Ralph Metzner Ph.D. is an American psychologist, writer, and researcher (born in Germany), who participated in psychedelic research at Harvard University in the early 1960s with Timothy Leary, Richard Alpert (Ram Dass), and Andrew Weil. Dr. Metzner is a psychotherapist and Professor Emeritus of psychology at the California Institute of Integral Studies in San Francisco, where he was formerly the Academic Dean and Academic Vice-president.

Dr. Metzner has been involved in consciousness research, including psychedelics, yoga, meditation, and shamanism for over 45 years. He is a co-founder and President of the Green Earth Foundation, a non-profit educational organization devoted to healing and harmonizing the relationship between humans and the Earth. Metzner was featured in the 2006 film Entheogen: Awakening the Divine Within, a documentary about rediscovering an enchanted cosmos in the modern world.

His books include Green Psychology: Transforming our Relationship to the Earth (1999), Well of Remembrance: Rediscovering the Earth Wisdom Myths of Northern Europe (2001, originally 1994), and The Unfolding Self: Varieties of Transformative Experience (2010), among many others.

He was the guest of Dr. David Van Nuys earlier this week on Shrink Rap Radio.

Shrink Rap Radio #386 – An Update on Mind-Expanding Substances with Ralph Metzner PhD

A psychology podcast by David Van Nuys, Ph.D.
copyright 2014: David Van Nuys, Ph.D.
Posted on January 16, 2014

Ralph Metzner, Ph.D., a graduate of Oxford and Harvard, is a recognized pioneer in psychological, philosophical and cross-cultural studies of consciousness and its transformations. He collaborated with Leary and Alpert in classic studies of psychedelics at Harvard University in the 1960s, co-authored The Psychedelic Experience and was editor of The Psychedelic Review. He is a psychotherapist and Professor Emeritus at the California Institute of Integral Studies, where he was also the Academic Dean for ten years in the 1980s. His books include The Unfolding Self, The Well of Remembrance, Green Psychology, The Expansion of Consciousness, Alchemical Divination, and Mind Space and Time Stream. He is the editor of two collections of essays on the pharmacology, anthropology and phenomenology of ayahuasca and of psilocybin mushrooms. He is also the president and co-founder of the Green Earth Foundation, dedicated to healing and harmonizing the relations between humanity and the Earth.

Podcast: Play in new window | Download 

Check out the following Psychology CE Courses based on listening to Shrink Rap Radio interviews:

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• Pros and Cons of Positive Psychology (5 CEUs)
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Sam Polk - For the Love of Money (Wealth Addiction)

This is an excellent first-person account of one man's struggle with addictions, first drugs and the wealth and power on Wall Street. This comes from the New York Times Sunday Review.

For the Love of Money

By SAM POLKJAN. 18, 2014

Launch media viewer Owen Freeman

IN my last year on Wall Street my bonus was $3.6 million — and I was angry because it wasn’t big enough. I was 30 years old, had no children to raise, no debts to pay, no philanthropic goal in mind. I wanted more money for exactly the same reason an alcoholic needs another drink: I was addicted.

Eight years earlier, I’d walked onto the trading floor at Credit Suisse First Boston to begin my summer internship. I already knew I wanted to be rich, but when I started out I had a different idea about what wealth meant. I’d come to Wall Street after reading in the book “Liar’s Poker” how Michael Lewis earned a $225,000 bonus after just two years of work on a trading floor. That seemed like a fortune. Every January and February, I think about that time, because these are the months when bonuses are decided and distributed, when fortunes are made.

I’d learned about the importance of being rich from my dad. He was a modern-day Willy Loman, a salesman with huge dreams that never seemed to materialize. “Imagine what life will be like,” he’d say, “when I make a million dollars.” While he dreamed of selling a screenplay, in reality he sold kitchen cabinets. And not that well. We sometimes lived paycheck to paycheck off my mom’s nurse-practitioner salary.

Dad believed money would solve all his problems. At 22, so did I. When I walked onto that trading floor for the first time and saw the glowing flat-screen TVs, high-tech computer monitors and phone turrets with enough dials, knobs and buttons to make it seem like the cockpit of a fighter plane, I knew exactly what I wanted to do with the rest of my life. It looked as if the traders were playing a video game inside a spaceship; if you won this video game, you became what I most wanted to be — rich.

IT was a miracle I’d made it to Wall Street at all. While I was competitive and ambitious — a wrestler at Columbia University — I was also a daily drinker and pot smoker and a regular user of cocaine, Ritalin and ecstasy. I had a propensity for self-destruction that had resulted in my getting suspended from Columbia for burglary, arrested twice and fired from an Internet company for fistfighting. I learned about rage from my dad, too. I can still see his red, contorted face as he charged toward me. I’d lied my way into the C.S.F.B. internship by omitting my transgressions from my résumé and was determined not to blow what seemed a final chance. The only thing as important to me as that internship was my girlfriend, a starter on the Columbia volleyball team. But even though I was in love with her, when I got drunk I’d sometimes end up with other women.

Three weeks into my internship she wisely dumped me. I don’t like who you’ve become, she said. I couldn’t blame her, but I was so devastated that I couldn’t get out of bed. In desperation, I called a counselor whom I had reluctantly seen a few times before and asked for help.

She helped me see that I was using alcohol and drugs to blunt the powerlessness I felt as a kid and suggested I give them up. That began some of the hardest months of my life. Without the alcohol and drugs in my system, I felt like my chest had been cracked open, exposing my heart to air. The counselor said that my abuse of drugs and alcohol was a symptom of an underlying problem — a “spiritual malady,” she called it. C.S.F.B. didn’t offer me a full-time job, and I returned, distraught, to Columbia for senior year.

