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N-acetylcysteine in the treatment of substance use disorders
1Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Istanbul - Turkey
Dusunen Adam Journal of Psychiatry and Neurological Sciences 2020; 33(1): 1-7 DOI: 10.14744/DAJPNS.2019.00055
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Abstract

N-acetylcysteine (NAC) is an agent best known for its clinical efficacy in bronchopulmonary disorders due to its mucolytic properties, and in the treatment of acetaminophen overdose. Given the strong clinical evidence from animal studies of its critical role in regulating glutamatergic receptors, NAC has also been the subject of research related to several psychiatric disorders as a promising treatment approach. This editorial is a brief discussion of the characteristics of NAC and its place in substance use disorders and other psychiatric disorders.

N-acetylcysteine (NAC) is an N-acetylated derivative of the naturally occurring amino acid cysteine (1). NAC is a white, crystalline compound; the molecular formula is C5H9NO3S (2). As a drug, it has been available for several years in intravenous, oral, and nebulizer forms (2,3). Inside several organs (including the brain), free cysteine is formed by deacetylation of NAC. Two cysteine molecules are then homodimerized via a disulfide bond, forming cystine. NAC is therefore a cystine prodrug that binds to the cystine-glutamate exchanger (or system xc-) and supports the synthesis of glutathione (4-6), the most important non-enzymatic substance scavenging free radicals in the intracellular spaces of the brain with the most generic action of all endogenous antioxidants. The level of glutathione in the brain is replenished by NAC as a precursor molecule (7,8). As a result, it is relevant as an antioxidant (9,10). Not only does system xc- promote glutathione synthesis; it also functions as antiporter protein carrying extracellular cystine into glial cells and moving intracellular glutamate from inside the glial cells into the extracellular environment, thus raising extracellular glutamate levels in many tissues including the brain (1,4,6).

The clinical efficacy of NAC as a mucolytic agent for bronchopulmonary disorders and in the treatment of acetaminophen overdose has been proven worldwide (6). On the other hand, an increasing number of clinical studies indicate the efficacy of NAC in various psychiatric conditions through mechanisms including glutamate modulation and other processes (11), such as substance use disorders (SUDs) (12), pathological gambling (13), obsessive-compulsive disorder (14) and other compulsive disorders (15-17), mood disorders (8,18), schizophrenia (19), and autism (20) as well as neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases (21).

It is a safe and well-tolerated agent, even at relatively high doses (22), with mild side effects like headache, lethargy, fever, and skin rash occurring approximately 1-5% of the time (23). The most commonly reported adverse events include pruritus, headache, gastrointestinal issues including flatulence, diarrhea, and abdominal cramps, dizziness, and elevated blood pressure (24).


Substance Use Disorders and N-acetylcysteine

Traditionally, dopamine and associated reward-based behavior have been in the focus of research into substance abuse; however, it has been suggested that glutamate dysregulation could be another path toward the development and maintenance of addiction (25,26). Preclinical studies in animal models suggest that NAC could restore the imbalanced cysteine-glutamate exchange in the brain and thus decrease drug-seeking behaviors (27-29).

For more than two decades, animal studies have created increasing preclinical evidence indicating that glutamate transmission and glutamate receptors play a major role in drug reward, reinforcement, and relapse (6,30-39). Accordingly, treatment of SUDs with NAC in clinical populations has been an active area of research (26). The role of glutamate dysregulation, the target of NAC treatment, has been proposed as a ubiquitous finding and underlying feature across SUDs (32,33,40). Thus, SUDs involving the abuse of a number of different substances are treated using glutamatergic agents (3). Considering that NAC influences craving, withdrawal, and the rewarding properties of substances of abuse, a number of studies have tried to establish how the administration of NAC affects these processes (3).

While not providing clear results, randomized clinical trials have pointed towards certain mechanistic and methodological factors through which NAC could promote abstinence and help prevent relapses with different substances of abuse (3). In recent findings, NAC is suggested to be most effective in maintaining abstinence rather than in promoting initial cessation (12,41,42). Despite inconsistent results in human clinical trials (41,43,44), the latest systematic review and meta-analysis found NAC to be significantly superior to placebo for reducing craving symptoms in SUDs. As a potential anti-craving agent, NAC could be important for relapse prevention (45).


