I wrote this academic review in the summer of 2019 as part of the completion of my Master of Science in Human Nutrition and Functional Medicine at the University of Western States. It is highly technical but may prove useful reading material for those interested in delving deeper into the current uses of NAC in various grooming disorders and how it may be having its effect.
Introduction: Grooming disorders such as HPD, SPD, and NB are relatively common in the general population but lack any FDA-approved treatments. NAC has been proposed as a potential over-the-counter treatment for these disorders due to its antioxidant and glutamate-modulating effects. This paper reviews the relevant literature on the use of NAC in GDs, potential mechanisms of action, and clinical recommendations.
Methods: The following terms were searched in July 2019 in PubMed and Google Scholar: (“trichotillomania” OR “hair pulling disorder” OR “dermatillomania” OR “skin picking disorder” OR “excoriation” OR “nail biting” OR “onychophagia” OR “grooming disorder” OR “barbering” OR “ulcerative dermatitis”) AND (“NAC” OR “n-acetylcysteine”).
Discussion: Eleven HPD cases, five SPD cases, and five NB cases reported positive results with NAC. Five clinical trials of NAC in HPD, SPD, and NB in pediatric and adult populations were included with mixed results. Doses between 800 - 2400 mg/day for 1 - 6 months have been reported. Two studies of NAC in barbering mice discuss animal models of GDs and the potential mechanisms of action for NAC.
Conclusion: NAC may be an effective treatment for GDs in doses between 1200 - 2400 mg/day, but additional research is necessary.
Keywords: N-acetylcysteine; NAC; trichotillomania; dermatillomania; skin-picking disorder; nail-biting
Grooming disorders (GDs) are a group of pathological body-focused repetitive behaviors classified in the Diagnostic and Statistical Manual of Mental Disorders - 5th edition (DSM-V) as obsessive-compulsive related disorders, although controversy still exists as to the appropriate nosology of these conditions (American Psychiatric Association, 2013; Grant, Odlaug, & Potenza, 2007). Some of the conditions included in this category include trichotillomania (hair-pulling disorder; HPD), dermatillomania (skin-picking disorder; SPD), and onychophagia (nail biting; NB). While each behavior is distinct, they are clinically similar in many ways, often considered in both the research literature and clinical setting together when discussing etiology and treatment options.
Grooming disorders generally have in common: 1) a chronic repetitive behavior focused on a part of the individual’s body (biting of the nail in NB, pulling of the hair in HPD, and picking of the skin in SPD), 2) repeated attempts (and desire) to stop the behavior without success, and 3) clinically significant functional impairment in one's quality of life as a result of the behavior (Sani et al., 2019). There is a high rate of comorbid psychiatric conditions (most commonly other GDs, obsessive compulsive disorder, depression, anxiety, body dysmorphic disorder, and/or alcohol use). Physical complications may include infection, oral/dental complications, scarring, alopecia (bald spots), and gastrointestinal blockages when hair is consumed (Anwar & Jafterany, 2019; Halteh, Scher, & Lipner, 2017; Leibovici et al., 2015; Lochner, Roos, & Stein, 2017; Pacan, Grzesiak, Reich, Kantorska-Janiec, & Szepietowski, 2014).
HPD and SPD usually begin in early adolescence (avg: 12 years old) and more often in females, although these behaviors can begin earlier in childhood with no gender predominance (Flessner, Knopik, & McGeary, 2012; Lochner et al., 2017). Without treatment, HPD and SPD patients are unlikely to experience any symptomatic relief and the disorders continue throughout life with a chronic relapsing-remitting pattern (Anwar & Jafterany, 2019). NB is slightly different than HPD and SPD in terms of prevalence, onset, gender ratio, and progression over time. NB is extremely common in the general population, with childhood estimates of nearly 50%, a diminished prevalence over time to approximately 20% by early adulthood, and a further reduction by late adulthood (4.5%) more similar to that found in HPD and SPD (1-3% and 1.4-5.4% respectively) (Anwar & Jafterany, 2019; Grant et al., 2016; Pacan et al., 2014; Sani et al., 2019). It is thought the prevalence of all grooming disorders may be underestimated, however, due to the stigma associated with seeking care and healthcare practitioners’ lack of knowledge of the disorder (Flessner et al., 2012; Halteh et al., 2017).