After graduation, I got a job at Bank of America, by the grace of a managing director willing to take a chance on a kid who had called him every day for three weeks. With a year of sobriety under my belt, I was sharp, cleareyed and hard-working. At the end of my first year I was thrilled to receive a $40,000 bonus. For the first time in my life, I didn’t have to check my balance before I withdrew money. But a week later, a trader who was only four years my senior got hired away by C.S.F.B. for $900,000. After my initial envious shock — his haul was 22 times the size of my bonus — I grew excited at how much money was available.

Over the next few years I worked like a maniac and began to move up the Wall Street ladder. I became a bond and credit default swap trader, one of the more lucrative roles in the business. Just four years after I started at Bank of America, Citibank offered me a “1.75 by 2” which means $1.75 million per year for two years, and I used it to get a promotion. I started dating a pretty blonde and rented a loft apartment on Bond Street for $6,000 a month.

I felt so important. At 25, I could go to any restaurant in Manhattan — Per Se, Le Bernardin — just by picking up the phone and calling one of my brokers, who ingratiate themselves to traders by entertaining with unlimited expense accounts. I could be second row at the Knicks-Lakers game just by hinting to a broker I might be interested in going. The satisfaction wasn’t just about the money. It was about the power. Because of how smart and successful I was, it was someone else’s job to make me happy.

Still, I was nagged by envy. On a trading desk everyone sits together, from interns to managing directors. When the guy next to you makes $10 million, $1 million or $2 million doesn’t look so sweet. Nonetheless, I was thrilled with my progress.

My counselor didn’t share my elation. She said I might be using money the same way I’d used drugs and alcohol — to make myself feel powerful — and that maybe it would benefit me to stop focusing on accumulating more and instead focus on healing my inner wound. “Inner wound”? I thought that was going a little far and went to work for a hedge fund.

Now, working elbow to elbow with billionaires, I was a giant fireball of greed. I’d think about how my colleagues could buy Micronesia if they wanted to, or become mayor of New York City. They didn’t just have money; they had power — power beyond getting a table at Le Bernardin. Senators came to their offices. They were royalty.

I wanted a billion dollars. It’s staggering to think that in the course of five years, I’d gone from being thrilled at my first bonus — $40,000 — to being disappointed when, my second year at the hedge fund, I was paid “only” $1.5 million.

Launch media viewer Owen Freeman

But in the end, it was actually my absurdly wealthy bosses who helped me see the limitations of unlimited wealth. I was in a meeting with one of them, and a few other traders, and they were talking about the new hedge-fund regulations. Most everyone on Wall Street thought they were a bad idea. “But isn’t it better for the system as a whole?” I asked. The room went quiet, and my boss shot me a withering look. I remember his saying, “I don’t have the brain capacity to think about the system as a whole. All I’m concerned with is how this affects our company.”

I felt as if I’d been punched in the gut. He was afraid of losing money, despite all that he had.

From that moment on, I started to see Wall Street with new eyes. I noticed the vitriol that traders directed at the government for limiting bonuses after the crash. I heard the fury in their voices at the mention of higher taxes. These traders despised anything or anyone that threatened their bonuses. Ever see what a drug addict is like when he’s used up his junk? He’ll do anything — walk 20 miles in the snow, rob a grandma — to get a fix. Wall Street was like that. In the months before bonuses were handed out, the trading floor started to feel like a neighborhood in “The Wire” when the heroin runs out.

I’d always looked enviously at the people who earned more than I did; now, for the first time, I was embarrassed for them, and for me. I made in a single year more than my mom made her whole life. I knew that wasn’t fair; that wasn’t right. Yes, I was sharp, good with numbers. I had marketable talents. But in the end I didn’t really do anything. I was a derivatives trader, and it occurred to me the world would hardly change at all if credit derivatives ceased to exist. Not so nurse practitioners. What had seemed normal now seemed deeply distorted.

I had recently finished Taylor Branch’s three-volume series on the Rev. Dr. Martin Luther King Jr. and the civil rights movement, and the image of the Freedom Riders stepping out of their bus into an infuriated mob had seared itself into my mind. I’d told myself that if I’d been alive in the ‘60s, I would have been on that bus.

But I was lying to myself. There were plenty of injustices out there — rampant poverty, swelling prison populations, a sexual-assault epidemic, an obesity crisis. Not only was I not helping to fix any problems in the world, but I was profiting from them. During the market crash in 2008, I’d made a ton of money by shorting the derivatives of risky companies. As the world crumbled, I profited. I’d seen the crash coming, but instead of trying to help the people it would hurt the most — people who didn’t have a million dollars in the bank — I’d made money off it. I don’t like who you’ve become, my girlfriend had said years earlier. She was right then, and she was still right. Only now, I didn’t like who I’d become either.

Wealth addiction was described by the late sociologist and playwright Philip Slater in a 1980 book, but addiction researchers have paid the concept little attention. Like alcoholics driving drunk, wealth addiction imperils everyone. Wealth addicts are, more than anybody, specifically responsible for the ever widening rift that is tearing apart our once great country. Wealth addicts are responsible for the vast and toxic disparity between the rich and the poor and the annihilation of the middle class. Only a wealth addict would feel justified in receiving $14 million in compensation — including an $8.5 million bonus — as the McDonald’s C.E.O., Don Thompson, did in 2012, while his company then published a brochure for its work force on how to survive on their low wages. Only a wealth addict would earn hundreds of millions as a hedge-fund manager, and then lobby to maintain a tax loophole that gave him a lower tax rate than his secretary.

DESPITE my realizations, it was incredibly difficult to leave. I was terrified of running out of money and of forgoing future bonuses. More than anything, I was afraid that five or 10 years down the road, I’d feel like an idiot for walking away from my one chance to be really important. What made it harder was that people thought I was crazy for thinking about leaving. In 2010, in a final paroxysm of my withering addiction, I demanded $8 million instead of $3.6 million. My bosses said they’d raise my bonus if I agreed to stay several more years. Instead, I walked away.

