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What Research Shows for NAC (N-Acetylcysteine) and Mental Health

NAC-n-acetylcysteine-and-mental-health

 

We just wrapped up our whole section on anti-viral supplements for the immune system.

 

Front and center were quercetin (mimics pathway of hydroxychloroquine) and NAC (thiol group - cysteine, interferes with virus function).

 

While researching how NAC actually worked on the body, we stumbled on study after study on its effects across another topic.

 

Mental health issues.

 

Not just one but multiple: 

  • Negative thoughts and ruminations
  • OCD
  • Bi-polar
  • Schizophrenia
  • Addiction
  • Depression
  • Anxiety

 

Goodness...for one substance to have NIH research across seemingly disparate mental health issues is intriguing.

 

Enough to where we want to do a deep dive into the research.

 

NAC's boosting of our antioxidant pathway (glutathione) gets much fanfare but its work on glutamate in the brain may be the hidden star of the show.

 

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Let's pull back the curtains!

 

We'll cover these topics: 

  • A quick introduction to NAC (N-acetylcysteine)
  • NAC and the oxidation pathway (glutathione)
  • NAC and glutamate in the brain
  • NAC and Negative thoughts and ruminations
  • NAC and OCD
  • NAC and Addiction
  • NAC and Bi-polar
  • NAC and Schizophrenia
  • NAC and Depression
  • NAC and Anxiety
  • NAC safety
  • How much NAC for mental health issues.

 

We've covered many of these issues in terms of CBD but when we have seen something that's interesting in the research, we'll turn our attention there.

 

Let's go!

A quick introduction to NAC (N-acetylcysteine) 

NAC is one of those supplements you don't usually stumble on till late in your supplementation game.

 

Maybe it's just the name… N-Acetylcysteine.

 

It sounds complicated and a bit too obscure.  It's not a vitamin and it's not a plant extract like turmeric.

 

So...what is it!

 

NAC is a way for us to get acetylcysteine.  It's one step away from a key amino acid we use called cysteine.

 

The "N" part just makes it easier for the gut to actually absorb it.

 

Usually, we get cysteine from meat and dairy products which of course leads to the need for folate, B6, and B12 to properly manage it.

 

So...despite the complicated name, it's actually a pretty basic building block.

 

The net-net is this….it's critical for very important pathways throughout the brain and body: 

NAC is exerting benefits beyond being a precursor to the antioxidant, glutathione, modulating glutamatergic, neurotropic, and inflammatory pathways. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044191/

 

That's a mouthful but don't worry, we'll drill down into each.

 

The two that most interesting are the glutathione and glutamatergic (glutamate) pathways for our discussion.

 

Of course, inflammation is no slouch for mental health so we'll touch on that as well.

 

Let's jump into the most known role...supporting glutathione function.

NAC and the oxidation pathway (glutathione) 

We covered glutathione in-depth at our CBD and glutathione or CBD and oxidative stress reviews.

 

Trust us...it's your new best friend.

 

A quick backstory is required.

 

In the course of making energy (thank you, mitochondria), there's a tremendous amount of waste created.

 

It's usually in the form of ROS or reactive oxygen species. 

 

That's a fancy word for roaming oxygen which is nature's scissors.

 

It will slice and dice most of what it comes in contact with including our cells and DNA.

 

That's why water and bleach are so great at cleaning things...they break down organic molecules with relish.

 

So you don't exactly want these kamikaze's roaming around our cells like drunks at a bar.

 

That's where glutathione comes into play.  It soaks up free-radicals as our primary anti-oxidant.

 

You've heard of vitamin C and E as powerful anti-oxidants?  That's because they support the glutathione pathway.

 

By the way, CBD is a much stronger antioxidant than both C and E 

 

So...what's the connection with NAC?

 

Glutathione is an interesting dance between three different molecules: 

  • Glycine (a calming pathway like GABA - see CBD and GABA)
  • Glutamate (the brain's gas pedal)
  • Cysteine

 

Ah-ha!!  The latter one is supported by NAC (hence the "C" for cysteine)

 

There's an interesting coming together and cycling of these three into glutathione and back out to its component pieces.  

