NAC is a N-Acetyl derivative of L-Cysteine, which is a semi-essential amino acid created in the body and present in eggs, dairy, meat and seeds (Witschi et al., 1992). | Source

Sometimes, A Little Medicine Is Needed

Many of us find ourselves unhappy and rumination-prone despite adhering to a lifestyle that should promote good mental health. We wonder whether we are naturally imbalanced, destined to always be subject to mood fluctuations, limerence and coping mechanisms like overeating.

The good news is that the brain possesses ‘set points’ and plasticity, and always strives to return to synaptic, neurochemical and emotional equilibrium (Denève et al., 2017). N-Acetyl Cysteine (NAC) is one of the few supplements that enhances these natural stabilizing mechanisms. In this article, I will discuss its ability to heal you from addiction, compulsive behavior and rumination, which are the issues that underpin OCD, limerence and food addiction.

The efficacy of NAC lies in its multifaceted mode of action. It works selectively to normalize the activity of several neurotransmitters in addition to reversing inflammation and oxidative damage.

Anti-depressants (SSRIs) are notoriously ineffective at treating the aforementioned conditions, because the serotonergic hypothesis is an inaccurate and oversimplified model of psychiatric distress. Serotonin is only one of many neurotransmitters implicated in mental illness; unless a). aberrant glutamate and dopamine activity, b). free radicals and c). inflammation are also dealt with, you will remain in a state of unhappiness.

Contents 1. NAC’s effects: a). anti-inflammatory, b). antioxidant, c). neurotransmitter activity 2. The form of NAC that I take and trust 3. How does NAC actually make you feel? 4. Safety, dosing & side effects 5. A Darwinistic look at supplements: are they natural?

A lovely reader has had great success with this NAC, and gave me permission to share her story with the rest of you.

1. NAC Heals The Inflamed Brain

The body strives to maintain a healthy immune response, but the conditions of modern living render us all prone to chronic inflammation. The brain was once considered an ‘immune-privileged’ organ, but it is now known that systemic (bodily) inflammation wreaks havoc on mood/cognition (Omara et al., 1997).

In fact, sustained high levels of the pro-inflammatory mediators known as cytokines accompany all forms of psychiatric distress. Though beyond the scope of this article, inflammation appears to be particularly implicated in major depression and potentially causal, as reducing it often clears symptoms (Slavich and Irwin, 2014). I suggest you read up on the inflammatory model of mental illness, as it really contextualizes the importance of a nourishing diet and sustainable lifestyle in keeping your inflammatory burden low.

An effective anti-inflammatory that can cross the blood-brain barrier, NAC halts the proliferation of cytokines including TNF-α, interleukin-6 and interleukin-1β. This takes the brain out of ‘disease mode’ and restores functionality to emotional regulation centers, allowing you to break free from states of impulsivity and pain (Lasram et al., 2014). Whether you fantasize about an ex that you want to get over, pick your skin (trichotillomania) or are addicted to sugar, NAC will make your reward of choice less salient and attractive and redirect you towards normal, goal-oriented thinking.

2. Antioxidant Effects of NAC

In addition to possessing potent antioxidant properties itself and scavenging for harmful free radicals, NAC increases cellular concentrations of glutathione. Known as the brain and body’s ‘master antioxidant’, glutathione is the key player in protecting cells from oxidative damage. A compromised glutathione system is seen in bipolar disorder, OCD and depression, as well as in almost all neurodegenerative and autoimmune diseases.

Interestingly, most dietary protocols for mental health promote glutathione biosynthesis; leafy greens, garlic, eggs, asparagus, avocados and parsley are some examples of sulfur-rich foods that trigger its production. Since it is metabolized in the liver and gut, administering glutathione orally is not sufficient in enhancing the survival of neurons. NAC, on the other hand, reaches the blood-brain barrier and enters neural cells, where it is rapidly converted into L-cysteine (the amino acid). L-cysteine itself is the precursor of glutathione (Bavarsad et al., 2014).

3. NAC Regulates Neurotransmitter Systems

I will not delve too deeply into neurobiology in this article, but much of NAC’s efficacy lies in its ability to flexibly modulate glutamate and dopamine pathways (activity-dependent plasticity). While dopamine overactivity is typically blamed for addictive tendencies, cortico-striatal glutamate transmission is arguably the key player in the formation of addiction pathways and intrusive thoughts that are hard to extinguish.

It all comes down to to the nuanced ways in which the two neurotransmitter systems interact with and modulate each other. Glutamate transmission from the nucleus accumbens onto dopamine-producing cells in the ventral tegmental area can be conceptualized as the neural correlate of addiction and obsession.