The first year was really hard. I went through what I can only describe as withdrawal — waking up at nights panicked about running out of money, scouring the headlines to see which of my old co-workers had gotten promoted. Over time it got easier — I started to realize that I had enough money, and if I needed to make more, I could. But my wealth addiction still hasn’t gone completely away. Sometimes I still buy lottery tickets.

In the three years since I left, I’ve married, spoken in jails and juvenile detention centers about getting sober, taught a writing class to girls in the foster system, and started a nonprofit called Groceryships to help poor families struggling with obesity and food addiction. I am much happier. I feel as if I’m making a real contribution. And as time passes, the distortion lessens. I see Wall Street’s mantra — “We’re smarter and work harder than everyone else, so we deserve all this money” — for what it is: the rationalization of addicts. From a distance I can see what I couldn’t see then — that Wall Street is a toxic culture that encourages the grandiosity of people who are desperately trying to feel powerful.

I was lucky. My experience with drugs and alcohol allowed me to recognize my pursuit of wealth as an addiction. The years of work I did with my counselor helped me heal the parts of myself that felt damaged and inadequate, so that I had enough of a core sense of self to walk away.

Dozens of different types of 12-step support groups — including Clutterers Anonymous and On-Line Gamers Anonymous — exist to help addicts of various types, yet there is no Wealth Addicts Anonymous. Why not? Because our culture supports and even lauds the addiction. Look at the magazine covers in any newsstand, plastered with the faces of celebrities and C.E.O.'s; the superrich are our cultural gods. I hope we all confront our part in enabling wealth addicts to exert so much influence over our country.

I generally think that if one is rich and believes they have “enough,” they are not a wealth addict. On Wall Street, in my experience, that sense of “enough” is rare. The money guy doing a job he complains about for yet another year so he can add $2 million to his $20 million bank account seems like an addict.

I recently got an email from a hedge-fund trader who said that though he was making millions every year, he felt trapped and empty, but couldn’t summon the courage to leave. I believe there are others out there. Maybe we can form a group and confront our addiction together. And if you identify with what I’ve written, but are reticent to leave, then take a small step in the right direction. Let’s create a fund, where everyone agrees to put, say, 25 percent of their annual bonuses into it, and we’ll use that to help some of the people who actually need the money that we’ve been so rabidly chasing. Together, maybe we can make a real contribution to the world.


~ Sam Polk is a former hedge-fund trader and the founder of the nonprofit Groceryships. A version of this op-ed appears in print on January 19, 2014, on page SR1 of the New York edition with the headline: For the Love of Money.

This is a cool interview with my favorite comedian, Eddie Izzard. It's fun to hear a little of his background with wanting it all right now as a young man, then putting in the work and finding amazing success.

Comedians@Google: Eddie Izzard

Uploaded on Aug 18, 2011


Eddie Izzard stops by Google for a conversation about his life, his influences, and comedy. The interview was conducted by Mark Day.

Gary Taubes - Why We Get Fat: And What to Do About It (Authors@Google)

This talk is going on three years old, but the information is still relevant and crucial to understand if we ever hope to do anything about the "obesity epidemic."

Gary Taubes - Why We Get Fat: And What to Do About It

Uploaded on May 4, 2011


Gary Taubes spoke to Googlers in Mountain View on May 2, 2011 about his book Why We Get Fat: And What to Do About It.

About the book:

An eye-opening, myth-shattering examination of what makes us fat, from acclaimed science writer Gary Taubes.

Building upon this critical work in Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health, Taubes revisits the urgent question of what's making us fat and how we can change in this exciting new book. Persuasive, straightforward, and practical, Why We Get Fat makes Taubess crucial argument newly accessible to a wider audience.

Taubes reveals the bad nutritional science of the last century, none more damaging or misguided than the calories-in, calories-out model of why we get fat, and the good science that has been ignored, especially regarding insulins regulation of our fat tissue. He also answers the most persistent questions: Why are some people thin and others fat? What roles do exercise and genetics play in our weight? What foods should we eat, and what foods should we avoid?

Packed with essential information and concluding with an easy-to-follow diet, Why We Get Fat is an invaluable key in our understanding of an international epidemic and a guide to what each of us can do about it.

About the Author:

Gary Taubes is a contributing correspondent for Science magazine, and his writing has also appeared in The Atlantic, The New York Times Magazine, and Esquire. His work has been included in The Best of the Best American Science Writing (2010), and has received three Science in Society Journalism Awards from the National Association of Science Writers, the only print journalist so recognized. He is currently a Robert Wood Johnson Foundation Investigator in Health Policy Research at the University of California, Berkeley School of Public Health.

Grain Brain, Sugars, and Brain Health

 

James R Hamblin's review (This Is Your Brain on Gluten) in The Atlantic (where he is a senior editor) of David Perlmutter's Grain Brain: The Surprising Truth about Wheat, Carbs, and Sugar--Your Brain's Silent Killers has generated a lot of backlash against Perlmutter's claims in the book.

Perlmutter makes a few claims that are nearly opposite of what mainstream nutrition teaches us is true (as in the 1992 USDA Food Pyramid above):

1. Gluten is poison, and we should not eat any wheat (or rye, barley, and several other grains)
2. Sugars, especially fructose, are also poisons and we should seriously restrict their intake
3. LDL cholesterol is only a problem when it becomes oxidized (which occurs with carbohydrate consumption)
4. Cholesterol is good for us - there is no such thing as too much
5. If we adhere to these four points, we can prevent a LOT of neurodegenerative diseases

Perlmutter has introduced his own "inverse food pyramid" that resembles the one created by Dr. Mercola, although Perlmutter places an even greater emphasis on consuming fats (they should be 70% of our calories according to his model) than Mercola does:

 

There is also a brief video of Perlmutter outlining his inverse food pyramid:


Hamblin's review in The Atlantic was highly skeptical in tone and content - but while he tried to refute several of Perlmutter's central ideas, the research he sites supports the premise, although it is not nearly as conclusive as Perlmutter presents it.