 

Picture the old English dances where partners are constantly switching partners and coming back.

 

Goodness, I need to lay off of the Jane Austin.

 

As part of this dance, it turns out that cysteine is a key "gate" for glutathione.

 

A rate-limiting agent technically but it means that if cysteine is running low, so is glutathione.

 

A perfect example of how this works is Tylenol overdose (potentially fatal and the largest cause of liver failure in the US).

 

There's a nasty metabolite of Tylenol called NAPQI (we'll save you from the full name) that kills liver cells with abandon.

 

Glutathione is a big player in the liver and tries to neutralize as much NAPQI as it can.

 

When your glutathione level is exhausted, the liver comes under attack and the story is a bad one.

 

NAC's primary prescription is for Tylenol (paracetamol, acetaminophen, Percocet, Vicodin, and others) overdose.

 

They administer it in large doses to bolster glutathione production in a race against time.

 

So...keep glutathione and oxidative stress on the back burner as we look at specific mental health issues below.

 

Let's look at some of the heavy hitters in the neurotransmitter world now.  

 

We'll start with a master regulator...dopamine

NAC and dopamine 

Most people think of dopamine as the reward neurotransmitter but it's so much more than that.

 

Technically, it's the "do that again" messenger but the reward is the more general stage.

 

Its effects though are interconnected with almost every behavior we have and there's a spider web of effects across other major pathways.

 

Push on one area of the web and all other areas move accordingly.

 

Dopamine and serotonin share this far-reaching effect (see CBD and serotonin).

 

Interesting studies looked at NAC's effect on dopamine.

 

First, the studies after meth use (essentially a massive spike of glutamate).

 

The resulting spike in the activity of glutamate actually creates neuron toxicity and death.

 

It's like revving an engine past the red zone for too long...you just burn out the engine.

 

Neurons need to cycle:  active firing and then recharge/rest

 

Without the rest cycle, there can be damage.

 

This damage can occur in the dopamine neurons which is a huge problem.

 

When researchers applied NAC before and after amphetamine in monkeys, the dopamine neurons (DAT for dopamine transporter) pathway was protected: 

These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP.  

https://www.nature.com/articles/1300512

 

A similar effect was shown after exposure to a toxin: 

The cell line study showed that NAC exposure resulted in significantly more mDA neurons surviving. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911055/ after exposure to rotenone compared to no NAC, consistent with the protective effects of NAC previously observed.

 

Interestingly, too much glutamate in the brain is toxic!

 

It's the over-revving car engine effect from above.

 

Read this statement slowly: 

Glutathione alone does not directly evoke dopamine release but may inhibit the depolarization-evoked release by preventing the toxic effects of high glutamate, and by modulating the cysteine-cystine redox state in Ca(2+ )channels. 

https://www.ncbi.nlm.nih.gov/pubmed/17401648/

 

Okay...let's decipher this.  Glutathione...NAC's main beneficiary prevented the toxic effects on dopamine release from too much glutamate!

 

There's glutamate front and center.

 

Let's go there now as this is the real power of NAC.

NAC and glutamate in the brain 

Glutamate is a workhorse in the brain.  Really a nuts and bolts neurotransmitter.

 

It's locked in a yin-yang tug of war with GABA across almost every process in the brain.

 

Gas pedal.  Brake pedal.  Go.  Stop.

 

The goal is a balance of course or homeostasis as a scientist like to call it.

 

Glutamate makes up one of the three components for glutathione (glutamate, cysteine, glycine).

 

So...how does NAC (a contributor of cysteine - part of the triumvirate) figure into glutamate activity?

 

Here's where it gets interesting: 

Cysteine assists in the regulation of neuronal intra- and extracellular exchange of glutamate through the cystine–glutamate antiporter 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044191/ 


That's a very 30,000 feet observation but we'll drill down further with below.