Cocaine and N-acetylcysteine

Cocaine has so far been in the focus of clinical research regarding the therapeutic effects of NAC on addictive behaviors (24). While findings have been mixed, they seem to suggest efficacy over placebo to prolong abstinence and reduce cue-related cocaine cravings for individuals past acute withdrawal (46). The review by Echevarria et al. (42) found studies demonstrating the potential of NAC to “reduce cravings, the desire to use cocaine, cocaine-cue viewing-time and cocaine-related spending” (2,22,43,44). As these studies either had small samples or had been carried out as open-label trials, their results are to be considered as preliminary, warranting further research (42).

In a large randomized control trial to assess efficacy of NAC in the treatment of cocaine dependence, while no significant correlation was found between NAC and relapse-related measures, a small subset of patients who had already been abstinent for at least one week before participating in the study showed a dose-dependent prolongation of days to relapse, suggesting that NAC might protect abstinent SUDs patients from resumption of substance use. In the majority of cases, however, the outcome was negative, indicating the need for further research (41).

One open-label, randomized, crossover clinical study with 22 human subjects (8 cocaine-dependent, 14 healthy) used proton magnetic resonance spectroscopy to image glutamate concentration in the dorsal anterior cingulate cortex (dACC) after a single dose of NAC, finding significantly higher baseline levels of glutamate in the dACC of the cocaine-dependent subjects. While glutamate levels of these individuals were reduced after administration of NAC, no effect was observed in healthy controls (25). These results indicate the capabilities of NAC to address imbalance in glutamate homeostasis (24,25).


Methamphetamine and N-acetylcysteine

Preclinical research studying the effect of NAC on the administration or reinstatement of methamphetamine has not been found in the literature (24) with the exception of one study conducted on female rats, where NAC was not found to have any effect on methamphetamine self-administration or reinstatement (47). However, in the absence of FDA-approved pharmacotherapies for methamphetamine use, clinical research with NAC has been undertaken (24).

In a study conducted in 2010, a combination of NAC and naltrexone was used for methamphetamine cravings and self-reported methamphetamine use. Participants in treatment showed no significant difference in cravings or drug use frequency (48).

A second study on methamphetamine use disorder used a double-blind, crossover design to examine craving (49). In contrast with the study discussed above, NAC treatment significantly reduced methamphetamine craving. 

NAC’s effect on methamphetamine use and other clinically related endpoints is uncertain. A study protocol to “evaluate the safety and efficacy of NAC as a take-home pharmacotherapy for methamphetamine dependence” was published in 2019; however, the results have not yet been released. The authors suggested that, “given the lack of approved medications currently available for managing methamphetamine dependence and the challenges involved in translating effective psychological interventions into practice settings, the discovery of a safe and effective pharmacotherapy would fill an important gap in treatment options for methamphetamine use” (50).


Cannabis and N-acetylcysteine

The strongest clinical findings to date for NAC in relation to SUDs are adolescent- and cannabis-specific (12). One open-label study treated 24 cannabis-dependent individuals aged 18-21 over a period of 4 weeks with 1200 mg NAC twice daily. In week 4 of the NAC treatment, subjects reported a significantly decreased number of days per week when they used cannabis and a tendency to reduce the daily quantity of marijuana. Objective evaluation did not find any change in the cannabinoid content of urine samples but a significant reduction of the scores on the Marijuana Craving Questionnaire, suggesting a relevant role for NAC in the treatment of cannabis abuse and dependence (51).

In a double-blind, randomized, placebo-controlled trial in cannabis-dependent adolescents using NAC in addition to a behavioral platform to promote abstinence, participants receiving NAC were twice as likely to have a negative urine cannabinoid test as those who received placebo (52).

A subsequent 12-week multisite, double-blind randomized, placebo-controlled trial with 302 treatment-seeking adults with cannabis use disorder (age range 18-50 years) obtained overall negative findings for the effect of NAC on cannabis abstinence. Subgroup analyses for participants aged 18-21 years (the range of the sample in the previous adolescent NAC cannabis trial) found this group to be twice as likely to have negative drug screens after receiving NAC vs. placebo, suggesting that NAC might be used specifically for treating adolescent cannabis use disorder (53). However, the efficacy of NAC in the treatment of cannabis use disorder has so far not been studied without adjunctive contingency management. Therefore, further research should single out the clinical effect of NAC among adolescents (12).