I read the book with an eye for the most dangerous claim. What stuck out to me was Perlmutter’s case for cholesterol. He basically says that we can’t have too much.

“Nothing could be further from the truth than the myth that if we lower our cholesterol levels, we might have a chance of living longer and healthier lives,” Perlmutter writes . He recommends disowning the notion that LDL is bad cholesterol and HDL is good cholesterol; rather, both are generally good. LDL is only bad when it is oxidized, and it only becomes so in the presence of the sort of oxidative stress brought about by carbs and gluten. Avoid those, and cholesterol is innocuous.

Beyond that, Perlmutter says that cholesterol-lowering statin medicines like Lipitor, which are prescribed for a quarter of Americans over 40, should actually be vehemently avoided. Cholesterol is necessary for the brain in high levels, he says, and lowering it is contributing to dementia.

I took this to Katz, too.

“Is there a weight of evidence that says we can totally ignore both dietary cholesterol and LDL? Absolutely not,” he said. “You can legitimately say we’re starting to rethink some things, but ignoring LDL could absolutely result in heart attacks and strokes. Perlmutter is way ahead of any justifiable conclusion.”

The medical community’s understanding of the danger of cholesterol is changing. Many cardiologists are starting to think that independent of other considerations, the level of LDL in our blood may not be as important as it previously seemed. In November, the American Heart Association and the American College of Cardiology released new guidelines that redefined the use of statins. While they continue to recommend that people at high risk for heart disease and people with LDL levels above 189 take a statin, the long-standing goal of lowering one’s LDL level to 70 is no longer deemed worthwhile to monitor.

The reality about cholesterol is not quite as clear-cut as Perlmutter argues, but it is true that there is only about a 5-15% correlation between dietary intake of cholesterol and blood levels of cholesterol. From Wikipedia:

Most ingested cholesterol is esterified, and esterified cholesterol is poorly absorbed. The body also compensates for any absorption of additional cholesterol by reducing cholesterol synthesis.^[9] For these reasons, cholesterol intake in food has little, if any, effect on total body cholesterol content or concentrations of cholesterol in the blood.

The primary reason for this, as Perlmutter describes, is that the body would much prefer to use dietary cholesterol for the many cellular and hormonal processes based on its metabolism (most notably as an essential structural component of cell membranes and necessary to establish proper membrane permeability and fluidity, as well as it's role as the building block of sex hormones like testosterone and estrogen). Making cholesterol from sugars and saturated fats is an energy demanding process. Importantly, cholesterol is NOT really a fat - it is technically a sterol, a modified steroid.

LDL cholesterol is the evil cause of heart disease and a host of other diseases according to the medical mainstream. However, research from a few years back indicates that low cholesterol may actually cause more non-coronary deaths than high cholesterol. Moreover, as Perlmutter argues, statins that lower cholesterol compromise brain function because they don't only stop the liver from making cholesterol, they also stop the brain from doing so.

Yeon-Kyun Shin, a biophysics professor in the department of biochemistry, biophysics and molecular biology, says the results of his study show that drugs that inhibit the liver from making cholesterol may also keep the brain from making cholesterol, which is vital to efficient brain function.

"If you deprive cholesterol from the brain, then you directly affect the machinery that triggers the release of neurotransmitters," said Shin. "Neurotransmitters affect the data-processing and memory functions. In other words -- how smart you are and how well you remember things."

Another fallacy around cholesterol and health is that fat is the primary source of increased circulating LDL cholesterol. Fructose is a much larger issue - as soon as fructose is ingested it goes straight to the liver where it is converted into triglycerides to be stored as fat. Considering the enormous levels of high-fructose corn syrup consumed by the Western world, it's no wonder obesity is such a rampant problem.

The effects of different dietary sugars, with or without exogenously induced hyperinsulinemia, on rat plasma triglyceride kinetics have been studied. Glucose, sucrose, or fructose were supplied as 10% drinking solutions. The sugar-supplemented groups were each divided into subgroups, one receiving 6 U of insulin per day for 2 wk from intraperitoneally implanted minipumps and the other receiving none. The same degree of hyperglycemia and of endogenous hyperinsulinemia was seen in each sugar-supplemented group. Infusing exogenous insulin restored normoglycemia and produced more pronounced but equal hyperinsulinemia in each subgroup. In those rats that received no exogenous insulin, triglyceride production increased 18% in the sucrose-supplemented group and 20% in the fructose supplemented subgroups, but not at all in the glucose-supplemented subgroup. This 20% increase in triglyceride production in the fructose-supplemented subgroup was accompanied by a six times greater (120%) increase in triglyceride concentration. This suggested that dietary fructose not only increased triglyceride production, but also impaired triglyceride removal. Exogenously induced hyperinsulinemia further increased triglyceride production in those rats receiving dietary fructose, either as the monosaccharide or as sucrose, but not in those receiving only glucose. Thus, in the presence of fructose, but not glucose, insulin stimulates triglyceride production. As exogenous insulin returned the triglyceride concentrations to normal in the fructose-supplemented rats, it also appeared to overcome any fructose-associated impairment of triglyceride removal.

[Emphasis added.] While fructose is clearly the culprit in triglyceride levels, glucose is not so harmless as the above study might indicate. Perlmutter claims that glucose is very damaging to the brain, and there is research to support a correlation, although not yet a causative relationship:

Our results indicate that even in the absence of manifest type 2 diabetes mellitus or impaired glucose tolerance, chronically higher blood glucose levels exert a negative influence on cognition, possibly mediated by structural changes in learning-relevant brain areas. Therefore, stratgies aimed at lowering glucose levels even in the normal range may beneficially influence cognition in the older population, a hypothesis to be examined in future interventional trials.