The etiology of grooming disorders is still unknown, though both genetic and environmental factors have been implicated. These disorders tend to run in families, as shown in twin studies of HPD and SPD, and there is a higher prevalence of HPD, SPD, and NB in first-degree relatives than the general population (Halteh et al., 2017; Novak, Keuthen, Stewart, & Pauls, 2009; Özten et al., 2015). Early genetic studies have further identified polymorphisms in serotonergic (5HT2A), glutamatergic (SAPAP3), and central nervous system (CNS) expression (Hoxb8) genes that may be associated risk factors for GDs (Bienvenu et al., 2009; Greer & Capecchi, 2002; Hemmings et al., 2006). Early childhood trauma is also more common in HPD (76-91% of patients) than the general population, leading many researchers to hypothesize the behavior may begin as a way of coping with unwanted negative emotions (Anwar & Jafterany, 2019).
No medication is currently FDA-approved for the treatment of HPD, SPD, or NB. Historically, clinicians have treated GDs with conventional pharmaceutical drugs used for OCD and mood disorders such as selective serotonin reuptake inhibitors (SSRIs). However, clinical trials have shown limited success in GDs with these medications. Some studies have shown SSRIs may be no better than placebo, leading health care practitioners and researchers to search for more efficacious treatments (Bloch et al., 2007). Given the relatively common occurrence of these disorders, the potential for serious impairment of quality of life and/or physical health complications, and the lack of efficacious treatments, identifying safe treatment options should be a public health concern.
N-acetylcysteine (NAC) is one such potential treatment that has recently has been explored for the use in grooming disorders. As a strong antioxidant, it is most commonly known for its use as an antidote for acetaminophen poisoning. However, research now suggests it may also be beneficial in a wide range of neurological and psychiatric conditions (Deepmala et al., 2015). NAC is thought to regulate reward-seeking behavior via glutamate modulation in the nucleus accumbens, a brain structure involved in the reward circuit and addiction, also found altered in GD patients (Isobe et al., 2018; White et al., 2013). Furthermore, NAC-induced replenishment of extracellular glutamate in the nucleus accumbens has been shown to block compulsive drug-seeking behaviors (Grant, Odlaug, & Kim, 2009). Low glutathione (GSH) levels have also been found in up to a third of HPD patients, suggesting a potential role for NAC as a neuroprotective antioxidant in GD patients due to its ability to upregulate the synthesis of GSH (Grant & Chamberlain, 2018). This paper aims to review the available evidence on the use of NAC as a treatment for grooming disorders and the potential mechanisms of action, discuss suggestions for the future direction of research, and suggest evidence-based recommendations for clinicians.
A literature search was conducted in July 2019. The following terms were searched in PubMed and Google Scholar: (“trichotillomania” OR “hair pulling disorder” OR “dermatillomania” OR “skin picking disorder” OR “excoriation” OR “nail biting” OR “onychophagia” OR “grooming disorder” OR “barbering” OR “ulcerative dermatitis”) AND (“NAC” OR “n-acetylcysteine”). Bibliographies of seminal papers, Dr. Joseph Garner’s and Dr. Jon Grant’s list of publications, and my personal library were also searched for additional relevant literature. The search was limited to English publications.
The search included experimental and clinical trials, pilot studies, case reports, and systematic reviews on clinical grooming outcomes in humans (hair pulling, skin picking, and/or nail biting behaviors) and mice (barbering and ulcerative dermatitis). Publications with a focus on other psychiatric conditions (e.g., autism, Tourette's Syndrome, obsessive-compulsive disorder, depression, etc.) were excluded. Papers that did not include NAC as the primary intervention were excluded. Duplicate articles, opinion pieces, and narrative reviews were excluded.
Overview of N-acetylcysteine
N-acetylcysteine (NAC) is a naturally occurring sulfur-containing amino acid having roles as an antioxidant and glutamate modulating agent. There are two main mechanisms in which NAC is thought to potentially provide a therapeutic effect in GDs.
First, NAC is converted to the oxidized form, cystine, which activates the cystine-glutamate antiporter (system xc−) on glial cells to increase intracellular uptake of cystine allowing for the reverse transport of glutamate into the extracellular space. Increased extracellular glutamate is thought to then stimulate inhibitory metabotropic glutamate receptors on synapses, thereby reducing synaptic glutamate release in the nucleus accumbens (Grant et al., 2016).
Second, NAC is readily converted to the prodrug cysteine after cystine enters the cell via the glutamate-cystine antiporter, the rate-limiting step in glutathione (GSH) synthesis. GSH is the major antioxidant in the brain and protects cells from reactive oxygen species (ROS) formed during normal metabolic processes. Excess ROS, however, can then lead to oxidative stress when uncontrolled, such as in a low antioxidant state.