 

This is shedding a whole new light on glutathione which till now, was just thought of as a master antioxidant.

 

It's so much more!

 

In fact: 

Given that relation, the amount of cysteine in the system, as well as the feedback via GSH production by neurons, may directly regulate the amount of glutamate present in the extracellular space. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044191/

 

What you're going to see below is that many mental health issues have a direct component tied to excess glutamate.

 

Think about it...too much activity: 

  • OCD - excessive thoughts and actions
  • Bi-polar - during the manic periods
  • Schizophrenia - delusions, and hallucinations (brain literally creating sensory inputs where there isn't any to use up ramped up horsepower)
  • Anxiety - check out the relationship between too much glutamate and too low GABA here
  • Depression - too much glutamate can be toxic to brain neurons and pathways
  • Addiction - excess cravings and fixations

 

We'll look at it below.

 

We've covered CBD and GABA (the opposing force to glutamate) for more information.

 

Let's get into the grist of it now.

NAC and Negative thoughts and ruminations 

This is one of the topics that caught our attention while researching NAC's antiviral effects for Covid19.

 

We've covered the mechanics of negative thoughts and CBD review.

 

As for NAC, there is an early indication from the people who actually deal with patients: 

On a clinical level, in day-to-day work with patients, NAC seems to help with ruminations, with difficult-to-control extreme negative self-thoughts. 

https://www.psychologytoday.com/us/blog/heal-your-brain/201810/nac-the-amino-acid-turns-psychiatry-its-head

 

How would glutamate drive this?

 

Let's flip it around...if we have excessive glutamate in a given area, that by defaults means insufficient (or suppressed) GABA (yin yang).

 

Now, what if that is in the hippocampus (see CBD and hippocampus).

 

Here we show that GABAergic inhibition of hippocampal retrieval activity forms a key link in a fronto-hippocampal inhibitory control pathway underlying thought suppression.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670182/

 

To translate, GABA is the trigger that allows us to control thoughts!

 

That's a great segue into the greater arena of uncontrolled activity.

 

This is the other article that caught our attention for NAC. 

NAC and OCD 

It was actually a specific vein of OCD called trichotillomania.  

 

You probably haven't heard of it but if you have, you know how brutal it can be.

 

It's chronic or obsessive hair pulling.  This can be applied to skin picking, nail-biting, and pretty much any aspect of behavior we can fixate on.
There's no great treatment for trichotillomania, unfortunately.

 

A study looked at NAC for hair pulling specifically: 

Fifty-six percent of patients "much or very much improved" with N-acetylcysteine use compared with 16% taking placebo (P = .003). 

 

https://www.ncbi.nlm.nih.gov/pubmed/19581567

 

Goodness!

 

Big Pharma has been going down the same, tired serotonin route (see CBD versus SSRIs) but really, it was glutamate.

 

There's a good review of other preliminary studies for nail-biting and skin picking here: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044191/

 

The key takeaway: 

Three participants taking NAC reported significant reductions in nail-biting during the 6-month course of treatment.

 

CBT has also been shown to help and it's essentially a hard-won version of neurogenesis (building new brain pathways).

 

Check out CBD and neurogenesis or CBD and BDNF.

 

Combining CBD and NAC might be a powerful shaper of behavior for repetitive behaviors.

 

What about the broader OCD world?

 

There is one general study for NAC and OCD in conjunctions with an SSRI and its results were promising: 

NAC augmentation of fluvoxamine resulted in a marked decrease in the Yale-Brown Obsessive Compulsive Scale (Y-BBOCS) score and a clinically significant improvement in OCD symptoms. 

https://www.ncbi.nlm.nih.gov/pubmed/16374600

 

The entire OCD suite of behaviors may be an imbalance in glutamate pathways.

 

We'll leave with this: 

Via its additional effect on glutamate via the cystine-glutamate exchange system, NAC has been shown to mediate impulsivity in preclinical models of addiction, reduce craving, and cue extinction. 

https://www.ncbi.nlm.nih.gov/pubmed/19773711

 

Think of glutamate as throttle and dopamine being the intended target. 

