I stumbled upon this first article pointing out the various possible benefits of the supplement, N-acetylcysteine (NAC), because it reduces inflammation. This made me curious, so I checked for studies of it in PubMed (2 of which are annotated later in this post) and found the article was correct in its assertions.
NAC is not only the treatment for mucus build-up in cystic fibrosis, but also acetaminophen overdose, perhaps to reduce the kidney toxicity of contrast dye (though that doesn’t seem to be holding up), in interstitial lung disease, and investigationally in reduction of noise-induced hearing loss, lessening the destruction of pancreatic beta cells, curing a hangover, and decreasing symptoms of the flu.
As usual it all goes back to glutamate, the excitatory neurotransmitter of doom. In short, having too much glutamate around is to your neurons rather like whipping your horse to go and go and go until you kill it
NAC seems to be able to get into some tricky areas of the brain and do some amazing management of glutamate.
Over the past few years, a number of intriguing studies have come out using NAC alone or as adjunct treatment for some difficult psychiatric conditions. Some of these were decent multicenter randomized controlled trials. The real deal.
Bipolar Depression (link is external) (another very difficult and disabling condition that doesn’t respond particularly well to therapy or medicine, and the condition I’ve seen respond most favorably to NAC in my own practice.
The studies vary between 2000-4800mg daily of the capsules
Many of the studies were as long as 6 months, which is a lifetime for randomized controlled clinical trials, and all of the studies had positive effects.
Why would a precursor for the master antioxidant have anything to do with glutamate in the brain?
Translating the sciencespeak: NAC helps excess (and toxic) glutamate stop being at the wrong place at the wrong time. It helps us put that brain out to pasture for some rest and recovery.
What are the downsides of NAC?
I can think of two problems that might be biggies – first off, NAC is a mucolytic that thins mucus by cutting disulfide bonds.
cutting disulfide bridges within the body is what that inflammatory baddie homocysteine (link is external) is supposed to do, leading to crispy collagen and inelastic elastin in the arteries (which would possibly first show up as high blood pressure)
But it does seem to have the potential to replicate, perhaps with some downsides, the natural brain glutamate situation of a lower-stress life with plenty of appropriate minerals and micronutrients
Author: Emily Deans, M.D., is a psychiatrist with a practice in Massachusetts.
Feeling Better: A 6-Week Mind-Body Program to Ease Your Chronic Symptoms (link is external)
Dr. Emily Deans’ Website
Below are two PubMed articles going into the details of how NAC works:
Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation.
This sounds like a list of disorders that would cause pain or fatigue. If NAC can improve any of these, it sounds very promising and an adjunctive therapy for our pain and fatigue – so intertwined that lessening one will improve the other as well.
Because it’s so safe I’m giving it try and takeing2,400mg daily for 25 days (start 3/20) to see if I can detect any change.
In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer’s disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy
Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis.
Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.
Over the past decade, clinical reports have documented the outcome of treatment with NAC for a multitude of psychiatric and neurological disorders, including schizophrenia, bipolar disorder, skin picking, trichotillomania, obsessive-compulsive disorder, autism and addiction to nicotine, cannabis, cocaine, methamphetamine, gambling (Berk et al., 2013); as well as epilepsy, amyotrophic lateral sclerosis, neuropathy (Bavarsad Shahripour et al., 2014) and traumatic brain injury (Hoffer et al., 2013).
Given the growing number of studies on its use as a treatment intervention in psychiatry and neurology, along with a very good safety and tolerability profile, we aimed to systematically review the literature and critically evaluate the level of evidence concerning the use of NAC for treating psychiatric and neurological disorders
We particularly concentrate on the evidence for any adverse effects during the use of NAC in controlled clinical trials to assess whether NAC is safe for the treatment of psychiatric and neurological disorders
3.1. Evidence of effectiveness of NAC in the treatment of psychiatric and neurological disorders
NAC has been used in several clinical trials examining various addictions, including cannabis, cocaine, methamphetamine, nicotine, and pathological gambling (Table 4).