Numerous case reports have been published describing results of improvement from the use of NAC as a stand-alone or add-on treatment in both pediatric and adult cases of HPD. Odlaug & Grant (2007) published the first known report of two patients who achieved complete remission of HPD with stand-alone NAC treatment. The first patient was a young adult male with HPD and co-occurring NB who began hair-pulling at the age of 12, worsening over time. He had a history of methylphenidate treatment for childhood attention deficit hyperactivity disorder (ADHD) from age five to nine and unsuccessful trials of conventional antidepressant medications following the HPD diagnosis prior to the current intervention. The patient began a trial of NAC at a dose of 600 mg/day for two weeks, then increased to 1200 mg/day for another two weeks. At this point, he began to notice a reduction in urges and increased the dose to 1800mg/day (600 mg TID). Within a week he experienced a complete cessation of urges lasting for at least the next four weeks. No other concurrent interventions were reported by the authors.
The second patient was a 40-year-old woman who had been engaging in the hair-pulling behavior daily for the past 22 years (starting at the age of 4) with no significant remission for more than two days. Earnest attempts with neither pharmacological nor behavioral treatment interventions provided the patient any symptomatic relief and she was not receiving any treatments during the NAC trial. The patient began with a dose of 600 mg/day NAC for one week and increased the dose to 1200 mg/day for another three weeks, at which point she began to experience some reduction in urges. The dose was again increased to 1800 mg/day for another four weeks and finally a dose of 2400 mg/day (1200 mg BID) for another two weeks, at which point she had a complete cessation of hair-pulling urges, sustained for at least five months. The authors did not report quantitative measures of improvement in either of the two cases presented above (Odlaug & Grant, 2007).
Another case series was presented in The International Journal of Trichology of two young women (19 and 23 years old) for which conventional treatments had been unsuccessful. However, treatment with NAC 1200mg/day for two to three months resulted in a complete regrowth of hair (Rodrigues-Barata, Tosti, Rodríguez-Pichardo, & Camacho-Martínez, 2012). While the primary outcome was hair regrowth, rather than a reduction in urges or a cessation of the behavior (which could have continued), hair regrowth is a clinically relevant outcome for patients’ quality of life, which was maintained at the 6-month follow-up .
Given the many co-occurring mood disorders and lack of straightforward treatment options, NAC has been included as an add-on treatment in three case reports. Silva-Netto et al. (2014) reported a 45-year-old woman who experienced a partial improvement in hair-pulling symptoms with a combination of the antidepressant venlafaxine and 1200 mg/day NAC, which worsened when treatment was discontinued and improved again after reinstating the combination treatment with an increased NAC dose of 1800 mg/day. No measures of the degree of improvement were reported. Another 31-year-old woman with a 20-year HPD history and current comorbid depression added 1200 mg/day NAC to concurrent SSRI medication. The patient self-reported significant decreases in hair-pulling symptoms after one month and NAC was discontinued after two months with a complete regrowth of an alopecic patch and hair-pulling remission maintained at the six-month follow up (Kiliç & Keleş, 2019). The only case report to include an objective measure of symptomatic improvement reported a 3-point decrease in The Massachusetts General Hospital Hairpulling Scale (MGH-HPS) score (maximum score = 28) and a three-week remission after adding NAC 1200 mg/day to existing naltrexone treatment (MGH-HPS = 8). The 23-year-old female patient relapsed (MGH-HPS = 14) after three months during a stressful period, however, and an SSRI medication was added resulting in a final MGH-HPS score of three (Satodiya et al., 2019). Each of these cases involved recent changes in pharmaceutical medications, possibly affecting results.
While HPD typically begins by adolescence, adult-onset HPD can occur. One such case was presented in which a 30-year-old female with new-onset HPD (one month prior) was successfully treated with NAC 1200 mg/day. Although HPD onset was recent, the patient experienced severe urges to pull her hair, resulting in a 20-cm diameter patch of hair loss on the front top of her head. No other interventions were reported, urges subsided at two months, and complete hair regrowth was observed at four months, at which time treatment was discontinued. Remission was maintained at seven months (Özcan & Seçkin (2016).