 

There's no "pleasure" associated with dopamine...that's the role of the opioid system (and anandamide, our bliss molecule - part of the endocannabinoid system).

 

Dopamine is strictly "do that again".  Now imagine an imbalanced throttle hitting the dopamine system.

 

Do that again.  Do that again.  Do that again.

 

Interestingly...the mind has this excess "compelling" to do something and will attach it to something...grooming...door locking...hair pulling.

 

Speaking of compelling repetition of actions...that's a great segue to CBD and addiction.

 

Check out CBD and OCD for more information on that pathway. Again, the new may be powerful players in that pathway.

NAC and Addiction 

There is a curious connection until you understand what we explained above.

 

Research has long found an association between oxidative stress and addiction.

 

ROS - the little free radicals we've trying to sponge up since the '80s.

 

First, let's look at the studies, and then we'll integrate that with what we know about glutamate as a key piece of the glutathione.

 

There is a very complicated and thorough walk-through on how exposure to drugs is tied to a dysregulation of the glutamate pathway.

 

It's quite technical but some points that are important.

 

Following periods of withdrawal (i.e. 1–14 days, up to 3 months) from self-administration of a substance of abuse such as cocaine, heroin, or nicotine, dysregulation of glutamatergic signaling has been found within a corticostriatal circuit [prefrontal cortex (PFC)–nucleus accumbens (NA) 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009342/

 

First, understand that the systems used between opioids like heroin and cocaine/nicotine are very different.

 

Yet, they share this common imbalance in glutamate.

 

The interesting piece in that statement deals with the two areas of the brain affected.  The nucleus accumbens is a key area for dopamine function (and addiction)!

 

A very brief summary:

 

The various drugs tested all reduce key components of the cysteine (our body's usable version of acetylcysteine) and glutamate pathways...  

 

Downstream genes and enzymes (xCT and GLT1) that are needed to process these two key components of glutathione.

 

It's easy to get lost in the weeds (THC is coming up) here but the net net is this: 

Presentation of a drug or a cue associated with drug-taking reinstates drug-seeking in a preclinical model of relapse and this behavior is associated with elevated extracellular glutamate derived from synaptic activity in the PFC-NA pathway.

 

Folks...this is the difference between recreational drug use and drug addiction.

 

When too much glutamate during withdrawal is running around with nowhere to go, it creates an anciness in the brain.  

 

One that is calmed down by the drug's drop in glutamate processing.

 

Excess glutamate feels terrible.  Take it down a notch from seizures (the extreme) and you can imagine how bad that feels.

 

Your worst caffeine jitters times 10.  Coming out of your skin.

 

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So...what about NAC and its effect?

 

The restoration of glutamate then activates the presynaptic mGluR2/3, which then reduces synaptic glutamate release and drug-seeking

 

It calms the latter drug jitters (glutamate).

 

The net effect of this?

 

Systemic administration of NAC has been shown to robustly decrease reinstatement of cocaine, heroin, and nicotine seeking in preclinical models

 

The article hints at NAC being able to absorb the free-floating glutamate with an unknown mechanism.

 

Might we already know it?

 

Remember how drug addiction is tied to a drop in glutathione or an increase in oxidative stress?

 

Here's the key point...cysteine is a rate-limiting agent for glutathione.

 

To make glutathione, you need cysteine, glycine, and glutamate.

 

If cysteine is lacking, you can't make glutathione and consequently, you can't soak up glutamate.

 

Hence, the increase in oxidative stress which on the surface, doesn't exactly match the presence of these drugs.

 

There's a range of studies across different drugs (alcohol, nicotine, opioids, cocaine, etc) here: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009342/

 

One more piece which is even more fascinating (to us, anyway).

 

Is glutamate imbalance the reason why some people are prone to addiction while others are not?

 

There's a very intriguing animal study on that matter.

