high dose (>600 mg BID). Duration was different for high dose: 26.85 months (29.9) versus 14.14 (11.8) months for low dose, (p= 0.026). Patients taking high dose oral NAC were older with an average age of 12.27 (3.0) years vs. 9.82 years (3.4) for patients taking low dose, (p=0.043). No significant adverse effects were observed. No significant differences were seen in adverse effect profiles between these groups.
Discussion:
Our retrospective cohort study demonstrated that three-quarters of individuals had positive responses to NAC. Our study is the largest performed to-date to evaluate the use of NAC for habit-tic disorders in the pediatric population, and had higher positive response rate compared to prior reviews of the literature.6–9 However, generalizability may be limited as we are a single-tertiary care center and outcomes data was missing for portions of the patient cohort, possibly due to non-compliance or loss to follow-up. Given that only about 40% of patients that NAC was discussed with took the medication, further research is needed to understand if prescriber practices may influence use. Nonetheless, NAC appears to be safe and effective across a range of habit-tic behaviors in children. We surmise that use of NAC also has the potential to reduce use of antipsychotics and antidepressants, which may have serious adverse effects, although more research is needed in this area.
In this retrospective single-center cohort study, NAC shows efficacy for habit-tic disorders. Clinical trials in children to establish dosing and length of therapy would be useful.
Supplementary Material
Acknowledgements:
We acknowledge and thank the Pediatric Dermatology Research Alliance (PeDRA) for support of Diana Zarowin with a PeDRA Research Fellowship Award. Sarah E Sheppard is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIA-HD009003–01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Statement on Consent for Publication: All authors consent to the terms of publication, with the addition of the NIH Publishing agreement.
Conflict of Interest Statement for all Authors: No conflicts of interest for any of the authors.
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