N-Acetylcysteine

Cysteine provision to a cell is said to be the rate-limiting step of glutathione synthesis.

N-Acetylcysteine is similar to both L-Cysteine (NAC being but an acetylated form of it) and the glutathione enzyme itself (being the direct precursor to glutathione synthesis); both L-cysteine and glutathione have also been explored for their usage as supplements.

Glutathione appears to have limited therapeutic usage due to being rapidly hydrolyzed by the intestines,^[2] and the increase in systemic glutathione seen with oral supplementation of glutathione is too small to be clinically relevant.^[2]

200-400mg of N-acetylcysteine appears to reach a peak plasma concentration of 350-400µg/L at a variable T_max of 1-2 hours.^[3]

Up to 70% of excretion of N-acetylcysteine appears to be nonrenal.^[3]

The main urinary metabolite of orally ingested N-acetylcysteine appears to be urinary sulphate.^[3]

In rodents, decreased tissue accumulation and increased urianry excretion of lead has been noted.^[4]

In humans, a reduction in serum lead has been noted.^[5]

N-Acetylcysteine may have a direct mineral chelating effect

Lead is a heavy mineral known as toxic secondary to inactivating glutathione, and the toxic effects of lead are heavily influenced by depletion of glutathione in cells;^[6] this is due to lead having a great affinity for thiol groups, and as such provision of cysteine (via NAC) is thought to alleviate the toxic effects of lead via providing more substrate and also reducing the interaction of lead with thiol groups.^[4][7]

When looking at animal studies there have been protective effects (assessed by biomarkers in serum and histopathological examination) against lead noted with NAC against the kidneys,^[4] the brain,^[7][8] and liver tissue.^[8]

NAC is thought to alleviate lead toxicity in part due to how lead has a high affinity for any thiol groups, which normally suppresses glutathoine concentrations in the body; provision of external thiol groups, which is what cysteine bears, can preserve glutathione

In workers with high levels of occupational lead exposure, supplementation of 200-800mg N-Acetylcysteine (400-800mg groups divided into two daily doses) for 12 weeks is able to reduce blood concentrations of lead by 4.72+/-7.08% (no dose dependence noted).^[5]

Erythrocytic lipofuscin appears to be decreased with NAC supplementation (200-800mg daily over 12 weeks) by around 11%^[5] which may be secondary to alleviating lead exposure (known to increase lipofuscin^[9] secondary to oxidative damage causing protein and lipid crosslinking^[10]).

Appears to be protective against lead toxicity in humans following standard oral supplemental dosages, possible related to reducing lead accumulation in the body as well as reducing the oxidative sequelae of lead exposure

N-acetylcysteine has been demonstrated to increase glutathione concentrations in neural tissue following oral administration to rodents, demonstrating that it crosses the blood brain barrier.^[11][12][13] This ability to increase neural concentrations of glutathione does not appear to exist with L-cysteine supplementation itself, as the acetylation of N-acetylcysteine hinders its metabolism^[14] and first pass metabolism is thought to limit much of the distribution of cysteine to the body.^[13]

The cystine–glutamate antiporter on astrocytes is known to mediate synaptic levels of glutmate, and takes up cystine (the dimer of cysteine) in exchange for glutamate release^[15] which includes inhibitory metabotropic glutamate receptors (known as group II) on glutamatergic nerve terminals and reduced further synaptic release of glutamate.^[16][15] It is thought that provision of additional cysteine, via N-acetylcysteine supplementation, can provide more substrate for this reaction to reduce glutaminergic stimulation.^[13]

This antiporter may also be downregulated and its function disturbed with usage of drugs, which is involved in the pathology of addiction;^[16] N-acetylcysteine may attenuate the reduction seen with drug administration^[17][18] and disrupt the transporters autoregulation.^[19]

It is thought that additional cysteine in the brain can reduce glutaminergic transmission by reducing the amount of neuronal glutamate release into the synapse (secondary to aiding its release from astrocytes)

One study on cocaine dependent individuals given 2,400mg N-acetylcysteine and measured one hour later (via MRI and MRS) noted that the elevated glutamate levels seen in cocaine dependent persons (higher than nondependent controls) was normalized to said controls.^[20]

Glutamate can be reduced in the brains of persons with high glutamate levels within an hour of oral ingestion of N-acetylcysteine