Pediatric cases may be different than adults because they are generally present with a more recent onset than adults and would be the optimal time to intervene in such a chronic life-long condition. In a stand-alone NAC treatment case, an 11-year-old boy achieved complete remission of hair-pulling behavior (and complete regrowth of a patch of hair loss) that had begun six months prior after treatment with 1200 mg/day NAC for three months followed by 1800 mg/day for another three months (Barroso et al., 2017). The patient had not begun or discontinued any other medications during treatment. Özcan & Seçkin (2016) published another pediatric report using 1200 mg/day NAC resulting in the complete remission (indicated by complete regrowth of a 10-cm alopecic patch and abstinence of behavior) of a new-onset HPD (two months prior) maintained at the eight-month follow-up. However, the 14-year-old girl did have a history of psychostimulant use in the past (reported to induce hair-pulling behavior) and had begun an antipsychotic medication six months prior—which was also discontinued at the same time NAC treatment began—so it remains unclear if the NAC addition or discontinuation of medications resulted in remission (Narine, Sarwar, & Rais, 2013). Another young girl (12 years old), with recent-onset HPD six months prior, saw significant improvement in hair regrowth (measured only by observational increase in capillary density from the diffuse and irregular hair thinning at diagnosis) six months after initiating treatment with 1800 mg/day NAC (600 mg TID) in combination with an SSRI, tricyclic antidepressant (TCA), and an antipsychotic (Pinto et al., 2017). Improvement was not reported prior to the six month follow up and no other outcomes (i.e. urges or behavior change) or were reported.
Two randomized placebo-controlled clinical trials (RCTs) have been conducted on the use of NAC in HPD: first in an adult population, and a follow-up in a pediatric population (Bloch, Panza, Grant, Pittenger, & Leckman, 2013; Grant et al., 2009). Grant et al. (2009) published the first RCT of the use of NAC in an adult population with HPD, which suggests it may be an effective treatment for some patients. Adults (n=50; age 18-59; 90% female) were given either NAC or a placebo for 12 weeks. Patients in the treatment group were given 1200 mg/day NAC for the first six weeks, with the option to titrate up to 2400 mg/day for the following six weeks. A significant reduction in hair-pulling symptoms was seen as early as nine weeks and by the end of the trial, 56% of NAC patients were “much or very much improved,” compared to 16% of the placebo group (p=0.003). Patients taking NAC also experienced an average 40.9% improvement in hair-pulling urges and behavior measured by the MGH-HPS score (a large effect size: −1.19; CI: −1.77 to −0.57; 2: 0.406). No change was seen in psychosocial functioning, although a reduction was seen in hair-pulling symptoms, comparable to or better than those seen with other interventions (i.e. an 8.4% MGH-HPS reduction with medications alone and 41.5% MGH-HPS reduction with combined medication and cognitive behavioral therapy). No adverse effects were experienced in the treatment group. While this study reports clinically significant improvements with NAC for some HPD patients, 44% did not respond, highlighting the likely heterogeneity of HPD subtypes that may not respond to NAC treatment.
Bloch et al. (2013) attempted to replicate this study in a pediatric population (ages 8-17). This study failed to show any benefit from NAC over placebo, although both groups did show statistically significant improvement in symptoms (p = 0.002; 25% response rate in NAC group vs. 21% in the placebo group). The intervention was designed similarly to the adult study, however, there were some differences: 1) patients received psychoeducation and were assessed more frequently, which may have enhanced the placebo response; 2) the placebo group experienced statistically more severe symptoms at baseline than the intervention group, possibly contributing to difficulty in detecting treatment effects; 3) blinding was more rigorous; and 4) the study size was slightly smaller (n=39). The age difference between the groups in each study may indicate a difference in the pathophysiology and clinical presentation of HPD between pediatric and adult sufferers should be investigated further. One possible explanation is that children may be less aware of their urges than adults, and if NAC reduces urges to pull hair and not the behavior itself —as indicated in Grant et al. (2009)—, this may help to explain some of the discrepancy in results.
Odlaug & Grant (2007) again presented the first case report of the successful treatment of SPD using NAC. A 52-year-old woman with comorbid bulimia nervosa and compulsive shopping, who had picked her skin daily since the age of 15, was treated with 600 mg/day NAC, which was increased to 1200 mg/day after one week. After two weeks of treatment, the patient reported a 50% reduction in urges to pick. After four weeks, the dose was increased to 1800 mg/day, and the patient reported an immediate remission in skin-picking behavior within two days. The patient maintained remission for the next four months while continuing 1800 mg/day NAC. The patient was not concurrently treated with any other medications and had not tried any pharmacological treatments in the past, reducing any possible confounding effects.
In the aforementioned case of a 45-year-old woman with HPD and comorbid SPD, while the hair-pulling behavior improved only partially, her skin-picking resolved completely after being treated with a combination of venlafaxine 75 mg/day and NAC 1200 mg/day. She experienced a relapse of skin picking after she discontinued treatment, but again went into remission after reinstating the combination treatment protocol. In another add-on treatment case, a 31-year-old woman with SPD and comorbid depression, internet addiction, and pathological jealousy reported a “substantial improvement” in skin-picking behavior—but no improvement in internet addiction or pathological jealousy—after beginning the SSRI fluoxetine 20 mg/day and NAC 1200 mg/day. The authors did not state how long after initiating treatment each patient experienced improvement, nor whether the improvement was sustained in the long term (Silva-Netto et al., 2014).
