N-acetyl Cysteine…New Miracle for Bipolar
N-acetyl Cysteine… New Miracle for Bipolar?
Hello, people… hope everyone is well! In last week’s blog, I introduced you to N-acetyl cysteine, or NAC, an amino acid supplement that’s garnering some serious attention in shrinky circles, as it has shown major potential to help treat multiple psych conditions. Recall from last week that NAC is most renowned for its ability to replenish levels of the body’s strongest antioxidant, glutathione, while it also regulates the very important neurotransmitter, glutamate, acta as an anti-inflammatory, and assists the body’s detoxification system.
The rationale for administering NAC for psych conditions is based on those roles: being a precursor of glutathione, as well as its action as a modulating agent of glutamatergic, dopaminergic, neurotropic, and inflammatory pathways. Those are the mechanics of NAC, the how and why it’s beneficial for brain function: NAC helps to produce glutathione, which, being the chief free radical scavenger, takes up all those nasties, reducing cellular damage. NAC also acts as an anti-inflammatory, so it decreases the blood levels of molecules that cause inflammation in the body and brain, such as interleukin-6, which incidentally may play a role in the pathogenesis of schizophrenia, bipolar disorder, and depressed mood. A third mechanism of action that has been proposed for NAC involves the stimulation, increased synthesis, and release of the neurotransmitters glutamate and dopamine. Let’s talk about those two for a moment.
As the most abundant neurotransmitter in the brain and CNS, glutamate plays an important role during brain development, as well as helping with learning and memory. Glutamate is an excitatory neurotransmitter. What is that? Excitatory neurotransmitters have excitatory effects on the neuron, meaning that they increase the likelihood that the neuron will fire a signal- called an action potential- in the receiving neuron. Because neurotransmitters can increase action potential, you can then probably imagine why neurotransmitter levels are very important. At high concentrations, glutamate can overexcitenerve cells and cause more neuronal firing. Prolonged excitation is toxic to nerve cells, and causes damage over time. So having excess glutamate, as an excitatory neurotransmitter, causes more neuronal firing, and you can actually damage cells this way. In fact, you can excite cells to death… a process referred to as “excitotoxicity.” Having too much glutamate in the brain has been associated with neurological diseases such as Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, stroke, and ALS, amyotrophic lateral sclerosis or Lou Gehrig’s disease. Problems in making or using glutamate have also been linked to a number of mental health disorders, including autism, schizophrenia, depression, and obsessive-compulsive disorder, OCD. Glutamate is also a metabolic precursor for another neurotransmitter called GABA, gamma-aminobutyric acid. GABA is the main inhibitory neurotransmitter in the central nervous system- the flip-side of the coin- which decreases the likelihood that the neuron it acts upon will fire. That’s why glutamate is so important, it’s the dominant neurotransmitter used for neural circuit communication, and it’s estimated that well over half of all synapses in the brain release glutamate.
Dopamine is the “feel good” neurotransmitter that’s strongly associated with pleasure and reward. It’s a contributing factor in motor function, mood, and decision making, and is also associated with some movement and psychiatric disorders. Dopamine is released when your brain is expecting a reward; when you come to associate a certain activity with pleasure, just the anticipation alone can be enough to raise dopamine levels. It could be a specific food, sex, shopping, or just about anything else that you enjoy. If your go-to comfort food is homemade chocolate chip cookies, your brain may increase dopamine levels when you smell them baking or see them come out of the oven. Then when you eat them, the flood of dopamine you receive acts to reinforce the craving, causing you to focus on satisfying it in the future. Dopamine is all about the cycle of motivation, reward, and reinforcement. Now imagine that you’ve been jonesing for those cookies all day, but your co-workers scarfed them all down while you were sidetracked by a conference call. Your disappointment might well lower your dopamine levels and dampen your mood. It might also intensify your desire for chocolate chip cookies, making you want them even more. Dopamine plays the main role in all of that, but keep in mind that dopamine doesn’t act alone. It works with other neurotransmitters and hormones, things like serotonin and adrenaline. Aside from its “feel good” function, dopamine is involved in many body functions, including blood flow, digestion, memory and focus, mood and emotions, motor control, pain processing, sleep, stress response, heart and kidney function, pancreatic function, and insulin regulation. Once again, as with all neurotransmitters, levels are important… theright amount of dopamine generally equates to a good mood. Ultimately, dopamine contributes to feelings of alertness, focus, motivation, and happiness, and a flood of dopamine can produce temporary feelings of total euphoria.
Those mechanisms I mentioned- glutathione reducing cellular damage, anti-inflammatory action, and the stimulation, increased synthesis, and release of the neurotransmitters glutamate and dopamine- are the proposed how NAC works, but why does NAC help people with varying psych diagnoses? Why might it work across so many conditions? This is the most intriguing thing to me. First and foremost, it seems to target biological pathways that are common across many mental disorders. For example, we know that patients with bipolar disorder have significantly higher levels of oxidative stress, and higher glutamate concentrations in their brains, especially during acute mania. It’s been suggested that people with schizophrenia may have the same, and that this may predispose them to changes in neuronal cell membranes and mitochondrial function that later manifest as symptoms of schizophrenia. It appears that NAC supplementation, by increasing CNS glutamate levels and reducing overall oxidative stress, may reduce the severity of these psychotic symptoms.