When looking at glutaminergic receptors, both oxidized and reduced glutathione is known to be a ligand for both NMDA and AMPA receptors^[21] where it seems to suppress the activity of ligands of the glutamate binding site yet enhances binding of the MK-801 agonist (on NMDA receptors).^[21][22]

Appear to modulate neurotransmission at the receptor level somewhat, as ligands of the glutamate binding sites are reduced in their ability to signal yet ligands at the MK-801 site appear to be enhanced

Vesicular dopamine release from neurons appears to be enhanced in the presence of N-acetylcysteine at low concentrations yet very high concentrations (10mM) tend to inhibit release^[23] which may be related to how glutathione can increase glutamate evoked dopamine release.^[24]

The reductions in the dopamine transporter expression in monkeys given methamphetamine appears to be attenuated with intravenous administration of N-acetylcysteine.^[25]

N-acetylcysteine has been noted in a few situations to aid symptoms of disorders associated with anxiety, such as a few case studies finding benefit with nail biting^[26] and some benefit to skin picking disorder.^[27]

In regards to irritability, two studies on autism have noted that irritability as a side-effect of autism appears to be significantly reduced relative to placebo when taken alongside standard medical therapy in the dosage range of 900-2,700mg daily.^[28][29]

Due to the usage of N-acetylcysteine in addiction^[13] and similarities in some brain regions between addiction and obsessive compulsive disorder (nuclear accumbens and anterior cingulate^[30][31]) N-acetylcysteine is also investigated for its usage in treating OCD.

Persons with OCD have been noted to have increased cerebral lipid peroxidation^[32][33] associated with reduced Vitamin E concentrations in the brain^[34] and mostly decreased antioxidant enzymes (aside from an increase in superoxide dismutase),^[35] and these oxidative changes appear to be correlated with symptom severity.^[32][35]

Due to similarities in addiction (where NAC is proven effective) and OCD, plus the prooxidative effects in OCD, supplemental NAC is thought to be therapeutic

In a mouse model of OCD (marble burying behaviour) it was noted that an intraperitoneal infusion of N-acetylcysteine at 150mg/kg was able to suppress marble burying behaviour, whereas 50-100mg/kg was ineffective and the antioxidant Vitamin E was ineffective at all tested doses (10-100mg/kg).^[36] When NAC was paired with subeffective doses of the serotonin reuptake inhibitor fluvoxamine, there was no additive effect.^[36]

Positive effects have been noted in animal models with infusions of N-acetylcysteine, and these benefits do not appear to be replicated by another reference antioxidant

One study in drug-dependent persons (cocaine) noted that these persons had elevated glutamate levels in the brain, and that this elevated of glutamate was correlated with overall impulsivity;^[20] N-acetylcysteine reduced brain glutamate, but impulsivity was not measured.^[20]

Impulsivity appears to be correlated with high cerebral concentrations of glutamate

Initially, a case study was conducted with N-acetylcysteine on a patient with OCD who was resistant to the standard therapy of serotonin reuptake inhibitors (SRIs; resistance occurring in up to 20% of patients^[37][13]), and following supplementation of up to 3,000mg daily he become responsive.^[38] This was later followed up with a trial in only persons with OCD failing to respond to SRIs, where 2,400mg NAC daily for twelve weeks increased the response rate (defined as more than a 35% improvement on the Y-BOCS rating scale) from 15% up to 52.6%.^[39]

Preliminary evidence suggests that N-acetylcysteine can augment SRI therapy for the treatment of OCD, but at this moment in time it is not known if NAC can be effective on its own in humans (suggesting adjuvant therapy rather than monotherapy)

Another disorder somewhat related to OCD in symptoms and treatment (due to being an impulse control disorder) is trichotillomania, the urge to rip out one's hair and consume it;^[40] it may be heterogeneous in nature, with some subsets having symptoms and pathology more similar to OCD and some more similar to addiction^[41] and thus N-acetylcysteine (with some efficacy in both) is sought out as a treatment option.^[13]

There are case studies noting benefit with 1,800mg daily^[42] and one trial using 1,200mg for six weeks followed by a doubling of the dose (2,400mg) in persons with trichotillomania noted that supplementation was more effective than placebo at reducing overall symptoms (31-45% reduction from baseline, depending on the rating scale used) as well as some comorbidities like anxiety (31% reduction) and depression (34% reduction).^[43]

The condition known as trichotillomania has some preliminary evidence for treatment with N-acetylcysteine, which may be due to NAC being effectve in addiction and OCD (two conditions that seem to have similar pathology to trichotillomania)