A recent study examined the effect of NAC on depressive symptoms in adults with cannabis use disorder and a possible correlation between NAC’s effect on cannabis cessation and baseline levels of depression. The outcome, however, did not support the use of NAC for treating co-occurring depressive symptoms and cannabis use disorder in adults concurrently (54).


Synthetic Cannabinoids and N-acetylcysteine

There is only one case report that demonstrates a full recovery of a patient suffering from hepatotoxicity caused by synthetic cannabinoids. The patient was treated with NAC, and the effects were attributed to its hepatoprotective properties, as NAC restores hepatic glutathione that scavenges oxygen-derived free radicals and improves endothelium-dependent vasodilation, offering protection from ongoing injury (55).


Alcohol and N-acetylcysteine

Beneficial effects of NAC treatment in ethanol withdrawal have been demonstrated in preclinical studies. NAC treatment prevented locomotor deficits and anxiety-like behavior as well as the lipid peroxidation and ethanol withdrawal-induced depletion of antioxidant defenses observed during ethanol withdrawal (56).

A recent preclinical study in an animal model of comorbid post-traumatic stress disorder and SUDs showed that NAC could be used prophylactically to prevent or reverse the vulnerability to undergo stress-induced escalation of alcohol use and conditioned stress-induced alcohol (57).

In one cannabis cessation trial, NAC was associated with decreased cannabis use as well as concurrent reduction in alcohol use among adolescents (58). In another cannabis cessation trial conducted with adults, subjects assigned randomly to the NAC group showed reduced alcohol use when compared to the placebo group, regardless of cannabis use, indicating that NAC might be used for treating AUD and possibly co-occurring alcohol and cannabis use (59).

There is a growing preclinical literature suggesting that NAC could help reducing alcohol use (60); however, there have been no clinical trials to date directly investigating the potential role of NAC on alcohol use disorder (61).


Nicotine and N-acetylcysteine

Chronic NAC administration has been shown to lead to an inhibition of nicotine-seeking and transient increases in synaptic plasticity within the nucleus accumbens in preclinical research with rodent models of nicotine self-administration (24,62). Similarly, acute administration of NAC was effective at reducing nicotine self-administration (63), indicating a high potential for NAC to be used in an effective treatment of nicotine addiction in a clinical setting. There are clinical studies that have shown that NAC leads to a reduction in withdrawal scores and measures of the rewarding properties of the first cigarette posttreatment (64), along with effects on reduction in cigarettes smoked per day and craving (65).

One clinical imaging study used functional magnetic resonance imaging (fMRI) to investigate the effects of NAC on the frontostriatal resting-state functional connectivity (rsFC) in nicotine withdrawal symptoms (66). The results of this study demonstrated that NAC led to an increase in the rates of abstinence, reduction in reported craving, and an increase in rsFC compared to placebo, helping to restore regular glutamate homeostasis and signaling (24).

So far, only small pilot studies have been carried out to establish the efficacy of NAC for treating tobacco-use disorder, providing promising initial evidence; however, without a comprehensive randomized clinical trial, it would be premature to suggest the use of NAC for smoking cessation (12).


Opioids and N-acetylcysteine

NAC has been shown to produce positive outcomes in rodents for opioids (29), and a recent study in opioid-dependent neonatal rats demonstrated that NAC mitigated behavioral withdrawal symptoms and oxidative stress (67). However, the efficacy of NAC in opioid dependence has not yet been tested in clinical populations (24), neither as a stand-alone treatment nor in addition to opioid-replacement therapies or behavioral treatment (3).


N-acetylcysteine and Other Psychiatric Disorders

NAC as a precursor of glutathione and an important antioxidant with the ability to modulate glutamatergic, dopaminergic neurotropic, and inflammatory pathways has created interest in its use for treating a number of psychiatric disorders (68). Oxidative stress may be a factor in psychiatric disorders such as bipolar and anxiety disorders, depression, and SUDs, but also in diagnoses such as autism and attention-deficit hyperactivity disorder (3,69).