 

It's not an easy setup but we'll walk through because it's too important.

 

They surgically created legions on the hippocampus (mentioned above - the seat of memory and an emotional hub) of rats in utero.

 

This lead to overactive food consumption when they grew up (rat proxy for addiction).

 

They then tested the adult rates for nicotine seeking.

 

The results: 

NAC did not alter RAM performance, but significantly reversed NVHL-induced increases in nicotine seeking during extinction and reinstatement. 

https://link.springer.com/article/10.1007/s00213-016-4421-8

 

Let's breakdown the Klingon there.

 

NAC in ADOLESCENTS was able to thwart the nicotine addiction later as adults.

 

Since we know that NAC helps to balance the glutamate pathway,  it makes you wonder if the reason some people seek drugs, to begin with, is due to an underlying glutamate "itch".

 

We look forward to further research.

 

We'll lead in with a study on cocaine since it's notoriously difficult to treat.

 

The effects of NAC on cocaine: 

In parallel, our preliminary clinical data indicate that repeated administration (4 days) of N-acetyl cysteine (1200–2400 mg/day) to cocaine-dependent human subjects (N=4 per group) produced a significant reduction in craving following an experimenter-delivered IV injection of cocaine. 

https://www.nature.com/articles/npp2010226

 

Significant reduction.

 

There are actually many studies across different drugs but we have to move on.

 

Also, check CBD and addiction to understand how NAC and CBD might be powerful tools for addiction.

 

Finally, the reason we did this whole article on NAC to begin with.

 

THC.  We know it well from all our work on CBD (See CBD versus THC).

 

Our question runs deeper...why do some people chronically use THC.

 

What are they getting from it?  What exactly are they self-medicating?

 

It's not just the high feeling if you're smoking multiple times a day.

 

Turns out...if you dig a little deeper, an old acquaintance pops up.

 

In this biological context, endocannabinoids are released to retain NMDAR activity within physiological limits. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342457/

 

NDMAR is the receptor for...glutamate.

 

It gets more interesting: 

In this context, the endocannabinoid system, though the activation of the cannabinoid 1 receptor (CB1R), plays a very relevant role in reducing NMDAR activity

 

CB1 is the primary receptor for Anandamide and guess what is a substitute for Anandamide?

 

THC.

 

Essentially, THC slows down glutamate processing.  In fact, Anandamide acts as a constraint on glutamate activity.

 

So, does NAC work like THC but without the drawbacks?

 

We would expect NAC to reduce the craving for THC since it's filling this role: 

Results from this preliminary open-label study indicate that treatment with NAC was well tolerated and associated with significant decreases in self-report measures of marijuana use and craving.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826714/

 

They were looking at chronic THC use among….adolescents!

 

Okay...we have to move on...there are dozens of NIH studies across the field of addiction.

 

Check out CBD and benzo withdrawals or CBD and SSRI withdrawal

NAC and Bipolar 

Bipolar is a complicated and brutal disease.  We covered the basic mechanics in our CBD and bipolar review.

 

What about the pathways we discussed above?

 

The mania side of the equation appears to be tied to specific effects we're familiar with now: 

These changes appear to be related to state, particularly in mania, where increased oxidative stress seems to be apparent. This is congruent with reports of hyperdopaminergic states during manic episodes. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044191/

 

Oxidative stress (which would point to reduced or exhausted glutathione) and a spike in dopamine (remember that glutamate is the throttle for neurotransmitters).

 

First, the glutamate connection: 

 Specifically, for bipolar disorder, which is characterized by periods of mania and depression [32], elevated glutamate neurotransmission has been demonstrated across multiple studies and converging methodologies, including post-mortem 

https://www.karger.com/Article/Pdf/496294

 

Interestingly, there may be high glutamate during the mania phase but low during the depression phase.

 

Remember how CB1 acted as a constraint on glutamate function via anandamide?

 

CBD boosts anandamide function.

 

What about NAC?