So it appears that Perlmutter is not so far off after all. He is a little too absolute given the current evidence, but it's not likely that the millions of Americans who read his book are actually going to stop eating wheat and other grain products - Americans are simply not that concerned with the long-term consequences of immediate whims and desires.

Here is a longer talk by Perlmutter being interviewed for Underground Wellness:


Here are time notes:

5:06 -- The impact Dr. Perlmutter had on Dr. Oz.
9:10 -- Why you shouldn't let the government tell you what to eat.
14:42 -- LDL vs oxidized LDL -- know the difference!
17:10 -- 4 vital functions that require cholesterol in the brain.
20:20 -- Why cholesterol should be your BFF, not your worst enemy.
23:43 -- Is whole-grain wheat bread more toxic than a Snickers bar?
29:07 -- Your brain on gluten.
32:20 -- Heard of leaky gut? There's even leaky brain.
34:15 -- Do your kids a favor -- put them on a gluten-free diet.
36:15 -- Dr. Perlmutter's opinion on quinoa.
38:40 -- The antioxidant hoax. And why Sean was right about Protandim.
40:52 -- 5 foods that prevent oxidative stress.
42:00 -- Caller Q: Can gluten-free products still affect the brain?
44:26 -- Caller Q: Is brain fog the result of a gluten sensitivity?
46:47 -- Caller Q: How effective is liposomal glutathione?
49:10 -- Caller Q: If you're on a gluten-free diet, do you only eat protein and vegetables?
51:06 -- Caller Q: Are there other harmful elements in grains beyond gluten?
55:45 -- Caller Q: Is there a difference between the diet Dr. Perlmutter recommends and the paleo diet?
57:30 -- Caller Q: What is Dr. Perlmutter's opinion on the supplement KetoForce?
1:01:24 -- Caller Q: Can you fully recover from damage caused by gluten?
1:03:10 -- Why MS is a gut-related disease
1:09:41 -- Suffering from blood sugar issues? Here's a marker you should test for.
1:15:35 -- How to lower triglycerides.
1:16:33 -- Report your gluten-free success stories to Dr. Perlmutter!
1:17:56 -- The Grain Brain breakdown.

The Future of Medicinal Marijuana - Less High (THC), More Healing (CBD)

Hashish Smokers by Gaetano Previati, 1877. Private collection. Photo by Getty Images

I'm sure this will harsh the high of some dedicated marijuana users, but the future of good weed lies in reducing the THC content through breeding while increasing the CBD content.

• THC: tetrahydrocannabinol, the primary psychoactive compound in cannabis and is what causes the subjective "high"
• CBD: cannabidiol, produces the calming, anti-anxiety effects of the drug

The illicit marijuana market has systematically increased the THC content by 10-15% over the last decade or so. At the same time, there has been a significant reduction of CBD, sometimes to levels as low as 0.1%. A recent article in The Guardian (UK) suggests that this high-THC/low-CBD marijuana, "skunk weed," is something new, but it was the goal 30 years ago when I was still smoking weed.

From Wikipedia:

Decades ago, growers in the US bred CBD almost entirely out of cannabis plants because their customers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.[50] To meet the demands of medical cannabis patients, growers are developing more CBD-rich strains.[52]

In November 2012, an Israeli medical cannabis facility announced a new strain of the plant which has only cannabidiol as an active ingredient, and virtually no THC, providing some of the medicinal benefits of cannabis without the euphoria.[53][54] The researchers said the cannabis plant, enriched with CBD, "can be used for treating diseases like rheumatoid arthritis, colitis, liver inflammation, heart disease and diabetes". Research on CBD enhanced cannabis began in 2009, resulting in Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC. Raphael Mechoulam, leading cannabinoid researcher, noted "It is possible that (Avidekel's) CBD to THC ratio is the highest among medical marijuana companies in the world, but the industry is not very organized, so one cannot keep exact track of what each company is doing".[55]

One wonders if all of the people on the internet arguing so vociferously for marijuana legalization based on its medicinal qualities would still support legalization if only the high-CBD strains were allowed.

From Project CBD:

Cannabidiol (CBD) is a compound in cannabis that has medical effects but does not make people feel “stoned” and can actually counter the psychoactive effects of THC. After decades in which only high-THC Cannabis was available, CBD-rich strains are now being grown by and for medical users.  

The reduced psychoactivity of CBD-rich cannabis makes it an appealing treatment option for patients seeking anti-inflammatory, anti-pain, anti-anxiety, and anti-psychotic effects without disconcerting lethargy or dysphoria.

Scientific studies underscore CBD’s potential as a treatment for many conditions, including chronic pain, diabetes, cancer, cardiovascular disease, alcoholism, PTSD, schizophrenia, antibiotic-resistant infections, rheumatoid arthritis, MS, epilepsy, and other neurological disorders. 

There is significant scientific evidence that THC has some seriously negative effects on the human brain. The results from a 2008 study in the British Journal of Psychiatry compared THC only, THC+CBD, and no cannabis found clear differences in levels of delusions and anhedonia:

Our results show higher levels of unusual experiences – an analogue of hallucinations and delusions – in individuals who had evidence of only Δ9-THC in their hair compared with those with both Δ9-THC and CBD, and those with no cannabinoid. There were also greater levels of delusions in this THC only group compared with individuals who showed no evidence of cannabinoids in their hair, with a similar trend in the THC+CBD group. The THC+CBD group reported less anhedonia than the other two groups.

A 2012 study in Psychological Medicine reached similar conclusions:

CBD attenuates the psychotic-like effects of cannabis over time in recreational users. Higher THC negatively impacts on memory and psychological well-being. These findings raise concerns for the harms stemming from use of varieties such as ‘skunk’ (sensimillia), which lack any CBD but currently dominate the supply of cannabis in many countries.