The final case, reported by Silva-Netto et al. (2014), involved an adult-onset case of SPD that may have been induced by medication. A 40-year-old woman being treated for several co-occurring psychiatric conditions developed SPD one month after initiating pharmacological doses of lithium and quetiapine, an antipsychotic medication. The skin-picking behavior stopped after she was treated with 1200 mg/day NAC for 10 months. The patient then experienced a relapse after discontinuing NAC treatment, but saw significant improvement again after resuming it. As lithium is known to affect extracellular glutamate levels in the brain, it is possible that the addition of NAC improved glutamatergic dysfunction in this case (Dixon & Hokin, 1998).
In the only pediatric case report of NAC treatment of SPD, Percinel & Yazici (2014) described a 12-year-old girl who saw significant improvement after 10 weeks of stand-alone NAC treatment. The girl began picking four years earlier and saw no improvement with neither behavioral nor pharmacological treatments (SSRIs, atypical antipsychotics, and mood stabilizers). The patient presented as moderately depressed with a Clinical Global Impression-Severity (CGI-S) score of five (maximum = 7). The patient began 600 mg/day NAC and experienced fewer urges after two weeks (CGI-Improvement score = 3; “minimally improved”). After two weeks, the dose was increased to 1200 mg/day, and within four weeks of treatment, the patient reported a dramatic reduction in skin-picking behavior (CGI-I score = 2; “much improved”). The dose was then increased to 1800 mg/day, and after four weeks at this dose, she had achieved a complete remission with only rare urges to pick (CGI-I score = 1; “very much improved”).
Grooming disorders, particularly SPD, occur in 80-95% of individuals with the genetic chromosomal disorder Prader-Willi Syndrome (PWS). Other treatments have had very limited success in this population, so Miller & Angulo (2014) conducted an open-label pilot study to assess the effectiveness of 450-1200 mg/day NAC in 25 children/adolescents and 10 adults with PWS (range = 5-39 years; mean = 15 years). The frequency and severity of skin-picking behavior and number of skin-picked lesions were measured at baseline and at study completion. All patients experienced improvement from NAC after 12 weeks, 71% of which saw a complete resolution indicated by cessation of skin-picking behavior and no open lesions. The other 29% saw a significant reduction in the number and size of active lesions. The dosage schedule was not reported, so it is unknown whether this dramatic improvement was seen with the lower dose of 450 mg/day NAC, or whether all patients were titrated up to 1200 mg/day . While these results require placebo-controlled replication, the study authors noted that “NAC could be a life-changing treatment” for individuals with SPD.
One RCT found NAC more effective than placebo in treating adults with SPD (Grant et al., 2016). Patients were started on 1200 mg/day NAC, increased to 2400 mg/day at three weeks, and again to 3000 mg/day at six weeks for another six weeks. As early as three weeks into treatment, statistically significant improvements over placebo were seen in the Yale-Brown Obsessive Compulsive Scale Modified for Neurotic Excoriation (NE-YBOCS) Urge/Thought Subscale (p<0.05), and they remained significant throughout the trial. By the study’s end at 12 weeks, those in the NAC group experienced a 38% reduction in skin-picking behavior and a 47% response rate (“very much improved”) compared to 19% for both measures in the placebo group (p<0.05 and p<0.01, respectively). While significant improvements were seen in decreased urges to pick and skin-picking symptom severity, no statistically significant changes were seen in quality of life or psychosocial functioning. This could simply be due to a lack of statistical power (there was a limited range for improvement due to participants beginning with only mild impairment) or a delay in psychosocial improvement following symptom improvement, as urges and behavior may improve before the physical manifestations of picking do (i.e. scars and emotional wounds take more time to heal). Some gastrointestinal disturbances were experienced by those taking NAC, but no serious adverse reactions were reported.
The first report of NAC treatment improving NB comes from a case published by Odlaug & Grant (2007) involving a patient suffering comorbid NB and HPD, described in the above HPD case reports. In addition to the 28-year-old male patient’s complete cessation of HPD, he also experienced a complete remission of NB after five weeks at a final dose of 1800 mg/day NAC.