An open label study using oral supplementation of 2,400mg N-acetylcystiene (two divided doses of 1,200mg) for four weeks in youth who self-reported addiction to marijuana have reported improvements in addictive symptoms (assessed via the Marijuana Craving Questionnaire^[44]) on the parameters of compulsivity, emotionality, and puposefulness but not expectancy.^[45] Self reported 'hits' of marijuana (after potency adjusting) was reduced 25% relative to baseline (effects seen after two weeks and maintaining thereforth) although urinary cannabinoids were not significantly different at any time.^[45]

Preliminary evidence suggests that N-acetylcysteine supplementation can provide a very mild boost in an intentional desire to reduce marijuana intake, thought to be related to the anti-addictive effects

N-acetylcysteine has been tested in cocaine dependent individuals who are abstaining (withdrawal symptoms assessed by Cocaine Selective Severity Assessment^[46]) given 2,400mg over the course of one day (600mg every six hours) noted that two hours after the first dose (peak serum NAC^[3]) that cravings were not improved at two hours but were lower at fourteen hours, persisting for 24 hours after the last dose.^[47]

N-acetylcystiene may acutely reduce cravings for cocaine during withdrawal

It appears that nicotine self-administration to rats over 21 days is able to reduce the expression of GLT-1 and the cystine–glutamate antiporter in the nuclear accumabens (prefrontal cortex and amygdala unaffected).^[48]

In subjects addicted to nicotine given 2,400mg N-acetylcysteine for four weeks relative to placebo, supplementation tended to reduce the frequency of cigarettes smoked after two weeks of supplementation.^[48]

Nicotine administration is able to reduce levels of the cystine–glutamate antiporter and GLT-1, and supplementation of N-acetylcysteine in humans appears to treat nicotine addiction (reducing cigarettes smoked without requiring an intentional desire to quit smoking)

400-800mg/kg N-acetylcysteine daily for 12 weeks is able to increase red blood cell concentrations of glutathione by 5-6% relative to control alongside an increase in activity of G6PD by 17% (all groups pooled).^[5]

Supplementation of N-acetylcysteine for six days prior to an intermittent sprint test conducted thrice a day, performance on the test conducted the subsequent day was preserved although the isokinetic force production test was not influenced;^[49] this study is duplicated in Pubmed.^[50]

Administration of N-Acetylcysteine at 150mg/kg (injections) prior to repeated maximal contractions of the calf is unable to influence power output in the rested state yet increased it by 15% relative to fatigued controls, suggesting an anti-fatigue effect; this was noted when fatigue was induced by a lower electrical setting (10Hz) but not a higher (40Hz) one.^[1]

A study assessing intermittent sprint performence with N-acetylcysteine supplementation that did note benefits failed to also find benefits to pre or post exercise isokinetic dynamometry.^[50]

Although there is technically an antifatigue effect associated with N-Acetylcysteine, it require a very large dose as well as injections thereof; even then the antifatigue effect is small in magnitude

The main mechanism of action for N-acetylcysteine is being substrate for glutathione.

Glutathione (GSH) sequesters reactive oxygen and nitrogen species in a process that reduces glutathione (into GSSG), and then GSSG is restored to GSH via the enzyme glutathione S-transferase (GST).^[51] This antioxidative cycle continues until glutathione is degraded via γ-glutamyltranspeptidase into free glutamate and a cysteine-glycine dipeptide, and eventually the free amino acids can be used to reform glutathione first by glutamate-cysteine ligase (to make the dipeptide again) and then by glutathione synthetase (to make glutathione);^[52] the first step is rate-limiting, and it is rate-limiting because of L-cysteine availability.

Glutathione participates in a cycle to sequester oxygen and nitrogen radicals, and eventually after enough cycles it will get degraded. It can be reformed easily enough, but the limiting factor in determining how much glutathione is made is the availability of L-cysteine; N-acetylcysteine supplementation merely provides L-cysteine to accelerate resynthesis

Superoxide (O₂^-) is an anion and free radical that is normally sequestered by the antioxidant enzyme known as superoxide dismutase (SOD).

N-Acetylcysteine per se,^[53] as well as both cysteine and glutathione,^[54][55][56] have relatively poor rate constants in vitro for sequestering O₂^-; N-acetylcysteine being even a poorer antioxidant in this regard than glutathione itself (also quite ineffective).^[53]

Against superoxide radicals in particular, N-acetylcysteine does not appear to be overly protective directly nor through producing glutathione

Hydrogen peroxide (H₂O₂) is a reactive oxygen species that can be generated in the body.