A 2012 study published in the Proceedings of the National Academy of Sciences found that ongoing marijuana use compromised cognitive functions across a the whole spectrum, including memory and intelligence. They also found that subjects who showed marijuana dependence by age 18 suffered greater IQ losses than those who did not. Here is the abstract:

Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health. Concomitantly, adolescents are initiating cannabis use at younger ages, and more adolescents are using cannabis on a daily basis. The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users. Participants were members of the Dunedin Study, a prospective study of a birth cohort of 1,037 individuals followed from birth (1972/1973) to age 38 y. Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 y. Neuropsychological testing was conducted at age 13 y, before initiation of cannabis use, and again at age 38 y, after a pattern of persistent cannabis use had developed. Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, even after controlling for years of education. Informants also reported noticing more cognitive problems for persistent cannabis users. Impairment was concentrated among adolescent-onset cannabis users, with more persistent use associated with greater decline. Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users. Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents.

The negative impact of cannabis use on young people is not unexpected. The adolescent and teen years are the second most important period of brain development in a person's life (after infancy). It is also not surprising then that cannabis use in kids and teens doubles the risk for psychosis and schizophrenia - Dialogues in Clinical Neuroscience, 2005.

The authors in the above study suggest that cannabis is not solely responsible for the higher rates of serious mental illness. They argue that young people with premorbid symptoms of future psychosis are much more likely to self-medicate with marijuana.

It's clear based on the information above that THC is the likely culprit in memory loss, IQ decline, and increased risk of mental illness. With this understanding, legalization of marijuana should be predicated on the production and sale of high-CBD strains with little or no THC.

Here is a recent article from The Guardian (UK) that suggests people are finally starting to understand that the benefits of marijuana are found in the CBD and not in the THC.

Cannabis and memory loss: dude, where's my CBD?

Legalisation presents an opportunity to promote cannabis rich in a chemical that protects against its negative effects

Dude, Where's My Car? CBD in cannabis is thought to protect against dependence, psychotic symptoms … and memory loss. Photograph: Sportsphoto/Allstar/Cinetext
It isn't often that science and pop culture overlap, but the two fields are in agreement when it comes to the familiar trope of the forgetful stoner.

A recent study published in Schizophrenia Bulletin is the latest to reveal the detrimental effects that cannabis can have on memory. The authors report that people dependent on the drug – both healthy individuals and patients with schizophrenia – show impairments in memory compared with healthy volunteers and non-smoking schizophrenia patients.

Even more striking, the cannabis-using groups had significant decreases in the volume of two brain areas that are important for processing rewards, learning and working memory – the thalamus and striatum – and these changes were linked to their memory problems. There was no evidence to connect cannabis use and schizophrenia – the authors simply compare the two groups. However, previous studies have found a higher prevalence of psychosis among regular cannabis smokers.

Reports of memory loss with long-term cannabis use are nothing new, and an influential paper published last year provided evidence that smoking marijuana has a deleterious effect on intelligence. In the investigation, the cognitive abilities of participants were tested several times over the course of 25 years. The researchers found that heavy cannabis users had significant decreases in intelligence and memory ability as they aged, not only compared with non-smokers, but also compared with their younger selves. Additionally, the earlier they started smoking pot, the bigger the cognitive decline.

Obviously these findings are worrying, especially given the recent spate of cannabis legalisations in states across the US and in countries such as Uruguay. However, before we all start worrying about the good people of Colorado and Washington, it might be helpful to look closer at what's actually in the cannabis we're smoking nowadays, and what ingredients are contributing to these cognitive deficits.

THC (tetrahydrocannabinol) is the primary psychoactive compound in cannabis and is what causes the subjective "high". This includes changes in perceptual sensations, a feeling of contentedness and increased appetite. However, THC is also linked to many of the potential negative consequences of cannabis use, such as dependence, psychotic symptoms, and impaired memory and cognition.

Another important component, CBD (cannabidiol, which works by increasing natural cannabinoid levels in the brain) is associated with the calming, anti-anxiety effects of the drug. In addition, CBD is thought to protect against many of the potential negative effects of marijuana, including dependence, psychotic symptoms and cognitive impairments.

The THC concentration in cannabis has increased by as much as 12% over the past 30 years, making the drug much stronger than it used to be. At the same time, there has been a significant depletion of CBD, sometimes to levels as low as 0.1%. "Skunk", as this new strain of high-THC/low-CBD marijuana is called, is flooding the illegal marijuana market, and it is this variety that is thought to be behind the rise in cannabis dependence diagnoses, links to schizophrenia, and cognitive deficits seen over the past decade.

The changing chemical make-up of cannabis appears to be partly accidental and partly deliberate. New strains are often bred to have higher levels of THC in them, increasing the drug's potency. However, modern growing techniques have also affected these chemical levels. For example, illegal growers have turned to indoor marijuana farms to avoid detection. Growing cannabis locally in such farms also circumvents the need to import the drug, and guarantees a more reliable harvest. However, the 24-hour lighting used in these farms inadvertently reduces CBD levels in the plant. Thus, these new strains are not only bred for higher potency, with elevated THC content, they are also lacking the protection provided by CBD against the drug's negative effects.

It should be noted that the majority of research into cognitive deficits and cannabis use has focused on heavy or dependent users, and there's little evidence that occasional smokers show any of the problems mentioned above. But with the recent changes in drug policy, the chances are that more people will be smoking cannabis than ever before, and the more potent and more popular high-THC/low-CBD marijuana that is available today will increase their risk of dependence.

The recent legalisation of recreational and medicinal marijuana in parts of the US has the potential to reduce significantly the harms caused through incarceration or criminal records for minor drug-related offences. However, it also provides an opportunity to reduce the cognitive and psychiatric harms linked to cannabis use. With this shift in drug policy, it is now possible for states to monitor the commercial production of cannabis, regulating the levels of THC and CBD present in the drug. To facilitate this, they could force growers to use strains with higher levels of CBD, and revert to more old-fashioned farming methods that don't use round-the-clock lighting.