Berk et al. (2009) published a serendipitous retrospective case series of spontaneous NB remission in three adult patients that were being treated with a trial of 2000 mg/day NAC (1000 mg BID) for bipolar disorder. A 46-year-old woman taking lithium and quetiapine reportedly stopped biting her nails two weeks after beginning the trial and had maintained remission seven months later. A 44-year-old woman taking concurrent mirtazapine stopped nail-biting behavior four months into the trial, which was maintained for at least two months. A 46-year-old man in the trial also reported a reduction in nail biting at 28 weeks, however he was not consciously trying to stop the behavior, so it was unclear if the behavior had begun to diminish earlier than that. As the primary outcome of the NAC treatment in these cases was bipolar symptoms, no quantitative measures of NB were reported.
The only pediatric case report was published by Ghanizadeh & Derakhshan (2012), in which 800 mg/day NAC was used in an eight-year-old autistic boy to control his severe nail-biting behavior. The child had been taking two antipsychotic medications (risperidone and thioridazine) for two years, with no improvement in his ADHD, autism or grooming behaviors. No change in his medications was reported at the time of initiating NAC, and it was noted that the child was not taking any other antioxidant or GSH prodrugs before or during the NAC treatment. A significant reduction in NB was noticed within 30 days of treatment initiation. The parents also reported a significant reduction in the boy’s preoccupation with cutting his hair daily as well as significant improvements in his ADHD and autistic symptoms. The authors did not state whether treatment was continued or whether improvement was sustained after 30 days.
Following the publication of several of the case reports summarized here, Ghanizadeh, Derakhshan, & Berk (2013) undertook a double-blind randomized placebo-controlled trial of NAC in the treatment of pediatric NB. Children and adolescents aged 6-18 (n=42) with severe NB were enrolled in a two-month NAC add-on trial starting at a dose of 200 mg/day, increased to 800 mg/day after one week. There was a high rate of psychiatric comorbidity, most commonly with ADHD, and as such, the majority of patients were taking other prescribed medications during the trial (the most common one being the psychostimulant methylphenidate). The primary outcome measure was nail growth, so patients were asked not to trim their nails during the trial, and measurements were taken at one month and two months. Only 60% of the enrollees agreed to participate and were included in the analysis (n=25). While the average nail length increased among all participants, a statistically significant increase in nail length was observed in the NAC group compared to the placebo group at one month (Levene’s Test for Equality of Variances= 0.063, t=2.10, df=23, p<0.04). However, this difference was no longer statistically significant at two months (Intent-to-treat analysis: t=53, df=40, p=0.59). No other measures were reported, such as quality of life or frequency/intensity of urges. NAC has been reported to act by reducing grooming urges in particular, so future studies would benefit by including such measurements. This study also utilized a much lower NAC dose than that used successfully in pediatric HPD and SPD cases as well as adult NB cases. Nonetheless, the increase in nail growth (a clinically relevant outcome in NB) suggests NAC may be an effective intervention for NB.
Animal Models and Mechanisms of Action
Animal models of grooming disorder behavior have shown to be invaluable in understanding the pathogenesis of these disorders and the possible mechanisms of NAC treatment. While many animal models of disease are experimentally induced, pathological grooming behavior occurs spontaneously and is commonly witnessed in laboratory mice. Barbering (the excessive grooming and plucking of hair) has been validated as a model for HPD and ulcerative dermatitis (UD) (excessive scratching of the skin resulting in serious lesions) has been proposed as a model for SPD. However, they are thought to be different behavioral expressions of the same disease process, and here they can be considered together as models of pathological grooming in humans (Garner, Weisker, Dufour, & Mench, 2004; Dufour et al., 2010; Vieira, Lossie, Jr, Radcliffe, & Garner, 2017).
Barbering in mice is quite similar to hair-pulling in humans in several ways: 1) similar areas of the body are involved (mainly the head, eyes, and pubic region); 2) the hair is usually manipulated orally; 3) there is a female bias with barbering being 1.5 times more common in females than males; 4) disease progression is associated with reproductive events; and 5) prevalence rates may be similar (Garner et al., 2004). UD had long been thought of as a dermatological condition, however Dufour et al. (2010) hypothesized it alternately as a behavioral disorder after witnessing spontaneous development of the behavior in mice fed a high-carbohydrate, high-tryptophan diet. George et al. (2015) later found NAC treatment cured skin lesions in mice with UD, supporting the hypothesis of UC as a model for SPD.
The neurobiology of GDs is still poorly understood. Some researchers have proposed that the pathogenesis involves glutamatergic dysfunction (Grant et al., 2009). Another hypothesis garnering support from animal research is the oxidative stress model, which is compatible with the glutamatergic dysfunction hypothesis.