220.127.116.11. Addiction overall
Overall, the evidence for NAC as a treatment for addiction is rather limited.
Although several controlled studies were positive for cocaine, the largest and most meticulously performed study was only positive for a small subset of participants that were abstinent at the beginning of the trial.
There is some evidence for cannabis but this is limited due to inconsistent findings. Other addictions have limited evidence that NAC is a useful treatment.
However, many of the studies conducted were rather preliminary in nature and hence making recommendations for or against the use of NAC in addiction is somewhat preliminary.
3.1.3. Amyotrophic lateral sclerosis
100% of the controlled studies and 75% of overall studies were negative, NAC does not seem to be a recommended treatment option for increasing survival in ALS at this time. (Table 6). [this was apparently a persistent rumor]
As there is only one case report, hence it is difficult to make any recommendations for NAC treatment for anxiety at this point
3.1.7. Bipolar disorder
Several controlled and uncontrolled studies have investigated NAC in treating and preventing symptoms during the maintenance phase of BPAD (Table 10).
In the first multicenter DBPC trial (N = 75; LOE 1b), when compared to placebo, the NAC group demonstrated a significant improvement on the Montgomery–Asberg Depression Scale (MADRS), Bipolar Depression Rating Scale (BDRS) and nine out of 12 secondary outcome measures in individuals in the maintenance phase of BPAD . However, the study failed to show any significant differences between the two groups in the frequency of or latency to new episodes of either depression or mania.
N-acetylcysteine (NAC) has been used as an antioxidant precursor to glutathione (γ-glutamylcysteinylglycine; GSH) in the treatment of paracetamol overdose for more than 30 years
As more is understood about the actions of NAC, the clinical applications have also broadened. N-acetylcysteine is now widely used as a mucolytic and in the treatment of HIV, and it has reported efficacy in chronic obstructive pulmonary disease and contrast-induced nephropathy
The present review will explore the role of NAC in the treatment of psychiatric conditions and the possible mechanisms of benefit for these disorders.
Role in oxidative homeostasis
The use of NAC in restoring GSH levels is well established (Fig. 1). Glutathione is the primary endogenous antioxidant. Glutathione neutralizes reactive oxygen and nitrogen species from the cell through both direct and indirect scavenging. As the most abundant and ubiquitous antioxidant, it is responsible for maintaining the oxidative balance in the cell
Glial cells contain much higher levels of GSH than neuronal cells and support neuronal GSH production. Astrocytes release GSH into the extracellular space
Oral NAC administration results in increased plasma cysteine levels, ultimately leading to increases in plasma GSH.N-acetylcysteine has been shown to successfully penetrate the blood–brain barrier and raise brain GSH levels in animal models, which may be relevant to psychiatry, where alterations in brain GSH and other redox pathways have been shown.
Interaction with inflammatory mediators
Alterations in pro- and anti-inflammatory cytokines, including interleukin (IL)-6, IL-1β and tumour necrosis factor (TNF)–α, have been reported in populations with depression, and to a lesser extent, bipolar disorder and schizophrenia.
These inflammatory cytokines are potential contributors to the underlying pathophysiology of these disorders.
N-acetylcysteine has been shown to have anti-inflammatory properties (Fig. 1) that are linked to oxidative pathways, which may provide another potential mechanism of action in the benefits of NAC in psychiatry.
increased TNF-α and IL-1β levels were reduced following NAC treatment in rat models of both traumatic brain injury and focal cerebral ischemia
The reductions in inflammatory cytokines by NAC treatment may be a potential mechanism by which NAC modulates the symptoms of psychiatric disorders.
This may be directly associated with the inflammatory pathway, or working through oxidative processes associated with inflammation. Further research is required to elucidate these mechanisms.