It appears to react slowly with NAC in vitro directly.^[57]

N-Acetylcysteine does not appear to hold much promise as a direct free radical scavenger against hydrogen peroxide

Hydroxyl radicals (OH^-) are relatively well scavenged by thiol antioxidants like glutathione and N-acetylcysteine.^[58]

Hydroxyl radicals (OH^-) are well scavenged directly and effectively by N-Acetylcysteine as well as indirectly via production of glutathoine

Hypochlorous Acid (HOCl) is an oxidant in the human body derived from myeloperoxidase (MPO) after combining a chloride anion with hydrogen peroxide, an enzyme mostly expressed in neutrophils (a type of immune cell) during oxidative burst.^[59]

N-acetylcysteine appears to be a relatively powerful scavenger of HOCl in vitro.^[58]

N-Acetylcysteine appears to sequester hypochlorous acid quite effectively

Supplementation of 200-800mg N-acetylcysteine for 12 weeks in workers exposed to lead is associated with a nonsignificant decrease in glutathoine-S-transferase activity in leukocytes.^[5]

Supplementation of 600mg of N-acetylcysteine for 10 weeks in persons with stable COPD has resulted in a decrease in eosinophil cationic protein (ECP), which is released when eosinophils are degranulated.^[60]

In subjects with helicobacter pylori infection who also experienced dyspepsia (heartburn), the addition of 600mg N-acetylcysteine to standard therapy was noted to increase the eradication rate slightly from 60.7% to 70%.^[61]

N-acetylcysteine was first reported to alleviate paracetamol toxicity in 1978 when given at 7g orally every 216 minutes for 17 doses.^[62]

It has been hypothesized that N-acetylcysteine (NAC) could inhibit renal carbonic anhydrase (CA) in humans^[63] which has been noted in vitro with bovine CA II at 1mM of NAC, cysteine, and glutathione itself^[63] thought to be related to the thiol groups which are known to interact with CA enzymes.^[64][65] The known CA inhibitor acetazolamide is known to increase urinary nitrate and nitrite (collectively referred to as NOx) concentrations due to CA inhibition.^[66][67]

It is thought CA increases resorption of NAC from the proximal tubules of the kidneys by forcing a reaction with carbon dioxide to form nitrito carbonate which is thought to be the form which is resorbed from the kidneys.^[67] It is not certain if short-term changes in urinary NOx is sufficient to predict nitric oxide (NO) activity^[66] as while a loss of urinary NOx is thought to be detrimental to systemic microcirculation chronically, other CA inhibitors seem to increase vasodilation in the kidneys^[68] (although by a mechanism not related to CA^[69]).

In a pilot study involving eight otherwise healthy subjects taking 600mg of NAC who were assessed over the course of five hours, it appeared that ingestion of NAC increased urinary NOx concentrations over the course of the study and appeared to trend to normalize after six hours.^[63] Urinary pH appeared to increase along a similar timeframe and did not influence urinary prostaglandins (PGE₂ and PGF_2α) significantly.^[63] This same study assessed the effects of intravenous NAC in cardiac patients found an increase in urinary nitrite at 3 hours with no other changes in prostaglandins or nitrate and no differences between NAC and placebo after 24 hours.^[63]

Consumption of NAC by otherwise healthy subjects seems to acutely increase levels of nitrate and nitrite (NOx) found in the urine, an effect which is no longer present after six hours. It is currently thought to be due to carbonic anhydrase inhibition (the enzyme normally works to absorb NOx back from the kidneys into circulation) and practical relevance uncertain at this point

In rats exposed to high levels of lead for eight weeks, supplementation of N-Acetylcysteine (intraperitoneal injections of 100mg/kg) is able to reduce lead levels in serum and tissues resulting in less damage to the kidneys.^[4]

In mice given 10mg/mL N-acetylcysteine (to get a serum level of 16.2+/-4.3μM^[70] comparable to a peak concentrations in a human study using thrice daily dosing of 600mg^[71]) over three weeks increased pulmonary pressure to a degree comparable to 10% normobaric hypoxic conditions and did not extend to the RV/LV+S ratio which was unaffected by NAC.^[70] It appeared that NAC was converted into S-nitoso-N-acetylcysteine (SNOAC) in deoxygenated red blood cells which was dependent on the eNOS enzyme^[70] which is known to produce S-nitrosothiol groups inherently as a byproduct of nitric oxide synthesis^[72] that then react with amino acids.^[73] SNOAC is thought to participate in NO transfer between target genes such as pVHL C162 and HIF-1α^[74][75][70] which are involved in vascular remodelling.