Through potentiation of the cysteine-glutamate transporter in the nucleus accumbens, NAC downregulates any excessive glutamate release and ‘unwires’ the brain of deeply-rooted addiction pathways. NAC has proved capable of reducing cocaine users’ desire to take the drug, in addition to silencing their cocaine-related thoughts (LaRowe et al., 2007). Unsurprisingly, it can also cure all other forms of obsessionality, including gambling, OCD behaviors, unrequited love obsession and compulsive overeating (Lafleur et al., 2006).

By increasing the expression of a glial transporter of glutamate (GLT-1) in the same reward-associated brain region, NAC promotes efficient uptake of glutamate by the glia. Deficiency in this glial activity (and a consequent excess of glutamate) is associated with depression, bipolar disorder, OCD, cocaine addiction and anxiety. In fact, NAC’s enhancement of GLT-1 activity may well be its principal mode of action in extinguishing repetitive, ‘loop’ behaviors (Gipson, 2016).

fMRI of the brain in addiction: activity is heightened in the reward circuitry and decreased in the cortex. | Source

Does NAC Damage Normal Motivation, Then?

In short, and paradoxically, no; NAC is very effective at silencing harmful hedonic drive, yet does not interfere with your pursuit of healthy rewards. Thanks to its selective modulatory activity, it only reverses the dopaminergic and glutamatergic alterations associated with addiction pathophysiology and does not impinge on normal neurotransmitter activity.

In contrast, anti-psychotics can lessen impulsivity and addictive behavior but often render you apathetic, demotivated and less sociable. This is because they are generalized dopamine antagonists, acting to block dopamine binding to D 2 /D 3 receptors in various parts of the brain beyond just the reward center. Tangentially, SSRIs can mask OCD symptoms but come with a multitude of troublesome side effects, dulling creativity and social drive.

Despite silencing thought-loops and lessening impulsive cravings, NAC is not associated with a decrease in productivity or cognition. On the contrary, OCD sufferers who find relief from fixations through the compound typically experience an increase in mental acuity and mood, due to its ability to reverse inflammatory and oxidative damage. In line with this, NAC markedly reduces the desire to binge-eat palatable and addictive foods, yet does not reduce healthy food intake or appetite (Hurley et al., 2016).

NAC: Relief From My Neurotic Mind

The product below is the most affordable high-quality form of NAC I have ever tried, and it is the one I recommend to all of my neuroscientist friends (who are equally big fans!).

I used to be prone to feelings of emptiness, but now find I am calmer, more focused and experience a significantly decreased desire to eat beyond my caloric needs. I have a great appetite and enjoy a paleo-style diet, but high-palatable, high-sugar ‘junk’ foods no longer appeal to me, allowing me to maintain a lean figure quite effortlessly! This has been a game-changer, as I was once trapped in a severe sugar addiction that I believed I would never rid myself of.

Lingering feelings of unrequited love have much, much less of an emotional hold over me. I am prone to limerence and have suffered manic-depressive, destabilizing episodes in which I’d crave my love interest’s reciprocation like a drug. NAC does not remove all feelings of ‘love’ for the person you cannot be with, but it removes the wild highs and lows of infatuation, the drug-like allure of the person and the intrusive, circular thinking. 5-HTP is also very useful in times of romantic distress and can be taken in adjunct, but NAC is superior. It targets a plethora of the biological correlates of infatuation and does not promote drowsiness like 5-HTP can.

NAC is also very useful at treating bipolar disease, principally due to its glutamatergic stabilizing effects. I initially started taking it to treat my OCD-related issues, but also find that it makes me less prone to both hypomania and depression. Life on NAC is cleaner and calmer, without it ‘numbing’ or dulling you down like most mood stabilizers can.

How Do You Really Feel On NAC?

You may be wondering whether NAC has any acute mental effects aside from providing relief from psychiatric distress. The answer is as follows: it depends whether your brain is currently working optimally or not.

Many people report feeling sharper, more energetic and more motivated shortly after taking it, which is undoubtedly due to its anti-inflammatory and antioxidant effects. We all harbor more inflammatory cytokines and free radicals than is ideal, due to our fast-paced lives, less-than-optimal diets and the myriad of toxins that we assimilate. People who consume a high-sugar diet, drink alcohol or are sleep-deprived are more likely to suffer from brain fog and be delighted by the mental clarity that they experience on NAC. Many deem it their ideal ‘nootropic’/’biohack’, because it can improve baseline mood and banish feelings of fatigue/lethargy that one has become accustomed to over the years.

If you already prioritize healthy food and exercise, you may only notice a gentle ‘sharpening’ effect rather than a marked boost. When I take NAC, I personally experience a subtle, generalized cognitive enhancement in addition to significant relief from my psychiatric issues. As someone who is prone to mood elevations and cannot drink coffee, I will add that NAC does not make you feel ‘buzzed’. Rather, it combats the vices of modern living and allows you to unlock your potential in terms of focus, mood and energy.

On that note, it’s important to be discerning and avoid supplements that make you euphoric, because hypomania is not sustainable and can precipitate depressive episodes. Highs and lows are two sides of the same coin; opt for stability, optimism and clarity instead.