Two recent studies in barbering/UD mice have provided some initial insight into the underlying pathways involved. Vieira et al. (2017) first provided evidence of elevated oxidative stress in barbering mice, and that NAC can both prevent and cure barbering behavior, at least in part by synthesizing GSH and decreasing oxidative stress. In a novel 24-week study design using 32 female mice, non-barbering mice were randomized to either a control diet or a “barbering diet”—a high-carbohydrate tryptophan-supplemented diet described by Dufour et al. (2010) to trigger barbering and UD. Existing barbers (spontaneously occurring) were fed only the control diet. All diets were also supplemented with DL-methionine for the first 12 weeks, but discontinued for the last 12 weeks due to suspected confounding. Half of the mice across all groups were also randomized to receive NAC 1g/kg BW/day (equivalent to approximately 1200 mg/day in humans). Barbering status was checked every two weeks, and biomarkers of oxidative stress—urinary total antioxidant capacity (TAC), urinary 8-Hydroxy-2’-deoxyguanosine (8-OHdG), plasma glutathione (GSH), and plasma oxidized glutathione (GSSG)—were collected at baseline, 12 weeks, and 24 weeks. NAC treated mice were significantly less likely to be barbers at the end of the study (p=0.0244), both curing barbering behavior (approximately 50% cure rate) in baseline barbers and preventing behavior onset in non-barbers given the barber-inducing diet. All biomarkers were significantly associated with barbering status at some point during the study. Mice with a higher TAC at baseline had a significantly higher chance of being a barber (n=26; p=0.0342), which the authors interpreted as an adaptive increase in antioxidant resources in response to oxidative stress. At the study end, mice with a higher TAC (p=0.0183), decreased 8-OHdG (p=0.0410), and increased GSH & GSSG (p=0.0012 and p=0.0363, respectively) were significantly more likely to be barbers, again consistent with activation of the antioxidant system in response to oxidative stress. Although no biomarkers were able to predict whether a mouse would respond to NAC treatment, and NAC treatment did not significantly affect 8-OHdG, GSH, or GSSG markers, a significant interaction was found between NAC and baseline barber status on TAC (p=0.0210). NAC treatment significantly increased TAC in non-barbers, but significantly decreased TAC in barbers over 24 weeks, suggesting a greater usage of antioxidants in barbers experiencing elevated oxidative stress (NAC being used to synthesize GSH) and an increased urinary excretion of excess antioxidants not necessary to synthesize GSH in non-barbers. The fact that a decreased 8-OHdG, rather than increased level, was associated with an increased risk of barbering at the end of the study may differentiate between barbers who effectively repaired oxidative DNA damage (elevated 8-OHdG) and those who failed to repair the damage, and were thus unable to effectively manage accumulating oxidative stress. A pilot study of oxidative stress biomarkers in HPD measured neither TAC nor 8-OHdG, so these results have not yet been corroborated in a human sample (Grant & Chamberlain, 2018).
Following the discovery of elevated oxidative stress biomarkers in barbering, George et al. (2015) further tested the hypothesis that UD (a model for SPD) is a disease of oxidative stress by comparing oral NAC to intranasal GSH. If NAC’s primary mechanism of action is the synthesis of GSH to combat oxidative stress, then GSH itself would theoretically be just as effective. Mice with UD (n=16) were randomized to receive either oral NAC (2133 mg/kg/day), intranasal GSH (165 mg/kg/day), or a control of topical antibiotics for eight weeks. While both the NAC and GSH groups experienced the same cure rate (40%) within eight weeks, there were significant differences in responses between each treatment. All mice in the NAC treatment group improved to some degree, regardless of baseline severity. However, mice in the GSH treatment group showed an all-or-nothing response: 40% were cured and 60% showed no improvement, with non-responders having significantly more severe lesions at baseline (p=0.0028). Of those who were cured, GSH-treated mice were cured in significantly less time than NAC-treated mice (2-4 weeks compared to 5-7 weeks; p=0.0070). These results support the proposed role of oxidative stress contributing to the pathogenesis of SPD (and potentially all GDs) and NAC’s effectiveness, at least in part, due to upregulating the synthesis of GSH. The different responses to NAC and GSH—particularly, the non-response in 60% of those treated with GSH, compared with all NAC-treated mice showing at least partial improvement—suggests multiple mechanisms of action for NAC (not addressed by GSH alone) and a possible subgroup for which oxidative stress may not be a driving force in the pathogenesis of the behavior. The study authors also suggested that intranasal GSH may target oxidative stress resulting from CNS metabolism, while oral NAC delivered more systematically is also able to address somatic metabolism.