One mouse study has suggested that via the eNOS enzyme, NAC can be converted into S-nitroso-N-acetylcysteine which seems to promote an increase in pulmonary hypertension via interacting with some enzymes. While no evidence currently exists assessing humans this is thought to occur at concentrations reasonable close to pharmacological doses of NAC (for cognitive effects)

N-Acetylcystiene appears to have mucolytic properties in the sputum of persons with COPD by reducing immune cell adhesion when taken as a daily preventative over ten months, but it appeared ineffective over eight weeks.^[76]

Acne vulgaris is a chronic skin disease characterized by follicular hyperkeratinization,hormonally-mediated sebum overproduction, and chronic inflammation of the pilosebaceous unit.^[77] It is believed that the damaging of lipids in the skin via free radicals is responsible for the inflammatory component of acne. Recent research has found that those who suffer from acne are unable to mitigate this damage efficiently because their antioxidant defense system is overwhelmed. ^[77]

Thus, based on this research, new studies have aimed to look at the effect of antioxidant supplementation on lesion counts.

A single-blind placebo controlled study that aimed to compare Silymarin, N-acetylcysteine, and Selenium to placebo in reducing lesion counts, found that after eight weeks of supplementation, there was a notable reduction in lesion count in all of the experimental groups, however, the reduction in lesion count was only statistically significant in the N-acetylcysteine and Silymarin groups. The N-acetylcysteine group saw a 50% reduction in total lesion counts after supplementing 1200 mg/day orally for 8 weeks. ^[78]

N-acetylcysteine may reduce lesion counts when supplemented for at least 8 weeks.

Chronic obstructive pulmonary disease (COPD) is a limitation of airflow that is not fully reversible and tends to be associated with abnormal inflammatory and oxidative responses to stressors, particularly in lung tissue.^[79][80] Due to the pathology being both oxidative and inflammatory (and intertwined^[81]), N-acetylcysteine has been investigated for its usage.^[82]

In persons with stable COPD, 600mg N-acetylcysteine twice daily was associated with less hydrogen peroxide (H₂O₂) in the exhaled air condensate after 15 days (22%), a month (29%), and two months (35%) relative to baseline^[83] suggesting less oxidative stress in lung tissue particularly from immune cells such as activated neutrophils or macrophages;^[84][85] placebo had steady increases in H₂O₂ and lung function was not assessed.^[83] This reduction in hydrogen peroxide may be related to an increase in glutathione peroxidase activity.

Ten months of NAC supplemented at 600mg daily is able to reduce adhesion of neutrophils (PMNs) whereas eight weeks of supplementation was ineffective; conversely, corticosteroids had the opposite effect since they acutely suppressed adhesion by 31% after eight weeks but eventually increased adhesion over ten months.^[76] This reduced adhesion may be directly related to an increase in glutathione, since NAC has been noted to reduce cellular adhesion factor ICAM-1 and IL-8 at 600mg daily^[60] and a decrease in these two factors is negatively correlated with the rise in glutathione peroxidase activity.^[60]

Short term usage of NAC is able to cause changes in breath biomarkers that suggests a suppression of oxidative from the immune system in lung tissue, which is critical to the pathology and symptoms of COPD and suggests a therapeutic usage

When assessing lung function, 600mg N-acetylcysteine twice daily over the course of three years (the BRONCUS study) failed to significantly reduce the deterioration rate of lung function overall compared to placebo.^[86]

The BRONCUS study suggested a protective effect in the patients not on corticosteroids (suggesting that adjuvant therapy was not additionally beneficial).^[86]

When looking at stable COPD symptoms, there may be some beneficial effects with long term usage but these have not been seen alongside corticosteroid usage (suggesting that the benefits from corticosteroids are similar to those from N-acetylcysteine and a combination is no more beneficial than corticosteroids alone)

In persons with exacerbated COPD given 600mg N-acetylcysteine daily for one week (concurrent with 40mg prednisone and 5mg salbutamol), there was no further influence of NAC on lung function or symptoms of breathlessness relative to placebo.^[87]