The depletion of glutathione during oxidative stress can be reversed with NAC treatment (3,70) and there is evidence supporting the study of glutathione as a novel therapeutic target in psychiatric disorders (3,71).

While NAC is not currently licensed for any psychiatric indication, its off-label use in a number of several psychiatric disorders has been researched as a promising treatment approach, mainly as an adjunctive medication, so far producing only preliminary data for areas of psychiatric use. Results on primary outcomes in most trials were not significant, while secondary outcomes or the analysis of subsamples has given some positive evidence. As most studies have used small samples, additional well-designed, larger controlled trials with longer follow-up periods would be desirable to establish reliable indications and clearer information on optimal dosage and side effects, safety and tolerability in the long-term use of NAC (68).


Conclusion

Current evidence supports NAC as a novel and effective treatment for some psychiatric conditions, with the best evidence being available for addictions and SUDs, reducing craving and preventing relapse in patients who are already abstinent. Yet the results of available studies and reviews are not uniform, indicating that more robust evidence should be generated in future clinical trials (26).

The role of NAC in reducing damage caused by oxidative stress is another area of research to be pursued. As oxidative stress has been shown to affect psychiatric disorders (69), avoiding this effect will be of particular relevance for the treatment of SUDs. Thus, the role of the oxidative stress mechanism in psychiatric disorders and its treatment with NAC appear to offer relevant guidance for future research addressing poly-substance use and psychiatric comorbidities (3).


REFERENCES

1. Melendez RI, Vuthiganon J, Kalivas PW. Regulation of extracellular glutamate in the prefrontal cortex: focus on the cystine glutamate exchanger and group I metabotropic glutamate receptors. J Pharmacol Exp Ther 2005; 314:139-147.
https://doi.org/10.1124/jpet.104.081521
PMid:15769865
 
2. LaRowe SD, Mardikian P, Malcolm R, Myrick H, Kalivas P, McFarland K, et al. Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict 2006; 15:105-110.
https://doi.org/10.1080/10550490500419169
PMid:16449100 PMCid:PMC1513138
 
3. McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM. Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs 2014; 28:95-106.
https://doi.org/10.1007/s40263-014-0142-x
PMid:24442756 PMCid:PMC4009342
 
4. Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 2002; 22:9134-9141.
https://doi.org/10.1523/JNEUROSCI.22-20-09134.2002
PMid:12388621 PMCid:PMC6757683
 
5. McBean GJ. Cerebral cystine uptake: a tale of two transporters. Trends Pharmacol Sci 2002; 23:299-302.
https://doi.org/10.1016/S0165-6147(02)02060-6
 
6. Olive MF, Cleva RM, Kalivas PW, Malcolm RJ. Glutamatergic medications for the treatment of drug and behavioral addictions. Pharmacol Biochem Behav 2012; 100:801-810.
https://doi.org/10.1016/j.pbb.2011.04.015
PMid:21536062 PMCid:PMC3154511
 
7. Dean OM, van den Buuse M, Bush AI, Copolov DL, Ng F, Dodd S, et al. A role for glutathione in the pathophysiology of bipolar disorder and schizophrenia? Animal models and relevance to clinical practice. Curr Med Chem 2009; 16:2965-2976.
https://doi.org/10.2174/092986709788803060
PMid:19689277
 
8. Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS, et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord 2011; 135:389-394.
https://doi.org/10.1016/j.jad.2011.06.005
PMid:21719110
 
9. Cuzzocrea S, Mazzon E, Costantino G, Serraino I, Dugo L, Calabro G, et al. Beneficial effects of N-acetylcysteine on ischaemic brain injury. Br J Pharmacol 2000; 130:1219-1226.
https://doi.org/10.1038/sj.bjp.0703421
PMid:10903958 PMCid:PMC1572181
 
10. Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, et al. N-acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res 2018; 52:751-762.
https://doi.org/10.1080/10715762.2018.1468564
PMid:29742938
 
11. Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 2011; 36:78-86.
https://doi.org/10.1503/jpn.100057
PMid:21118657 PMCid:PMC3044191
 
12. Tomko RL, Jones JL, Gilmore AK, Brady KT, Back SE, Gray KM. N-acetylcysteine: a potential treatment for substance use disorders. Curr Psychiatr 2018; 17:30-36, 41-42, 55.
 