A meta-analysis and systematic review of placebo-controlled studies on NAC as a stand-alone treatment of depressed mood in people diagnosed with major depressive disorder, bipolar disorder, and other psychiatric disorders, found evidence for “moderately improved” depressed mood and improved global functioning. In a four-month, double-blind study, individuals treated with NAC plus their usual antidepressant improved more than individuals taking a placebo with their antidepressant medication.
In a large, six-month, double-blind study, individuals with schizophrenia who had failed to respond to multiple trials on antipsychotics were treated with 1,000 mg NAC twice daily versus a placebo, while also taking their usual antipsychotic medication. Those taking NAC experienced moderate improvements in symptoms of apathy and social withdrawal, the so-called “negative” symptoms of schizophrenia, as well as improvements in day-to-day functioning, and fewer of the abnormal involuntary movements that are commonly caused by some antipsychotic meds.
NAC has also been investigated as a treatment for substance use disorders, with promising results. The findings of small, placebo-controlled studies suggest that NAC helped heavy Cannabis users to reduce their use, and that it may reduce the intensity of withdrawal and cravings in people in early stages of cocaine recovery. As in mood disorders, the beneficial effects of the NAC may be related to its role in restoring neurotransmitter activity that has been affected by chronic substance abuse.
In addition to its mood-enhancing benefits, there is evidence that NAC may reduce trichotillomania (compulsive hair pulling) and other impulse control disorders, like nail-biting, skin picking, and pathological gambling. There was one eight-week, open-label study on pathological gamblers, and over 80 percent of them responded to NAC. They were then subsequently enrolled in a six-week, placebo-controlled trial, and continued to report “significant reductions” in gambling.
As for potential treatment targets, a systematic review of all of the evidence suggests that NAC may be effective at treating major depressive disorder, bipolar disorder, drug addiction, obsessive-compulsive disorder, impulse control disorders, autism, schizophrenia, Alzheimer’s disease, and even certain forms of epilepsy, specifically progressive myoclonic seizures. NAC has also been shown to potentially reduce the severity of mild traumatic brain injury in soldiers, and animal studies show that it can improve cognition after moderate traumatic brain injury. Other disorders such as anxiety and ADHD have some interesting preliminary evidence, but require larger studies.
The jury’s still out as to the mechanism, whether NAC’s benefits are the result of glutathione reducing cellular damage, the anti-inflammatory action, or the actions on glutamate and dopamine. Even though we don’t know exactly why yet, on a clinical level, NAC seems to help with ruminations, the difficult to control, extreme negative self-thoughts. These thoughts are very common in depression and anxiety disorders, and also in eating disorders, schizophrenia, and OCD. NAC seems to help some patients when other modalities, even meds and psychotherapy, haven’t helped much. It doesn’t always work, but when it does, irrational thoughts seem to gradually decrease in intensity and frequency. Negative thoughts, like “I’m a bad person,” “Nobody likes me,” or ruminations about other people or other issues that can’t seem to be quieted by reasonable evidence to the contrary- those really pesky negative thoughts that keep intruding on someone’s awareness, hour after hour, day after day, despite all efforts to control them- seem to decrease with NAC. If they do continue to occur, they’re less distressing, and can be observed from more of a distance, and are less likely to trigger depression or other negative effects.
Overall, NAC seems pretty special. Its ability to successfully cross the blood-brain-barrier to increase CNS glutathione levels, while reducing glutamate and overall oxidative stress, in addition to its anti-inflammatory properties- all conditions linked to depression and other mental health disorders- makes it an interesting treatment candidate for many psych conditions. If you take NAC, you’re basically giving your body an efficient way to soak up excess glutamate, an excitatory neurotransmitter that’s not good in excess concentrations. You’re also reducing oxidative stress and inflammation by giving it glutathione. As a result, this seems to help alleviate a number of different mental health conditions: depressed mood, schizophrenia, impulse control disorders, and substance use disorders. Studies indicate that people benefit from taking anywhere between 250 mg to 500 mg daily. Lower doses are better because high doses of NAC can sometimes redistribute heavy metals into the brain… this is not a good thing, so you obviously want to avoid that. You can take NAC with leucine, another amino acid, as taking leucine with it prevents mercury from being reabsorbed into the central nervous system. As always, please bear in mind that large placebo-controlled studies are needed to confirm the beneficial effects of NAC in mental health care, and to determine safe, optimal dosages for standalone or adjunctive treatment. But if you think it might be helpful, talk to your physician to determine if NAC is a good supplement choice for you.
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Thank you and be well people!