When looking at COPD exacerbations, NAC has been noted to be ineffective at treating the exacerbations

Autism is known to be associated with higher basal oxidation rates in the brain,^[88] blood,^[89][90] and urine.^[91] N-acetylcysteine in particular is thought to be therapeutic for persons with autism since this state is characterized by lower glutathione levels in the cerebellum (34.2%) and temporal cortex (44.6%) relative to persons without autism^[92] and genetic alterations in the glutathione pathway are involved in autism.^[93][94]

Furthermore and unrelated to the oxidation balance, excess glutamate is thought to contribute to the pathology of autism to a minor degree^[95] (and glutamate antagonists aid symptoms of autism in animals^[96][97]) and supplemental N-acetylcysteine is known to reduce glutamate when it is elevated (a mechanism underlying some of its anti-addictive properties^[20]).

N-acetylcysteine is thought to benefit symtoms of autism in part due to possibly having an antioxidant effect, but it is also thought to reduce excessive glutamate levels in the brain; both the oxidation and glutamate are abnormally elevated in persons with autism relative to normal controls

Supplemental N-acetylcysteine showed promise in one case study^[98] and the first pilot study to investigate this claim (double blind) used 900mg of N-acetylcysteine daily for four weeks before doubling the dose for another four weeks (1,800mg) and increasing it further (2,700mg) over the course of 12 weeks;^[29] it was found that, in subjects with autism and stable medication, that N-acetylcysteine was able to reduce irritability (As assessed by the Aberrant Behavior Checklist^[99]) after 12 weeks but failed to influence any other parameter on the ABC rating scale or any parameter on either the SRS or RBS scales.^[29] This was replicated later on subjects with autism on stable risperidone therapy, where 1,200mg daily for eight weeks reduced irritability on the ABC scale and no other parameter.^[28]

Preliminary evidence suggests that N-acetylcysteine can reduce irritability in persons with autism and that it is well tolerated alongside medical therapy, but no other parameter or symptom of autism appears to be influenced aside from irritability

Supplementation of N-acetylcysteine has once been noted to aid the ocular symptoms of Sjögren's syndrome by reducing ocular irritability and dryness, with a reduction in halitosis and thirst also noted.^[100]

It has been reported that N-acetylcysteine may bind highly to charcoal in the intestines, with charcoal being claimed to bind up to 96% of N-acetylcysteine^[3] and trials looking at the coingestion of the two supplements noting that 100g of activated charcoal reduced N-acetylcysteine (140mg/kg) absorption by 39% and reduced peak plasma levels 26%.^[101]

This is not fully confirmed, as there is some evidence saying that 60g of activated charcoal does not influence the kinetics of 140mg/kg N-acetylcysteine.^[102]

It is possible that N-acetylcysteine is bound to activated charcoal in the intestines (activated charcoal being used to bind to toxins and excrete them from the body), suggesting coadministration should not be used

In regards to oxidative stress, usually assessed by glutathione content and activity, N-acetylcysteine (NAC) supplementation to rats alongside alcohol seems to suppress the alcohol-induced decrease in glutathione acutely,^[103] over four weeks,^[104] and over half a years time.^[105] While the liver is most commonly assessed, this appears to also influence serum and brain tissue.^[106] In rats fed alcohol without NAC, who are then given NAC alongside continued alcohol consumption, there appears to be a protective effect noted after 15 days as assessed by reduced oxidative stress in the liver although there was more protection when NAC was ingested and alcohol discontinued.^[107]

Acutely and when comparing times of administration in mice, administration of NAC 30 minutes prior to ethanol exposure appears to exert a protective effect whereas administration 4 hours after ethanol aggravated damage.^[103] This study also noted a reduction in histological damage of the mice pretreated with NAC.^[103]

Pretreatment (30 minutes) of NAC in rodents given alcohol appears to reduce liver damage while giving NAC after alcohol (four hours) may aggravate the damage induced by alcohol

On other parameters, the alcohol induced stimulation of mitochondrial biogenesis (assessed by PGC-1α expression) seems to be suppressed with 1.7g/kg NAC in rats^[105] while the structural integrity and function of mitochondria seems to be impaired by ethanol regardless of NAC coadministration.^[105]

One study assessing mitochondrial structure of liver tissue in alcoholic rodents found that administration of NAC seemed to prevent the hormetic response to alcohol while not necessarily preventing other forms of damage to mitochondria; this observation occurred alongside the standard reduction in oxidative damage