Several findings from these animal studies may help to answer questions regarding the human application of NAC. First, the response rates to both NAC and GSH in barbering/UD mice were similar to those found in human studies of NAC in HPD and SPD, further validating them as models of GDs (Grant et al., 2009; Grant et al., 2016). It’s important to note that not all of those affected responded to NAC, and of those who did, different pathways may have been responsible (e.g. GSH, glutamate). Future research would benefit from identifying differences between responders and non-responders to treatment. Second, the identification that more severe cases of UD experienced a complete non-response to GSH, but partial improvement with NAC, may help to address the previous question. It is possible that more severe cases require higher doses or have experienced irreversible oxidative damage—possibly supported by decreased 8-OHdG levels in barbers reported by Vieira et al. (2017)—but NAC may provide partial relief via other reversible pathways (i.e., glutamate modulation). Third, a high-carbohydrate diet was used to induce pathological grooming in animals, further supporting a role of metabolically induced oxidative stress in the pathogenesis of the behavior (Dufour et al., 2010). While the animal studies controlled for diet, none of the human studies described here have done so, which could affect the response to NAC in some trials. Fourth, prophylactic NAC in susceptible non-barbers (those fed a barbering-inducing diet) seemed to prevent the onset of barbering in mice, which could have important clinical implications for healthy children and adolescents at risk of developing a GD (i.e. family history, comorbidities, biomarkers) if the findings are replicated in a pediatric population.
There were several limitations to this review. First and foremost, the bulk of the evidence presented comes from case reports and series, which have inherent methodological limitations and possible publication bias. The success reported in these case studies cannot be generalized to all patients and require follow up in clinical trials. Randomized controlled trials are limited, rarely replicated, and heterogeneous in terms of study populations (i.e. HPD vs. SPD vs. NB, pediatric vs. adult, general population vs. PWS, comorbidities), interventions (i.e. dosage, duration), and measurements of improvement (i.e. reduction in urges measured by validated scales, nail length, number of lesions, subjective improvement). This review includes no clinical trials longer than 12 weeks, limiting the ability to assess whether results are sustained over longer periods of time. Several possible confounding variables were not controlled for in most of the human research, including other medication use (e.g. SSRIs, lithium, psychostimulants), antioxidant supplement use, diet (i.e. high-carbohydrate, fasting), or behavioral interventions (e.g. cognitive behavioral therapy, habit reversal therapy).
Numerous case reports suggest that doses between 1200 mg - 2400 mg NAC for 1-4 months may be an effective treatment (alone or as part of a comprehensive treatment plan) for HPD. Clinical trials have reported mixed results, however, and further research is necessary to identify discrepancies between the 56% response rate found in adults versus the non-significant response rate found in a pediatric population.
There is still very limited research for the use of NAC in SPD, yet what has been published suggests it may be a beneficial intervention for some patients. The results found in the Prader-Willi Syndrome study may show strong indication of NAC’s effectiveness, but RCT replication in a non-PWS patient population would be necessary to extrapolate to SPD without chromosomal abnormalities. The discrepancy between the 100% response rate in the PWS pilot study and 47% response rate in the Grant et al. (2016) trial calls for further research to identify responders and non-responders.
Case reports provide very promising results that NAC doses of 800-2000 mg/day may result in complete remission of NB in some individuals, even when severe, life-long, and co-occurring with other psychiatric disorders. Research is extremely limited, however, and additional RCTs in both children and adults of longer durations (three months minimum) and higher doses (1200-2000 mg/day) are necessary to validate NAC as an evidence-based treatment for NB.
The pathogenesis of GDs likely involves the complex interaction of genetic and environmental factors. There is some evidence supporting oxidative stress as a potential underlying cause of these conditions and that NAC can reduce GD behavior via reducing oxidative stress. Given the safety, tolerability, and easy accessibility of NAC, and the evidence reported here supporting its effectiveness, a trial of 1200-2400 mg/day NAC for at least three months is recommended. Clinicians should keep in mind that some patients may require higher doses than others, that improvement may not be seen until three to four months, and that a subgroup of patients may not respond to the treatment. With further research identifying responders and nonresponders to NAC treatment, clinicians may be able to identify patients who may respond to NAC via family history, patient clinical presentation, genetic mutations, and/or the existence of co-occurring psychiatric disorders.
Higher-quality research is needed to establish NAC as an evidence-based treatment for GDs, especially in children and adolescents. Future research would also benefit from a trial of intranasal GSH in humans, particularly less severe cases and/or those identified as having biomarkers of elevated oxidative stress. Studies should also assess the effects of diet (e.g. high-carbohydrate, antioxidant-rich, fasting) on oxidative stress markers, behavior severity, and treatment response.
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