 

A double-blind study looked at this and found: 

Rating scores on the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Bipolar Depression Rating Scale showed large decreases in depressive symptoms (about 9 points on the MADRS between NAC and placebo groups at the endpoint) 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044191/

 

More importantly, when the participants stopped NAC, the effects went back to where the placebo group was.

 

Just a note, studies are showing that NAC really needs 6+ months to have its effects.

 

Notice how it really helped with the depressive side of things where there might be too little glutamate.

 

First, glutathione is one most abundant molecules in our body: 

Glutathione, a tripeptide of glutamate, cysteine and glycine, displays high intracellular concentrations, 1-10 mM, making it the most abundant low molecular weight thiol of bacteria, plant and animal cells. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923312/

 

So glutathione appears to be a widely available source and sink of glutamate!

 

Using selective inhibitors of different steps of the cycle, we now show that glutathione serves as a source for a major portion of glutamate in HT22 hippocampal neurons, PC12 cells and primary cortical neurons. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923312/

 

Just look at how lithium works: 

Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in the mouse cerebral cortex.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20981/

 

"Stabilizes glutamate uptake".

 

Stabilize is the keyword.

 

The key here with NAC is that it directly boosts glutathione levels.  Since glutamate is everywhere, cysteine appears to be a much-needed component when running low.

 

Otherwise, just adding NAC wouldn't directly result in increased glutathione.

 

Back to NAC and bipolar.

 

Another look at a different test across multiple points for bipolar results: 

Improvements in MADRS, BDRS, SOFAS, and LIFE-RIFT scores from baseline to the week 20 post-discontinuation visit were significantly greater in the CT group compared to those in the placebo. 

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1257-1

 

Here's are lead into the next section: 

But, more surprisingly, it was clear that a substantial comorbidity index between bipolar disorder and schizophrenia was present. 

https://www.ncbi.nlm.nih.gov/pubmed/19538905

 

Comorbidity just points to similar pathways.  Could one of them be glutamate?

NAC and Schizophrenia 

This is the big one.  Why?

 

Because there are few therapeutic options (sans brutal side effects).

 

Check out the review of CBD and schizophrenia for a detailed look at what research is showing.

 

CBD had a very impressive effect on the complexity of the disease.

 

As for glutamate...there are some tantalizing clues.

 

Let's start at the beginning of the thread.

 

First, glutathione, our primary detox chemical in the body.

 

There's a known tie-in with oxidative stress and schizophrenia: 

Abnormal oxidative stress parameters have been reported in peripheral blood (3), red blood cells (RBCs) (4), neutrophils (5), platelets (6), cerebrospinal fluid (7), and postmortem brain (8) in patients with schizophrenia. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018767/

 

This would point to a connection with either source of inflammation (mitochondria, immune hyperactivation, outside chemical causes, glutamate excess, etc) or poor anti-oxidant function (glutathione, the endocannabinoid system, etc)

 

All of these actually show in the research!

 

We'll save glutamate for last but what about glutathione?

 

One study (of many) actually measured levels to compare initial psychosis with ongoing schizophrenia: 

These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness. 

https://www.nature.com/articles/s41380-018-0104-7

 

This is interesting...essentially a trauma occurs earlier which causes cell death.

 

Glutamate, if excessive, is neurotoxic.  Literally kills off neurons.

 

The trauma could also be from early exposure to infection or chemicals during development or in utero even (priming immune system for hyperactivation and inflammatory response).

 

There's a known tie-in now with microglia, our brain's immune responders and schizophrenia.

 

Guess where the whole glutathione and glutamate dance takes place primarily: 

These results show that microglial glutamate uptake is directly coupled to glutathione synthesis and release of glutamate and/or glutamate metabolites.  

https://www.ncbi.nlm.nih.gov/pubmed/16925588

 

In fact, drugs (like PCP) that mimic psychosis generally have this effect on glutamate's primary receptor the NDMAR: 

One of these receptors, the N-methyl-D-aspartate (NMDA) receptor, is the site of action of psychotomimetics such as phencyclidine and related anesthetics, which can reproduce in normal individuals most of the symptomatic features of schizophrenia. 

https://www.ncbi.nlm.nih.gov/pubmed/9384954

 

 New research is pointing to genes tied to NDMA function and schizophrenia risk.