13. Grant JE, Kim SW, Odlaug BL. N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry 2007; 62:652-657.
https://doi.org/10.1016/j.biopsych.2006.11.021
PMid:17445781
 
14. Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S, Akhondzadeh S. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther 2016; 41:214-219.
https://doi.org/10.1111/jcpt.12370
PMid:26931055
 
15. Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2009; 66:756-763.
https://doi.org/10.1001/archgenpsychiatry.2009.60
PMid:19581567
 
16. Kilic F, Keles S. Repetitive behaviors treated with N-acetylcysteine: case series. Clin Neuropharmacol 2019; 42:139-141.
https://doi.org/10.1097/WNF.0000000000000352
PMid:31232748
 
17. Grant JE, Chamberlain SR, Redden SA, Leppink EW, Odlaug BL, Kim SW. N-acetylcysteine in the treatment of excoriation disorder: a randomized clinical trial. JAMA Psychiatry 2016; 73:490-496.
https://doi.org/10.1001/jamapsychiatry.2016.0060
PMid:27007062
 
18. Berk M, Dean OM, Cotton SM, Jeavons S, Tanious M, Kohlmann K, et al. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 2014; 75:628-636.
https://doi.org/10.4088/JCP.13m08454
PMid:25004186
 
19. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetylcysteine as a glutathione precursor for schizophrenia-a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008; 64:361-368.
https://doi.org/10.1016/j.biopsych.2008.04.022
https://doi.org/10.1016/j.biopsych.2008.03.004
PMid:18436195
 
20. Hardan AY, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry 2012; 71:956-961.
https://doi.org/10.1016/j.biopsych.2012.01.014
PMid:22342106 PMCid:PMC4914359
 
21. Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 2013; 34:167-177.
https://doi.org/10.1016/j.tips.2013.01.001
PMid:23369637
 
22. Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:389-394.
https://doi.org/10.1016/j.pnpbp.2006.10.001
PMid:17113207
 
23. Miller LF, Rumack BH. Clinical safety of high oral doses of acetylcysteine. Semin Oncol 1983; 10(1 Suppl.1):76-85.
 
24. Powell G, McClure EA, Olive MF, Gipson CD. Clinical treatment of addictive disorders with N-acetylcysteine; In Frye RE, Berk M (editors). The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine. Singapore: Springer Nature, 2019, 219-233.
https://doi.org/10.1007/978-981-10-5311-5_13
 
25. Schmaal L, Veltman DJ, Nederveen A, van den Brink W, Goudriaan AE. N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology 2012; 37:2143-2152.
https://doi.org/10.1038/npp.2012.66
PMid:22549117 PMCid:PMC3398721
 
26. Ooi SL, Green R, Pak SC. N-Acetylcysteine for the treatment of psychiatric disorders: a review of current evidence. Biomed Res Int 2018; 2018:2469486.
https://doi.org/10.1155/2018/2469486
PMid:30426004 PMCid:PMC6217900
 
27. Baker DA, Khroyan TV, O'Dell LE, Fuchs RA, Neisewander JL. Differential effects of intra-accumbens sulpiride on cocaine-induced locomotion and conditioned place preference. J Pharmacol Exp Ther 1996; 279:392-401.
 
28. Baker DA, McFarland K, Lake RW, Shen H, Toda S, Kalivas PW. N-acetylcysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci 2003; 1003:349-351.
https://doi.org/10.1196/annals.1300.023
PMid:14684458
 
29. Zhou W, Kalivas PW. N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking. Biol Psychiatry 2008; 63:338-340.
https://doi.org/10.1016/j.biopsych.2007.06.008
PMid:17719565 PMCid:PMC2709691
 
30. Bird MK, Lawrence AJ. Group I metabotropic glutamate receptors: involvement in drug-seeking and drug-induced plasticity. Curr Mol Pharmacol 2009; 2:83-94.
https://doi.org/10.2174/1874467210902010083
PMid:20021449
 
31. Bowers MS, Chen BT, Bonci A. AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future. Neuron 2010; 67:11-24.
https://doi.org/10.1016/j.neuron.2010.06.004
PMid:20624588 PMCid:PMC2904302
 
