N-Acetylcysteine, a Glutamate Modulator, in the Treatment of Trichotillomania: A Double-blind, Placebo-Controlled Study
Abstract
Context Trichotillomania is characterized by repetitive hair pulling that causes noticeable hair loss. Data on the pharmacologic treatment of trichotillomania are limited to conflicting studies of serotonergic medications. N-acetylcysteine, an amino acid, seems to restore the extracellular glutamate concentration in the nucleus accumbens and, therefore, offers promise in the reduction of compulsive behavior. Objective To determine the efficacy and tolerability of N-acetylcysteine in adults with trichotillomania. Design Twelve-week, double-blind, placebo-controlled trial. Setting Ambulatory care center. Patients Fifty individuals with trichotillomania (45 women and 5 men; mean [SD] age, 34.3 [12.1] years). Interventions N-acetylcysteine (dosing range, 1200-2400 mg/d) or placebo was administered for 12 weeks. Main outcome measures Patients were assessed using the Massachusetts General Hospital Hair Pulling Scale, the Clinical Global Impression scale, the Psychiatric Institute Trichotillomania Scale, and measures of depression, anxiety, and psychosocial functioning. Outcomes were examined using analysis of variance modeling analyses and linear regression in an intention-to-treat population. Results Patients assigned to receive N-acetylcysteine had significantly greater reductions in hair-pulling symptoms as measured using the Massachusetts General Hospital Hair Pulling Scale (P Conclusions This study, the first to our knowledge that examines the efficacy of a glutamatergic agent…
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N-acetyl cysteine has shown evidence of efficacy in double-blind placebo-controlled studies for trichotillomania and skin-picking disorder.
“The glutamate modulator n‐acetyl cysteine has shown evidence of efficacy, in double‐blind placebo‐controlled studies, for OC‐related disorders trichotillomania and skin‐picking disorder”
From Obsessive-compulsive disorder: Etiology, neuropathology, and cognitive dysfunction (2023) · cites this paper as Grant et al., 2009
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The chemistry and biological activities of N-acetylcysteine
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“Other disorders of compulsive behavior In addition to the effects on substance abuse listed above, NAC has demonstrated efficacy for treatment of pathological gambling (70, 85), and demonstrated a large effect size for treatment of trichotillomania (86).”
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“These findings are consistent with the reports of previous trials of NAC with the same dose and route of administration, which showed the agent to be safe and well tolerated.(30,45) Although this study has the advantage of being randomized and placebo controlled, we would like to note that generalizability of the conc…”
ResultFarhat, L. C., Olfson, E., Nasir, M., Levine, J. L. S., Li, F., Miguel, E. C., & Bloch, M. H. (2020) · Depression and Anxiety · doi:10.1002/da.23028 · Cited by 133 · see citing works
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Trichotillomania and its treatment: a review and recommendations
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“[62] Trichotillomania 1200–2400 mg 50 Double-blind placebo controlled trial Improved MGH-HPS, PITS, and CGI”
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“The glutamatemodulator n-acetyl cysteine has shown evidence of efficacy, in double-blind placebo-controlled studies, for OC-related disorders trichotillomania and skin-picking disorder, which are OCrelated disorders (Grant et al., 2009; Grant et al., 2016).”
BackgroundBehavioural addiction—A rising tide?
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“Opioid antagonists (e.g., naltrexone, nalmefene), well researched for the treatment of alcohol and opiate use disorders, have shown efficacy in controlled clinical trials (three positive) for gambling disorder and (one positive trial) for kleptomania (Grant et al. 2009a; van den Brink 2012).”
Self-citationPharmacotherapy for trichotillomania
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“The Fernandes study (35) also included tobacco use disorder (59) and trichotillomania (60), hence explored a heterogeneous sample.”
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“NAC has demonstrated benefit for both trichotillomania and cocaine addiction (53, 54).”
BackgroundSelf-citationGrant, J., Odlaug, B., Chamberlain, S., & Kim, S.-W. (2010) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e3181e617a1 · Cited by 86 · see citing works
Self-citationThe Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders
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Pilot trial of dialectical behavior therapy-enhanced habit reversal for trichotillomania
Keuthen, N. J., Rothbaum, B. O., Welch, S. S., Taylor, C., Falkenstein, M., Heekin, M., Jordan, C. A., Timpano, K., Meunier, S., Fama, J., et al. (2010) · Depression and Anxiety · doi:10.1002/da.20732 · Cited by 81 · see citing works
“More recently, Grant et al.([10]) reported successful outcomes using N-acetylcysteine, an amino acid known to modulate glutamate function, in a doubleblind, placebo-controlled study of TTM.”