Effects on neurotransmission
Cysteine assists in the regulation of neuronal intra- and extracellular exchange of glutamate through the cystine–glutamate antiporter. Whereas this antiporter is ubiquitous throughout all cell types, in the brain it is preferentially located on glial cells.
reduce the synaptic release of glutamate.
Use in psychiatry
There is a growing body of literature exploring the use of NAC in the treatment of psychiatric illness.
There is provisional evidence of the potential benefit of NAC in a wide range of disorders. Many of these disorders have limited treatment options or suboptimal outcomes with current treatments.
The present review outlines the clinical use of NAC in psychiatry (summary in Table 1).
Alterations in oxidative metabolism have also been described in populations with bipolar disorder.
- Changes in antioxidant levels,
- increased markers of lipid peroxidation and
- protein carbonylation
have all been reported. These changes appear to be related to state, particularly in mania, where increased oxidative stress seems to be apparent.
after discontinuation of NAC treatment, there was a convergence with scores between the NAC and placebo groups, showing a loss of benefit following washout.
The apparent lack of specificity of NAC in initial studies is intriguing and suggests that it may be targeting pathways that are common across disorders; oxidative stress appears to be a fairly nonspecific finding in a range of psychopathologies, and dysregulation of glutamate, inflammatory pathways and DA are similarly widely reported.
Whereas the tolerability profile of NAC appears benign, it needs to be stressed that there is no extensive evidence base with longer-term use
Similarly, the modulation of inflammatory pathways may also play a role in the benefits seen following NAC treatment.
Pain wasn’t studied here, but any reduction of inflammation would be helpful for chronic pain.
The role of inflammation in depression has received the greatest attention; however, inflammatory pathways are implicated in the etiology of other disorders, such as schizophrenia.
So, the depression in chronic pain patients could definitely be related to inflammation, which make the “catastrophizing” theory even more suspect.
Overall this unlikely therapeutic tool is implicating novel pathways as viable therapeutic targets. This opens the way for the development of other rational, hypothesis-based therapies. That NAC appears safe, tolerable and affordable and is readily available adds to its interest.
Among its known mechanisms of action, NAC-induced brain glutathione (GSH) replenishment is the most studied.
Glutathione is the primary endogenous antioxidant of the cell, and has the ability to scavenge oxygen and nitrogen species, therefore maintaining the oxidative balance.
In addition to restoring GSH levels, NAC modulates inflammation by exerting anti-inflammatory actions, and presents direct effects on glutamatergic and dopaminergic neurotransmission.
The inflammatory-modulating effects of NAC may be important for its mood stabilizing efficacy, mainly due to the recently described relevance of systemic inflammation in bipolar disorder pathophysiology
More specifically, its usefulness on depressive episodes may be linked to innovative mechanisms of action, which we speculate to be taking part throughout its treatment. Among them, modulation of cellular signaling pathways by NAC may ultimately increase mitochondrial resilience, as supported below.
Chronic stress has been thought to play a key role in the pathophysiology of bipolar disorder [and pain!]
The effects of stress are mediated mainly through glucocorticoids, which exert several body changes commonly known as ‘stress response’.
Dysregulation of glucocorticoids is associated with cognitive impairments and depressive disorder, supporting the notion that stress response may be impaired in affective and mood disorders
More recently, adult hippocampal neurogenesis has been found to buffer stress responses and depressive behavior (Snyder et al.). In addition, inflammation downregulates neurogenesis, mainly through modulation of mitochondrial viability (Voloboueva et al.). Thus, neuroprotective properties of NAC may be related to its neurogenesis-inducing ability, which is likely related to mitochondria-protective mechanisms.
Of note, mitochondrial dysfunction has been described as one of the pathways underlying neuroprogression in bipolar disorder (Berk et al.). Further studies are warranted in light of NAC effects on treating depressive episodes in bipolar disorder. As far as it seems, NAC may be the first pharmacological intervention that increases mitochondrial resilience and prevents allostatic load in psychiatry (Kapczinski et al.).