32. Gass JT, Olive MF. Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 2008; 75:218-265.
https://doi.org/10.1016/j.bcp.2007.06.039
PMid:17706608 PMCid:PMC2239014
 
33. Kalivas PW, Lalumiere RT, Knackstedt L, Shen H. Glutamate transmission in addiction. Neuropharmacology 2009; 56:169-173.
https://doi.org/10.1016/j.neuropharm.2008.07.011
PMid:18675832 PMCid:PMC3280337
 
34. Moussawi K, Kalivas PW. Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction. Eur J Pharmacol 2010; 639:115-122.
https://doi.org/10.1016/j.ejphar.2010.01.030
PMid:20371233 PMCid:PMC4351804
 
35. Olive MF. Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev 2009; 2:83-98.
https://doi.org/10.2174/1874473710902010083
PMid:19630739 PMCid:PMC2717506
 
36. Olive MF. Cognitive effects of Group I metabotropic glutamate receptor ligands in the context of drug addiction. Eur J Pharmacol 2010; 639:47-58.
https://doi.org/10.1016/j.ejphar.2010.01.029
PMid:20371237 PMCid:PMC2891107
 
37. Reissner KJ, Kalivas PW. Using glutamate homeostasis as a target for treating addictive disorders. Behav Pharmacol 2010; 21:514-522.
https://doi.org/10.1097/FBP.0b013e32833d41b2
PMid:20634691 PMCid:PMC2932669
 
38. Tzschentke TM, Schmidt WJ. Glutamatergic mechanisms in addiction. Mol Psychiatry 2003; 8:373-382.
https://doi.org/10.1038/sj.mp.4001269
PMid:12740594
 
39. Uys JD, LaLumiere RT. Glutamate: the new frontier in pharmacotherapy for cocaine addiction. CNS Neurol Disord Drug Targets 2008; 7:482-491.
https://doi.org/10.2174/187152708786927868
PMid:19128205
 
40. Kalivas PW, Volkow ND. New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 2011; 16:974-986.
https://doi.org/10.1038/mp.2011.46
PMid:21519339 PMCid:PMC3192324
 
41. LaRowe SD, Kalivas PW, Nicholas JS, Randall PK, Mardikian PN, Malcolm RJ. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am J Addict 2013; 22:443-452.
https://doi.org/10.1111/j.1521-0391.2013.12034.x
PMid:23952889 PMCid:PMC4348575
 
42. Nocito Echevarria MA, Andrade Reis T, Ruffo Capatti G, Siciliano Soares V, da Silveira DX, Fidalgo TM. N-acetylcysteine for treating cocaine addiction-a systematic review. Psychiatry Res 2017; 251:197-203.
https://doi.org/10.1016/j.psychres.2017.02.024
PMid:28213190
 
43. LaRowe SD, Myrick H, Hedden S, Mardikian P, Saladin M, McRae A, et al. Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry 2007; 164:1115-1117.
https://doi.org/10.1176/ajp.2007.164.7.1115
PMid:17606664
 
44. Amen SL, Piacentine LB, Ahmad ME, Li SJ, Mantsch JR, Risinger RC, et al. Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology 2011; 36:871-878.
https://doi.org/10.1038/npp.2010.226
PMid:21160464 PMCid:PMC3052624
 
45. Duailibi MS, Cordeiro Q, Brietzke E, Ribeiro M, LaRowe S, Berk M, et al. N-acetylcysteine in the treatment of craving in substance use disorders: systematic review and meta-analysis. Am J Addict 2017; 26:660-666.
https://doi.org/10.1111/ajad.12620
PMid:28898494
 
46. Schechter JD. Effects of N-acetylcysteine on treatment outcomes for cocaine abusers. 2019. https://ubir.buffalo.edu/xmlui/handle/10477/81329.
 
47. Charntikov S, Pittenger ST, Pudiak CM, Bevins RA. The effect of N-acetylcysteine or bupropion on methamphetamine self-administration and methamphetamine-triggered reinstatement of female rats. Neuropharmacology 2018; 135:487-495.
https://doi.org/10.1016/j.neuropharm.2018.03.021
PMid:29604294 PMCid:PMC5975194
 
48. Grant JE, Odlaug BL, Kim SW. A double-blind, placebo-controlled study of N-acetylcysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol 2010; 20:823-828.
https://doi.org/10.1016/j.euroneuro.2010.06.018
PMid:20655182
 
49. Mousavi SG, Sharbafchi MR, Salehi M, Peykanpour M, Karimian Sichani N, Maracy M. The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study. Arch Iran Med 2015; 18:28-33.
 