Selles, R. R., McGuire, J. F., Small, B. J., & Storch, E. A. (2016) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2016.04.001 · Cited by 80 · see citing works
Obsessive compulsive disorder and the glutamatergic system
Kariuki-Nyuthe, C., Gomez-Mancilla, B., & Stein, D. J. (2014) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000017 · Cited by 80 · see citing works
“Notably, however, NAC was effective in a RCT of trichotillomania in adults [70] with some case reports of efficacy in skin picking [71].”
BackgroundSarris, J., Oliver, G., Camfield, D., Dean, O., Dowling, N., Smith, D. J., Murphy, J., Menon, R., Berk, M., Blair-West, S., et al. (2015) · CNS Drugs · doi:10.1007/s40263-015-0272-9 · Cited by 79 · see citing works
“4g/day) significantly reduced symptoms on the Massachusetts General Hospital Hair Pulling Scale, and the Psychiatric Institute Trichotillomania Scale [24].”
BackgroundNasir, M., Trujillo, D., Levine, J. L. S., Dwyer, J. B., Rupp, Z. W., & Bloch, M. H. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.548505 · Cited by 89 · see citing works
“However, when anxiety symptoms were analyzed in placebo-controlled trials looking at major depressive disorder (154) and trichotillomania (155), no significant differences were found in anxiety scores as measured by Hamilton Anxiety Rating Scale (HAM-A).”
MethodKranzer, K., Elamin, W., Cox, H., Seddon, J., Ford, N., & Drobniewski, F. (2015) · Thorax · doi:10.1136/thoraxjnl-2015-207245 · Cited by 72 · see citing works
“Grant, 2009 b [11] USA Trichotillomania 1200 (6wks), 2400 (6wks) 1 12 25 25 32.”
BackgroundInfluentialN‐acetylcysteine as a new prominent approach for treating psychiatric disorders
Smaga, I., Frankowska, M., & Filip, M. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15456 · Cited by 73 · see citing works
“4.8.2 | Controlled In 2009, the first double-blind, placebo-controlled trial examining NAC in patients with TTM was published (Grant et al., 2009).”
BackgroundMethodInfluentialRichert, B., & André, J. (2011) · American Journal of Clinical Dermatology · doi:10.2165/11537110-000000000-00000 · Cited by 71
“The dosage in adults ranges between 1200 and 2400mg/day.([119]) For severe cases, antidepressants (e.”
An open‐label pilot study of N‐acetylcysteine for skin‐picking in Prader–Willi syndrome
Miller, J. L., & Angulo, M. (2014) · American Journal of Medical Genetics. Part A · doi:10.1002/ajmg.a.36306 · Cited by 70 · see citing works
“…valproic Ac; GH, growth hormone; MEF, metformin; QPE, quetiapine; RSP, risperdone; SPR, spiro aLesions present for over 90 days prior to treatment. bPatient had in addition trichotillomania, which resolved with treatment. and nail biting [Grant et al., 2009; Rodrigues-Barata et al., 2012].”
BackgroundMechanisms of divalent metal toxicity in affective disorders
Menon, A. V., Chang, J., & Kim, J. (2015) · Toxicology · doi:10.1016/j.tox.2015.11.001 · Cited by 74 · see citing works
Lara, D. R., Bisol, L. W., Brunstein, M. G., Reppold, C. T., de Carvalho, H. W., & Ottoni, G. L. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.08.036 · Cited by 76 · see citing works
“…as diverse as schizophrenia (mostly negative and general symptoms) (Berk et al., 2008a), cocaine addiction (LaRowe et al., 2007), bipolar depression (Berk et al., 2008b), pathological gambling (Grant et al., 2007), trichotillomania (Grant et al., 2009) and possibly nail biting (Berk et al., 2009).”
BackgroundEffect of N‐acetylcysteine on motivation, seeking and relapse to ethanol self‐administration
Lebourgeois, S., González-Marín, M., Jeanblanc, J., Naassila, M., & Vilpoux, C. (2018) · Addiction Biology · doi:10.1111/adb.12521 · Cited by 65 · see citing works
N-acetylcysteine in the Treatment of Trichotillomania
Rodrigues-Barata, A. R., Tosti, A., Rodriguez-Pichardo, A., & Camacho-Martínez, F. (2012) · International Journal of Trichology · doi:10.4103/0974-7753.100090 · Cited by 65 · see citing works
Neuromodulation for obsessive-compulsive disorder
Lapidus, K. A. B., Stern, E. R., Berlin, H. A., & Goodman, W. K. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0287-9 · Cited by 63 · see citing works
“Also, preliminary evidence suggests that glutamatergic agents such as riluzole and ketamine may be useful in OCD [28–31].”