 

Okay...we could spend pages looking at the interactions with oxidative stress, glutathione, glutamate, and schizophrenia.

 

The key takeaway is that glutamate imbalance can lead to toxic effects (where it's too high) or reduced function (where it's too low).  The so-called positive and negative symptoms of schizophrenia.

 

One final reminder (sorry, this stuff is complicated), glutathione isn't just about oxidative stress: 

As a neuromodulator, it displaces ionotropic glutamate receptor ligands from their binding sites and regulates calcium influx through N-methyl-D-aspartate receptor-governed ionophores.  

https://www.ncbi.nlm.nih.gov/pubmed/10812215/

 

That sentence may be the most important one in this whole review.

 

Glutathione manages glutamate levels at the very NDMA receptor we just discussed.

 

It also affects dopamine and GABA.  Goodness.  Busy little bee.

 

What about NAC and schizophrenia?

 

First, studies on people with schizophrenia already on an anti-psychotic: 

Treatment at 8 weeks was less efficacious than placebo, but at 24 weeks produced significant reductions vs placebo in Positive and Negative Syndrome Scale (PANSS) negative (d = 0.52), general (d = 0.46), and total (d = 0.57) scores.  

https://europepmc.org/article/med/27490835

 

Another study: 

Eight weeks of treatment led to clinically significant reductions vs placebo in PANSS negative (d = 0.96), general (d = 0.59), and total (d = 0.88) scores.

 

PANSS is the industry standard test for schizophrenia symptoms.

 

A key takeaway is that it can take time for NAC's effect to build.

 

That would speak to a neurogenesis effect...a literal physical changing in the pathways or better yet receptors of the brain.

 

If the effect was immediate, it would likely be just a change in the level of neurotransmitter (i.e. glutamate, etc).

 

The fact that it takes so long probably means the brain has normalized to jacked-up glutamate (or reduced in other parts of the brain) by offsetting receptor numbers and/or sensitivity.

 

You can learn all about this in our CBD and tolerance here (looking at benzos and GABA function) or CBD and GABA.

 

It can take weeks for the DNA to actually start making the proteins for new receptors!

 

Some hints to this effect: 

Mice with Reduced NMDA Receptor Expression Display Behaviors Related to Schizophrenia. 

https://www.sciencedirect.com/science/article/pii/S0092867400819728

 

So...too much glutamate and the brain pushes back the other way (out of self-protection) by downregulating NMDA receptor function.

 

Again, we're in early days of research on this front but it definitely fits together.

 

Glutamate and NDMA are the new directions for schizophrenia research.

 

Next, up depression.

NAC and Depression 

We saw clues to this in the bi-polar study where NAC had more pronounced effects on the depressive side of the equation.

 

First, a lay of the depression landscape.

 

Research is pointing depression as a result of damage.  Oxidative damage.  Inflammatory damage….or the inability to repair (neurogenesis).

 

Just look at psilocybin's effect on depression (See psilocybin review) which can have major, long-term effects on depression in just one dose.

 

If you dig deeper, it's about an explosion in neurogenesis (see CBD and neurogenesis here).

 

Why would this matter for glutathione, glutamate, and NAC?

 

Depressed females have overactive glutamate receptor gene 

https://www.sciencedaily.com/releases/2015/07/150730172348.htm

 

Hmmm.  Too much glutamate is toxic to neurons.

 


Ketamine has been shown to block NDMAR activity in studies for depression.

 

Of course, there are direct ties with inflammation and oxidative stress which both cause damage.

 

Let's start with glutathione.