50. McKetin R, Dean OM, Turner A, Kelly PJ, Quinn B, Lubman DI, et al. A study protocol for the N-ICE trial: a randomised double-blind placebo-controlled study of the safety and efficacy of N-acetyl-cysteine (NAC) as a pharmacotherapy for methamphetamine ("ice") dependence. Trials 2019; 20:325.
https://doi.org/10.1186/s13063-019-3450-0
PMid:31164169 PMCid:PMC6549263
 
51. Gray KM, Watson NL, Carpenter MJ, LaRowe SD. N-acetylcysteine (NAC) in young marijuana users: an open-label pilot study. Am J Addict 2010; 19:187-189.
https://doi.org/10.1111/j.1521-0391.2009.00027.x
PMid:20163391 PMCid:PMC2826714
 
52. Gray KM, Carpenter MJ, Baker NL, DeSantis SM, Kryway E, Hartwell KJ, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry 2012; 169:805-812.
https://doi.org/10.1176/appi.ajp.2012.12010055
PMid:22706327 PMCid:PMC3410961
 
53. Gray KM, Sonne SC, McClure EA, Ghitza UE, Matthews AG, McRae-Clark AL, et al. A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults. Drug Alcohol Depend 2017; 177:249-257.
https://doi.org/10.1016/j.drugalcdep.2017.04.020
PMid:28623823 PMCid:PMC5535813
 
54. Tomko RL, Baker NL, Hood CO, Gilmore AK, McClure EA, Squeglia LM, et al. Depressive symptoms and cannabis use in a placebo-controlled trial of N-acetylcysteine for adult cannabis use disorder. Psychopharmacology (Berl) 2020; 237:479-490.
https://doi.org/10.1007/s00213-019-05384-z
PMid:31712969
 
55. Sheikh IA, Luksic M, Ferstenberg R, Culpepper-Morgan JA. Spice/K2 synthetic marijuana-induced toxic hepatitis treated with N-acetylcysteine. Am J Case Rep 2014; 15:584-588.
https://doi.org/10.12659/AJCR.891399
PMid:25548903 PMCid:PMC4282190
 
56. Mocelin R, Marcon M, da Rosa Araujo AS, Herrmann AP, Piato A. Withdrawal effects following repeated ethanol exposure are prevented by N-acetylcysteine in zebrafish. Prog Neuropsychopharmacol Biol Psychiatry 2019; 93:161-170.
https://doi.org/10.1016/j.pnpbp.2019.03.014
PMid:30946939
 
57. Garcia-Keller C, Smiley C, Monforton C, Melton S, Kalivas PW, Gass J. N-acetylcysteine treatment during acute stress prevents stress-induced augmentation of addictive drug use and relapse. Addict Biol 2019:e12798.
https://doi.org/10.1111/adb.12798
 
58. Squeglia LM, Baker NL, McClure EA, Tomko RL, Adisetiyo V, Gray KM. Alcohol use during a trial of N-acetylcysteine for adolescent marijuana cessation. Addict Behav 2016; 63:172-177.
https://doi.org/10.1016/j.addbeh.2016.08.001
PMid:27521979 PMCid:PMC4993655
 
59. Squeglia LM, Tomko RL, Baker NL, McClure EA, Book GA, Gray KM. The effect of N-acetylcysteine on alcohol use during a cannabis cessation trial. Drug Alcohol Depend 2018; 185:17-22.
https://doi.org/10.1016/j.drugalcdep.2017.12.005
PMid:29413434 PMCid:PMC5889716
 
60. Quintanilla ME, Rivera-Meza M, Berrios-Carcamo P, Salinas-Luypaert C, Herrera-Marschitz M, Israel Y. Beyond the "first hit": marked inhibition by N-acetyl cysteine of chronic ethanol intake but not of early ethanol intake: parallel effects on ethanol-induced saccharin motivation. Alcohol Clin Exp Res 2016; 40:1044-1051.
https://doi.org/10.1111/acer.13031
PMid:27062046
 