These changes could help protect individuals from the damaging effects of the drug, prevent the development of dependence in new users, and maybe even help our favorite Hollywood stoners remember where they left their car.

Why Sugar Makes Us Feel So Good (NPR)

Dr. Nicole M. Avena is the author of Why Diets Fail (Because You're Addicted to Sugar): Science Explains How to End Cravings, Lose Weight, and Get Healthy and the subject of this NPR story.

This revolutionary eating plan reveals definitive proof that sugar is addictive, and presents the first science-based program to cut out the sugar, stop the cravings that cause most diets to eventually fail, and lose weight--permanently.
If you’re like most people, you’ve tried a few (or maybe many) different diets without success. The truth is, most diets work for a while, but there’s usually a point at which the dietary restrictions become too difficult to maintain. Why? Because whether you’re following a low-carb, paleo, gluten-free, or even an all-liquid green juice diet, the addictive nature of sugar causes cravings to take over and sabotage your diet-of-the-moment.

In Why Diets Fail, Dr. Nicole M. Avena and John R. Talbott reveal definitive proof that sugar is addictive and present the first science-based program to stop the cravings and lose weight—permanently. A neuroscientist and food addiction expert, Dr. Avena has conducted groundbreaking research showing that sugar triggers the same responses in the brain as addictive drugs like cocaine, nicotine, and alcohol. And like those other substances, the more sugar you eat, the more you need to get the same pleasurable feelings. (No wonder your last diet didn’t stick.)

Avena and Talbott’s eight-step plan walks you through the process of going sugar-free and surviving the make-or-break withdrawal period—those first few weeks when your body feels the absence of its favorite sweetener most acutely. An easy-to-use Sugar Equivalency Table developed by Talbott lists the amount of sugar in hundreds of common foods so you know precisely what to eat and what to avoid. And when it comes to what you can eat, you have a lot to choose from. In fact, you’ll probably eat more on this diet than you normally do—while continuing to lose weight.

This science-based program is the diet to end all diets. It will help you break the yo-yo dieting cycle, end those maddening sugar cravings, and develop a new longing for the good food that will keep you fit, healthy, and happy.

Sugar (as well as gluten) is one of the most destructive substances in the human diet. Sugar acts much like heroin in the brain - a lot of dopamine gets released. The dopamine flood is not as great as with heroin, but it has many of the same addictive properties.

Why Sugar Makes Us Feel So Good

by Eliza Barclay
January 16, 2014


Last week, I reported that scientists are working their way toward a consensus that sugar is addictive. While some researchers are still hesitant to liken sweet stuff to drugs or alcohol, the evidence is accumulating to explain why some of us really struggle to resist or moderate our sugar intake. (I count myself among them.)

I mentioned a new book called Why Diets Fail (Because You're Addicted to Sugar): Science Explains How to End Cravings, Lose Weight, and Get Healthy by Nicole Avena, a neuroscientist and research psychologist at Columbia University who has done a lot of work in this area. She's particularly interested in the neurotransmitters and brain receptors involved in eating. In lab experiments with rats, she's shown how overeating tasty foods (like sugar) can produce changes in the brain and behavior that resemble addiction.

Avena has also just put out a clever TED-Ed video with colorful visuals to help explain the details of just why sugar makes our brains go bonkers.

As the video shows, the key player in the reward system of our brain — where we get that feeling of pleasure — is dopamine. Dopamine receptors are all over our brain. And doing a drug like heroin brings on a deluge of dopamine.

Guess what happens when we eat sugar? Yes, those dopamine levels also surge — though not nearly as much as they do with heroin.

Still, too much sugar too often can steer the brain into overdrive, the video says. And that kickstarts a series of "unfortunate events" — loss of control, cravings and increased tolerance to sugar. All of those effects can be physically and psychologically taxing over time, leading to weight gain and dependence.

The takeaway is pretty clear: If you're sensitive to sugar and inclined to indulge in a supersugary treat, do it rarely and cautiously. Otherwise, there's a pretty good chance that your brain is going to start demanding sugar loudly and often. And we're probably better off without that extra voice in our head.

 

This is an excellent review article on what we know about the potential of N-acetyl-cysteine for the treatment of various health issues. The most "exciting" work is in the ability of NAC to heal brain dysfunctions and neuropathies.


Full Citation:
Bavarsad Shahripour, R., Harrigan, M. R. and Alexandrov, A. V. (2014, Jan 13). N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain and Behavior. doi: 10.1002/brb3.208

N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities

Reza Bavarsad Shahripour, Mark R. Harrigan, Andrei V. Alexandrov

Abstract

Background

There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways.

Aim and discussion

Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht–Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.

Conclusion

Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage.

Introduction

Although N-acetylcysteine (NAC) is widely known as an antidote to acetaminophen overdose, it has multiple other uses supported by varying levels of evidence. These diverse clinical applications are linked to its ability to support the body's antioxidant and nitric oxide systems during stress, infections, toxic assault, and inflammatory conditions (Dekhuijzen 2004). Any situation resulting in a sudden or chronic overconsumption of oxygen can lead to the production reactive oxygen species (ROS). Production of ROS can occur in:

1. mitochondria,
2. inside the capillary system, and
3. an oxidative burst induced by inflammatory cells.