A Practical Approach to the Diagnosis and Management of Hair Loss in Children and Adolescents
Xu, L.-W., Liu, K. X., & Senna, M. (2017) · Frontiers in Medicine · doi:10.3389/fmed.2017.00112 · Cited by 63
“While N-acetylcysteine is a promising agent that reduces symptoms in adults, no benefit was seen in children (64, 65).”
BackgroundOdlaug, B. L., Chamberlain, S. R., Derbyshire, K. L., Leppink, E. W., & Grant, J. E. (2014) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2014.08.010 · Cited by 67 · see citing works
Self-citationGhanizadeh, A. J., Derakhshan, N., & Berk, M. (2013) · Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry · doi:10.2174/1871523011312030003 · Cited by 64 · see citing works
Obsessive-Compulsive and Related Disorders
Leigh, H. (2014) · Springer eBooks · doi:10.1007/978-3-319-11005-9_24 · Cited by 32 · see citing works
Dronabinol, a cannabinoid agonist, reduces hair pulling in trichotillomania: a pilot study
Grant, J., Odlaug, B., Chamberlain, S., & Kim, S.-W. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2347-8 · Cited by 60 · see citing works
“…R. Chamberlain Department of Psychiatry, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK demonstrated that N-acetyl cysteine (Grant et al. 2009), olanzapine (Van Ameringen et al. 2010), and clomipramine (Swedo et al. 1993) all show some promise in reducing hair-pulling…”
BackgroundResultInfluentialSelf-citationSarris, J., Camfield, D., & Berk, M. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.04.051 · Cited by 59 · see citing works
Emerging treatments in alopecia
Falto-Aizpurua, L. A., Choudhary, S., & Tosti, A. (2014) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.2014.974550 · Cited by 59 · see citing works
“1 N-acetylcysteine Recently, N-acetylcysteine was investigated as a potential drug given that it increases glutamate extracellular concentration in the nucleus accumbens [66].”
BackgroundHistory of Psychosurgery: A Psychiatrist's Perspective
Lapidus, K. A. B., Kopell, B. H., Ben‐Haim, S., Rezai, A. R., & Goodman, W. K. (2013) · World Neurosurgery · doi:10.1016/j.wneu.2013.02.053 · Cited by 85 · see citing works
Camfield, D., Sarris, J. J., & Berk, M. (2011) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2011.02.011 · Cited by 61 · see citing works
“In a double-blind randomized placebo-controlled study Greenberg et al. (2009) administered 60 g/day of glycine to 24 adult OCD outpatients as augmentation therapy.”
MethodN-acetylcysteine in dermatology
Adil, M., Amin, S. S., & Mohtashim, M. (2018) · Indian Journal of Dermatology Venereology and Leprology · doi:10.4103/ijdvl.ijdvl_33_18 · Cited by 65 · see citing works
Jones, G., Keuthen, N., & Greenberg, E. H. (2018) · Clinical Dermatology · doi:10.1016/j.clindermatol.2018.08.008 · Cited by 54 · see citing works
Emamzadehfard, S., Kamaloo, A., Paydary, K., Ahmadipour, A., Zeinoddini, A., Ghaleiha, A., Mohammadinejad, P., Zeinoddini, A., & Akhondzadeh, S. (2016) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12394 · Cited by 55 · see citing works
“Another 12-week open-label trial of riluzole on six treatment-resistant children with OCD showed that four had >46% reduction in the Children’s Yale– Brown Obsessive–Compulsive Scale severity scores.(48) The authors noted that the side-effect profile was benign and that all patients elected to remain on riluzole post-…”
BackgroundTherapeutic potential of glutathione-enhancers in stress-related psychopathologies
Zalachoras, I., Hollis, F., Ramos‐Fernández, E., Trovò, L., Sonnay, S., Geiser, E., Preitner, N., Steiner, P., Sandi, C., & Morató, L. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.03.015 · Cited by 67 · see citing works
Möller, M., du Preez, J. L., Viljoen, F. P., Berk, M., & Harvey, B. H. (2013) · Metabolic Brain Disease · doi:10.1007/s11011-013-9433-z · Cited by 48 · see citing works
“In this regard N-acetyl cysteine (NAC), a glutathione precursor, antioxidant (Kerksick and Willoughby, 2005) and glutamate modulator (Grant et al., 2009), is a promising therapeutic agent (Dean et al.”
