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[note reference at the bottom : vitamin D stimulates the formation of glutathione in the brain, and NAC provides the cysteine to manufacture more.]

7/3/2019:  This is embarrassing. When I first used NAC about a decade ago, I frequently had tremendous results. Last few years the NAC seemed not as effective. I just found out why. In the first textbook (2019) on NAC, edited by Richard Eugene Fry and Michael Berk, reveals that when NAC is exposed to air, it is oxidized and becomes inactive, or worse. When I started using it, most patients took it in capsules. In recent years I have encouraged people to use the powder because it is less expensive. One-third of the container is air and every time the container, the NAC is exposed to more air.  Hopefully, I will now go back to having frequent great success with NAC.

The Therapeutic use of N-acetyl cysteine (NAC) in Medicine, editors Richard Eugene Frye and Michael Berk  (2019) pub ADIS/  ISBN 978-981-10-5310-8

        Michael Berk, MD [Melbourne] did 2 initial studies with NAC.  For depression, it took 5 months to have dramatic benefit –probably because only 10% of the cysteine reaches the bloodstream.   In a 2nd study on schizophrenia, it had a significant benefit in 6 weeks, though the benefit was not as dramatic as it was for bipolar depression.    Interestingly, I have had a positive benefit in 1-2 weeks with schizophrenia.    When it helps depression in my experience, it usually takes ≥ 1 month–but in a few bipolar patients there was a very dramatic response in a week from profound depression, and the rapid response was unlike any previous experience with these patients.

One could argue that I established the standard dose at 4 grams, and that dose is arbitrary.   He arbitrarily chose 2 grams.   I arbitrarily increased the dose to 4 grams.  He said I must be right as not one of his patients had such a dramatic response  as some of mine had.  In subsequent he demonstrated that 4 grams is significantly better than 2 grams.   He picked 2 grams out of the air and I picked 4 g out of the air—why not 6 or 8 g?   Three of my patients did best with 12 grams:  4 g three times a day.   A 29 you with very severe TRD (treatment resistant depression) said no other antidepressant had ever worked as well as 12 g of NAC.  She later did well on 8 grams.

INSTRUCTIONS.: Take 7 pills [of 600mg] per day or 4 pills of 1 gram [1000mg] of NAC [N-acetyl cysteine] capsules for 3-4 months. If it seems to be helping, we may will stay on it or try to decrease the dose.  If it seems not to help at all, we will probably stop it abruptly. Dr Berk correctly says when it is stopped abruptly there is almost always an immediate relapse.  If you feel worse in some way after stopping, it is probably not a coincidence.

            NAC purportedly works better if you take vitamin C also500mg of C with the NAC might be a good idea.   

INFORMATION on dose and mechanism. 

  • The proven and accepted dose is 4 grams per day. Since it is a food, maybe one could safely take seemingly huge doses.
  • Cysteine is an amino acid, the building block of protein.  It is naturally found in humans.  We make it ourselves>  it is present in small amounts of food.    Below is an abstract presented at an international bipolar conference in Pittsburgh in June 2007 by Michael Berk, MD.   This may be the first psychiatric treatments based on knowing the basic science.  All our treatments are variations on treatments found by accident.    Neuroscientists have determined that in bipolar depression there is significant oxidative stress in the brain, which means more rapid metabolism producing excessive free radicals [which are toxins/poisons we produce and must neutralize].  Glutathione is the most important free radical scavenger [antioxidant]  in the body [i.e., it cleans the body of these highly charged,  toxic chemicals].   Glutathione itself is a combination of  3 amino acids [the middle one being cysteine] and is thus too large to pass the blood brain barrier. It is present in virtually all cells, including red blood cells, and is important to maintain cell health.  Brain cells make their own glutathione.  It has been known for years that if you administer the amino acid N-acetyl cysteine {NAC}, cells use it to produce more glutathione.  NAC is small enough to pass the blood-brain barrier.   Glutathione is not well absorbed by the stomach.  Nor does it cross the BBB.
  • It was a 6-month study—part of abstract is below.]  For the 1st 5 months the patients on NAC did about the same as the patients on placebo [they did better numerically than placebo, but it was not statistically significant].   After 5 months, the patients on acetyl cysteine suddenly did dramatically better than people on placebo on 8 different scales–mostly measures of depression and overall functioning–and maintained that benefit for the two weeks remaining in the study.  When the study was stopped the responders gradually lost  the benefit and a month later were at the same level of depression as the patients on placebo.   I suspect the reason for the 5 ½ month delay in benefit is because the dose was too low.   NAC is rapidly metabolized.  Only 10 percent of the amount consumed reaches the bloodstream–and some authorities say only 2 to 5%.   Thus, of a 2000mg dose, only 200mg stays in the blood for an appreciable time, and only a fraction of this enters the brain.  I suspect 4000mg [4 grams/day] would be a better dose.
  • This is practically the first time treatment in psychiatry was devised by looking at the mechanism of the disorder first, and then postulating a place to intervene–whereas all other treatments in psychiatry were found by accident. Later, better drugs have been “me-too” drugs designed to mimic the original ones.  
  • From Berk’s abstract: Antioxidant treatment of the glutathione deficiency in bipolar disorder with n-acetyl cysteine: a double-blind randomized placebo-controlled trial.  M Berk DL Copolov a, Background: Oxidative stress is documented to occur in bipolar disorder. Existing mood stabilizers have effects on oxidative biology. Glutathione is the body’s major endogenous free radical scavenger. N-acetyl cysteine (NAC) is a tolerable, orally bioavailable precursor of glutathione. Methods: 75 individuals with bipolar disorder who were treated with NAC (1-gram BID) as an add-on to their usual mood stabilizer medication over a 6-month period, At the one-month post discontinuation visit there was no longer any significant difference between the groups on any of the outcome measures. There were no significant between-group differences in treatment-emergent adverse events. A calculation of effect sizes revealed significant improvements in the medium range, from 0.3930 to 0.64. Conclusions: NAC ameliorates depressive symptoms in the maintenance phase, addressing a major unmet need.  

SIDE EFFECTSI have seen  mild dyspepsia rarely—i.e., an upset stomach.  My first NAC patient found 9600mg/d worked best.  He had insomnia on 12,000mg.  

         Daily levels of 1,000 milligrams of NAC per kilogram in rats for several months did not produce adverse effects in behavior, weight gain, hematology, liver function and kidney function. (That’s the equivalent of 60 grams/ 120 pills of NAC per day for a 132-pound person.)   The very large quantities of NAC used for treating acetaminophen overdoses have produced adverse reactions such as nausea, vomiting, and other gastrointestinal symptoms–and sometimes allergic reactions.  For acetaminophen overdose in someone who weighs 220 lbs  the dose is 15 grams initially and then 7.5 grams every 4 hours for 3 days [17 doses] = 142.5 grams = 236 of the 600mg pills in 3 days—~10 times the daily dose for depression.

In a study treating severe alcoholic hepatitis (NEJM 11/10/11, p 1781), the max NAC used was 100mg/kg I.V. over 16 hours.  For a 70 kg person,  7000 I.V. is equivalent to 70,000 mg p.o.—i.e., 70 grams vs the 4 grams suggested for NAC

NAC (N acetyl cysteine) apparently lowers triglycerides but I don’t know the dose;  NAC helps diabetes [adding taurine to NAC accentuates the benefit of NAC].  It works for many things in medicine and psychiatry. There are was a report of  NAC working for nail biting

 NAC and Vitamin D for OCD, di Michele, Flavia Current Pharmaceutical Design, 2018  [vitamin D has a specific property of stimulating the formation of glutathione in the brain]. 

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