61. Morley KC, Baillie A, Van Den Brink W, Chitty KE, Brady K, Back SE, et al. N-acetylcysteine in the treatment of alcohol use disorder in patients with liver disease: rationale for further research. Expert Opin Investig Drugs 2018; 27:667-675.
https://doi.org/10.1080/13543784.2018.1501471
PMid:30019966
 
62. Gipson CD, Spencer S, Stankeviciute N, Allen N, Garcia-Keller C, Kalivas PW. N-acetylcysteine inhibits nicotine relapse-associated synaptic plasticity and restores glial glutamate transport in nicotine-withdrawn animals. Drug Alcohol Depend 2015; 156:e80.
https://doi.org/10.1016/j.drugalcdep.2015.07.1134
 
63. Ramirez-Nino AM, D'Souza MS, Markou A. N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking. Psychopharmacology (Berl) 2013; 225:473-482.
https://doi.org/10.1007/s00213-012-2837-3
PMid:22903390 PMCid:PMC3697766
 
64. Schmaal L, Berk L, Hulstijn KP, Cousijn J, Wiers RW, van den Brink W. Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study. Eur Addict Res 2011; 17:211-216.
https://doi.org/10.1159/000327682
PMid:21606648
 
65. McClure EA, Baker NL, Gipson CD, Carpenter MJ, Roper AP, Froeliger BE, et al. An open-label pilot trial of N-acetylcysteine and varenicline in adult cigarette smokers. Am J Drug Alcohol Abuse 2015; 41:52-56.
https://doi.org/10.3109/00952990.2014.933839
PMid:25062287 PMCid:PMC4262740
 
66. Froeliger B, McConnell PA, Stankeviciute N, McClure EA, Kalivas PW, Gray KM. The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: a double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend 2015; 156:234-242.
https://doi.org/10.1016/j.drugalcdep.2015.09.021
PMid:26454838 PMCid:PMC4633320
 
67. Ward P, Moss HG, Brown TR, Kalivas P, Jenkins DD. N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats. Pediatr Res 2020, https://doi.org/10.1038/s41390-019-0728-6. [Epub ahead of print]
https://doi.org/10.1038/s41390-019-0728-6
 
68. Minarini A, Ferrari S, Galletti M, Giambalvo N, Perrone D, Rioli G, et al. N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects. Expert Opin Drug Metab Toxicol 2017; 13:279-292.
https://doi.org/10.1080/17425255.2017.1251580
PMid:27766914
 
69. Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 2008; 11:851-876.
https://doi.org/10.1017/S1461145707008401
PMid:18205981
 
70. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine - a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007; 7:355-359.
https://doi.org/10.1016/j.coph.2007.04.005
PMid:17602868 PMCid:PMC4540061
 
71. Berk M, Ng F, Dean O, Dodd S, Bush AI. Glutathione: a novel treatment target in psychiatry. Trends Pharmacol Sci 2008; 29:346-351.
https://doi.org/10.1016/j.tips.2008.05.001
PMid:18538422



Madde kullanım bozuklukları tedavisinde N-asetilsistein
1Bakırköy Psikiyatri Nöroloji ve Nöroşirürji Eğitim ve Araştırma Hastanesi Alkol ve Madde Bağımlılığı Araştırma, Tedavi ve Eğitim Merkezi (AMATEM), İstanbul - Türkiye
Dusunen Adam Journal of Psychiatry and Neurological Sciences 2020; 1(33): 1-7 DOI: 10.14744/DAJPNS.2019.00055

N-asetilsistein (NAC), mukolitik özellikleri ile bronkopulmoner bozukluklarda ve asetaminofen aşırı doz tedavisinde klinik etkinliği ile iyi bilinen bir ajandır. Glutamaterjik reseptörlerdeki kritik rolüne ilişkin hayvan çalışmalarından elde edilen güçlü klinik kanıtlar göz önüne alındığında; NAC, umut verici bir tedavi yaklaşımı olarak çeşitli psikiyatrik bozukluklar üzerinde araştırılmıştır. Bu yazıda, NAC'nin özellikleri ve madde kullanım bozuklukları ve diğer psikiyatrik bozukluklardaki yeri kısaca tartışılacaktır.