 

Studies show that stress, either traumatic or chronic, eat up glutathione: 

The results suggest a close link between stress-induced behavioral depression, increased monoaminergic utilization, oxidative stress, and brain GSH. 

https://www.sciencedirect.com/science/article/pii/0091305794901910

 

Glutathione levels were literally used-up in the brains following trauma.

 

A key form of glutathione was reduced in people with major depression: 

GST Mu levels were significantly decreased in patients with MDD and SCZ but not BD.  

https://academic.oup.com/ijnp/article/14/8/1069/697118

 

A review of many different studies pointed to net effects on depression: 

Subjects receiving N-acetylcysteine had better depressive symptoms scores on the Clinical Global Impressions-Severity of Illness scale at follow-up than subjects on placebo (SMD = 0.22; 95% CI = 0.03 to 0.41; P < .001). In addition, global functionality was better in N-acetylcysteine than in placebo conditions. 

https://www.ncbi.nlm.nih.gov/pubmed/27137430

 

A specific study sheds some light: 

NAC treatment significantly improved depressive symptoms on the Montgomery-Asberg Depression Rating Scale (MADRS) over 16 weeks of the trial.  

https://www.ncbi.nlm.nih.gov/pubmed/28318471

 

Interestingly, they looked at inflammatory markers and they weren't changes so this points to the glutamate function (as opposed to the anti-oxidant effect).

 

They also looked at BDNF, our brain's fertilizer which wasn't affected.  CBD is a powerful booster of BDNF (see CBD and BDNF here).

 

This leaves the glutamate balancing effect.

 

Again...glutamate and glycine are readily available in the brain (via their precursors).

 

Cysteine appears to be the limiting agent!

 

What about anxiety?

NAC and Anxiety 

This is right in our wheelhouse.

 

We've looked at extensive studies on CBD and anxiety and CBD and GABA for anxiety.

 

GABA is the opposing force to glutamate.

 

When GABA gets eaten up (excessive glutamate), anxiety is a documented result.

 

This can occur due to stress, trauma, genetics, and even gut health.

 

Something we're all dealing with these days, chronic stress is especially powerful: 

The deleterious effects of chronic stress in the central nervous system are a result of glutamatergic hyperactivation, glutathione (GSH) depletion, oxidative stress, and increased inflammatory response, among others. 

https://www.ncbi.nlm.nih.gov/pubmed/29876880

 

That's a Who's who on our list for NAC.

 

In that same animal study: 

NAC reversed the anxiety-like behavior and oxidative damage observed in stressed animals.

 

Think of an NAC as a stress-response reserve.  When glutathione runs low, our management of glutamate and GABA suffers.

 

NAC props this backup.

 

In a study of NAC for OCD (where anxiety is a critical lever): 

Adding NAC was superior to placebo in reducing anxiety symptoms (P = .02) 

https://www.psychiatrist.com/JCP/article/Pages/2017/v78n07/16m11101.aspx

 

Again, NAC and CBD might be interesting cohorts in yet another disease tied to glutamate imbalance.

 

What about safety.

NAC safety 

This may be the best part especially in light of the alternatives (antipsychotics, antidepressants, benzos, etc).

 

The safety profile is very strong across multiple studies and decades of use (remember the Tylenol overdose use).

 

The most common side effects listed are GI issues (diarrhea, constipation, etc).

 

The net net: 

Oral NAC seems to be associated with very few side effects and is considered to have an excellent safety profile. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562654/

 

Up to how much?

How much NAC for mental issues 

In most of the studies referenced, the dosage was generally 600 mg to 2000 mg per day.

 

The standard dosages available are usually around 600 mg which can be taken up to 3 times a day per their instructions (1800 mg).

 

NAC may start to get tougher to find due to its antiviral effects for the immune system but production should ramp up.  

 

As noted in some of the studies, it can take time for it to kick in...weeks.  We look forward to results from new trials that are in the works now as we speak across a range of mental health issues.

 

Hopefully, we've explained the mechanism (management of glutamate by glutathione) to help you understand why.

 

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Always work with a doctor or naturopath with any supplement!

The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.

 

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