Dosing & Safety Profile

Despite its relevance to mental health, NAC has long been a first-line treatment for paracetamol overdose and cystic fibrosis and its safety profile has been extensively studied. Unlike anti-depressants and anti-anxiety medications, NAC is not associated with any significant side effects nor do you build a tolerance/dependence. Mild skin irritation, headache and nausea are possible following high doses, but the majority of people experience nothing but subtle-to-powerful improvements to their mental health (Tirouvanziam et al., 2006).

I recommend initially taking 600mg (1 capsule) once a day on an empty stomach, since the protein in food can interfere with the absorption of amino acid-derived compounds. Some people find that this dose is sufficient in alleviating their symptoms, while severe cases of OCD/addiction may require 1200-1800mg daily. Despite NAC being biologically safe and very well-tolerated, it is always better to take the lowest dose possible (and save yourself some cash!).

A look at NAC’s mechanisms of action within the glutamatergic system of the brain. | Source

But Aren’t Supplements Unnatural?

I used to be anti-supplementation, believing that regular cardio and ‘brain foods’ could cure all. Since studying, dealing with my own mental health issues and researching for years, I’ve come to understand that this attitude is slightly untenable on a Darwinistic level.

You see, for the bulk of our evolutionary period (4 million years), our ancestors were living in a survival-focused reality paradigm. Being goal-oriented conferred individuals with a huge advantage in the face of food scarcity, and an obsessive mindset rendered them able to constantly monitor the safety of their offspring. The ability to become madly infatuated with a partner was also very beneficial, as clinging to someone for long enough to raise your child together promoted its survival.

Of course, all of these tendencies are still very much present in our current neurobiological makeup – the issue is that they are a poor match for modern life. Instead of helping us to locate food, shelter and keep our infants safe, these traits now manifest themselves as neuroses and mental health disorders. Many people wonder why they are never ‘happy’, but the truth is that we have not evolved to be content and blissed-out. That disposition has simply never been favored by evolution. We are prone to feelings of dissatisfaction, anxiety, romantic longing. Highly-processed and palatable foods are also available in abundance, and in the absence of any real famines, obesity is on the rise.

We are simply not living in accordance with our genetic makeup, which is why certain ‘biohacks’ prove extremely useful. If you are someone who is high up the spectrum for the neurotic traits that no longer serve us, you may find that certain supplements complement your neurochemistry perfectly and stabilize your emotions. Feel free to explore any substance that has been thoroughly researched, but steer clear of anything that induces a). wild mood elevations or b). strong neurochemical dependence.

References

Bavarsad, S.R.; Harrigan, M.R.; Alexandrov, A.V. N-acetylcysteine (nac) in neurological disorders: Mechanisms of action and therapeutic opportunities. Brain Behav. 2014, 4, 108–122.

Denève, S., Alemi, A. and Bourdoukan, R. (2017). The Brain as an Efficient and Robust Adaptive Learner. Neuron, 94(5), pp.969-977.

Gipson, C. (2016). Treating Addiction: Unraveling the Relationship Between N-acetylcysteine, Glial Glutamate Transport, and Behavior. Biological Psychiatry, 80(3), pp.e11-e12.

Hurley, M., Resch, J., Maunze, B., Frenkel, M., Baker, D. and Choi, S. (2016). N-acetylcysteine decreases binge eating in a rodent model. International Journal of Obesity, 40(7), pp.1183-1186.

Lafleur DL, Pittenger C, Kelmendi B, et al. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl) 2006;184:254–6.

LaRowe SD, Myrick H, Hedden S, et al. Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry. 2007;164:1115–7.

Lasram, M., Lamine, A., Dhouib, I., Bouzid, K., Annabi, A., Belhadjhmida, N., Ahmed, M., El Fazaa, S., Abdelmoula, J. and Gharbi, N. (2014). Antioxidant and anti-inflammatory effects of N-acetylcysteine against malathion-induced liver damages and immunotoxicity in rats. Life Sciences, 107(1-2), pp.50-58.

Omara, F.O.; Blakley, B.R.; Bernier, J.; Fournier, M. Immunomodulatory and protective effects of N-acetylcysteine in mitogen-activated murine splenocytes in vitro. Toxicology 1997, 116, 219–226.

Slavich, G. and Irwin, M. (2014). From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. Psychological Bulletin, 140(3), pp.774-815.

Tirouvanziam, R., Conrad, C., Bottiglieri, T., Herzenberg, L., Moss, R. and Herzenberg, L. (2006). High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proceedings of the National Academy of Sciences, 103(12), pp.4628-4633.

Witschi, A., Reddy, S., Stofer, B. and Lauterburg, B. (1992). The systemic availability of oral glutathione. European Journal of Clinical Pharmacology, 43(6), pp.667-669.