BackgroundFrança, K., Kumar, A., Castillo, D., Jafferany, M., Hyczy da Costa Neto, M., Damevska, K., Wollina, U., & Lotti, T. (2019) · Dermatologic Therapy · doi:10.1111/dth.12622 · Cited by 51 · see citing works
Disordered reward processing and functional connectivity in trichotillomania: A pilot study
White, M. P., Shirer, W. R., Molfino, M. J., Tenison, C., Damoiseaux, J. S., & Greicius, M. D. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.05.014 · Cited by 50 · see citing works
“This may be relevant to recent clinical inroads in the treatment of TTM using agents that modulate glutamate (Grant et al., 2009) and dopamine (Van Ameringen et al.”
BackgroundInfluentialFlessner, C., Knopik, V., & McGeary, J. (2012) · Psychiatry Research · doi:10.1016/j.psychres.2012.03.039 · Cited by 51 · see citing works
“…treatment study of the dopamine blocker pimozide (Stein and Hollander, 1992) and a more recent randomized controlled trial of N-acetylcysteine (NAC) for HPD (Grant et al., 2009) provides some additional support for the potentially important role of dopamine in the pathophysiology of HPD.”
Sani, G., Gualtieri, I., Paolini, M., Bonanni, L., Spinazzola, E., Maggiora, M., Pinzone, V., Brugnoli, R., Angeletti, G., Girardi, P., et al. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666190320164223 · Cited by 50 · see citing works
The Effect of N-Acetylcysteine on Alcohol Use during a Cannabis Cessation Trial
Squeglia, L., Tomko, R., Baker, N., McClure, E. A., Book, G. A., & Gray, K. M. (2018) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2017.12.005 · Cited by 48 · see citing works
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Glutamate drugs and pharmacogenetics of OCD: a pathway-based exploratory approach
Grados, M. A., Specht, M. W., Sung, H.-M., & Fortune, D. (2013) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2013.845553 · Cited by 49 · see citing works
Habit reversal training in trichotillomania: guide for the clinician
Morris Sarah, H., Zickgraf Hana, F., Dingfelder Hilary, E., & Franklin Martin, E. (2013) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2013.827477 · Cited by 47 · see citing works
Connor, C. J. (2017) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s111041 · Cited by 46 · see citing works
“NAC is an amino acid that acts as a glutamate modulator and may exert its effects by normalizing dysregulated extracellular glutamate concentrations in the nucleus accumbens: an area of the brain that plays a key role in motivation and reward.(126) The common dose of NAC for trichotillomania is 1,200 mg/day, with few…”
Investigational and Experimental Drugs to Treat Obsessive-Compulsive Disorder
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Pharmacological Augmentations of SRIs for Obsessive Compulsive Disorder
Leppink, E. W., & Grant, J. E. (2017) · Wiley eBooks · doi:10.1002/9781118890233.ch16 · Cited by 43 · see citing works
Self-citationTreatment options for alopecia: an update, looking to the future
Miteva, M., & Tosti, A. (2012) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2012.685160 · Cited by 43
“N-acetylcysteine, an amino acid, seems to restore the extracellular glutamate concentration in the brain, and therefore offers promise in the reduction of compulsive behavior [64].”
BackgroundObsessive-Compulsive Related Disorders
Breet, E., & Lochner, C. (2015) · Springer eBooks · doi:10.1007/978-3-319-13060-6_5 · Cited by 43 · see citing works
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Current Treatment Practices for Children and Adults With Trichotillomania: Consensus Among Experts
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Cortico-striatal oxidative status, dopamine turnover and relation with stereotypy in the deer mouse
Güldenpfennig, M., Wolmarans, D. W., du Preez, J. L., Stein, D. J., & Harvey, B. H. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.03.008 · Cited by 45 · see citing works
“A recent placebo-controlled trial has also described its use in trichotillomania [53].”
Background
- Authors
- Grant, J. E., Odlaug, B. L., & Won Kim, S.
- Affiliations
- University of Minnesota (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2009-07-01
- Volume
- 66
- Issue
- 7
- Pages
- 756
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2038083244
- Cited by
- 424
- References
- 0
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 17 · 2023: 35 · 2022: 15 · 2021: 22 · 2020: 23 · 2019: 22 · 2018: 31 · 2017: 23 · 2016: 31 · 2015: 41 · 2014: 28 · 2013: 27 · 2012: 29
- FWCI
- 29.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Social Sciences › Psychology › Clinical Psychology › Body Image and Dysmorphia Studies
- Keywords
- trichotillomania, N-acetylcysteine, glutamate modulation, glutamatergic agents, compulsive behavior, hair pulling, nucleus accumbens, pharmacotherapy, treatment efficacy, tolerability, depression, anxiety, psychosocial functioning
- MeSH terms
- Acetylcysteine, Adolescent, Adult, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Personality Inventory, Psychometrics, Trichotillomania, Excitatory Amino Acid Agents, Young Adult
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