Approximately 2–5% of oxygen passing through the electron transport system inside the mitochondria results in superoxide. Superoxide is the most well-known of the free radicals as it is commonly produced during the natural pathway of oxidative phosphorylation (Kerksick and Willoughby 2005). ROS are produced primarily by the mitochondria as a by-product of normal cell metabolism during conversion of molecular oxygen (O2) to water (H2O). These include superoxide radical (O2−•), hydrogen peroxide (H2O2), and hydroxyl radical (•OH). Peroxisomes produce H2O2 during fatty acid degradation. H2O2 is mostly degraded into water by catalase, but some molecules may also escape into the cell (Ames et al. 1993). Oxidative stress occurs when there is an imbalance between oxidants and antioxidants. ROS can modify or damage DNA, proteins, and lipids in cells by oxidation and peroxidation (Beckman and Ames 1997; Lander 1997; Adler et al. 1999; Frank et al. 2000). There are several antioxidant defense mechanisms; however, both oxidants and antioxidants have a profound impact on the expression of genes. Antioxidants include vitamins C and E, and enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSHpx) (Yu 1994) as well as endogenous thiols, or sulfhydryl containing compounds such as glutathione (GSH) and thioredoxin (Pahl and Baeuerle 1994; Sen and Packer 1996; Arrigo 1999; Davis et al. 2001). NAC is a thiol, a mucolytic agent, and a precursor of l-cysteine and reduced GSH. NAC is a source of sulfhydryl groups in cells and scavenger of free radicals as it interacts with ROS such as OH• and H2O2 (Aruoma et al. 1989).

GSH is currently one of the most studied antioxidants as it is endogenously synthesized basically in all cells. Among many, established roles for GSH are the following:

1. antioxidant defense,
2. detoxification of electrophilic xenobiotics,
3. modulation of redox (oxidation–reduction reaction)-regulated signal transduction,
4. storage and transport of cysteine,
5. regulation of cell proliferation, synthesis of deoxyribonucleotide synthesis,
6. regulation of immune responses, as well as
7. regulation of leukotriene and prostaglandin metabolism.

GSH has an important role in maintaining the redox state of the cell (Kerksick and Willoughby 2005). It thereby exerts a profound protective effect on cells. Of the three amino acids in the GSH structure (glutamate, glycine, and cysteine), cysteine has the lowest intracellular concentration (Aruoma et al. 1989). Cysteine availability can limit the rate of GSH synthesis during times of oxidative stress. NAC is an acetylated cysteine residue able to increase cell protection to oxidative stress. NAC is an effective scavenger of free radicals as well as a major contributor to maintenance of the cellular GSH status. NAC can minimize the oxidative effect of ROS through correcting or preventing GSH depletion (Kerksick and Willoughby 2005).

By doing so, NAC may decrease the inflammation that occurs in conditions such as chronic obstructive pulmonary disease (COPD), influenza, and idiopathic pulmonary fibrosis. In addition to its antioxidant action, NAC acts as a vasodilator by facilitating the production and action of nitric oxide. This property is an important mechanism of action in the prophylaxis of contrast-induced nephropathy and the potentiation of nitrate-induced vasodilation (Millea 2009).

Uses of NAC in different diseases including cancer, cardiovascular diseases, human immunodeficiency virus (HIV) infections, acetaminophen-induced liver toxicity and metal toxicity have been reviewed previously (Kelly 1998; N-acetylcysteine 2000). This review focuses on the recent studies on the effects of NAC in a variety of neurological disorders and brain functions in animals and humans (Table 1).

Table 1. Summary of NAC mechanisms of action across different neurological disorders.

Disease	Mechanism
Neurodegenerative disorders: SCD, tardive dyskinesia, myoclonus epilepsy, Unverricht–Lundbor type	Antioxidant effect by free-radical scavenging and increased levels of glutathione (Arakawa and Ito 2007)
Down syndrome	Increase and modulation of the level of super oxidase dismutase (Busciglio and Yankner 1995; Behar and Colton 2003)
Multiple sclerosis	Free-radical scavenging and inhibition of TNF toxicity (Lehmann et al. 1994; Stanislaus et al. 2005)
Amyotrophic lateral sclerosis	Increasing the level of glutathione peroxidase and free-radical scavenging (Rosen et al. 1993; Louwerse et al. 1995)
Parkinson's disease	Increasing the level of glutathione and free-radical scavenging (Schapira et al. 1990; Martínez et al. 1999)
Huntington's disease	Free-radical trapping and preventing mitochondrial dysfunction (Fontaine et al. 2000; Stanislaus et al. 2005)
Alzheimer's disease	Increasing the level of glutathione (Adair et al. 2001; Tchantchou et al. 2005; Tucker et al. 2005)
Focal cerebral ischemia	NOS inhibition, regeneration of endothelium-derived relaxing factor, increasing glutathione levels, improving microcirculatory blood flow, and tissue oxygenation (Dawson and Dawson 1997; Cuzzocrea et al. 2000b)
Subarachnoid hemorrhage	Free-radicals scavenger, endothelial apoptosis inhibition, lipid peroxidation reduction, increasing glutathione levels, and SOD enzymatic activities, endothelial integrity protection (Findlay et al. 1989; Sen et al. 2006)
Traumatic brain injury	Repair of TBI-induced mitochondrial dysfunction, increasing the reduced antioxidant enzyme and glutathione levels, inhibition of the activation of NF-κB and TNF-α (Hoffer et al. 2002; Akca et al. 2005; Hsu et al. 2006; Chen et al. 2008)

Basic pharmacology of NAC

NAC exerts survival-promoting effects in several cellular systems (Mayer and Noble 1994). Cysteine is transported mainly by the alanine-serine-cysteine (ASC) system, a ubiquitous system of Na+-dependent neutral amino acid transport in a variety of cells (Bannai and Tateishi 1986; Ishige et al. 2005). NAC, however, is a membrane-permeable cysteine precursor that does not require active transport and delivers cysteine to the cell in a unique way (Fig. 1) (Sen 1997). After free NAC enters a cell, it is rapidly hydrolyzed to release cysteine, a precursor of GSH. GSH is synthesized by the coactions of c-glutamylcysteine synthetase and GSH synthetase. The synthesis of GSH is limited by the availability of substrates; cysteine is usually the limiting precursor (Meister 1995). C-glutamylcysteine synthetase is inhibited by feedback from GSH (Richman and Meister 1975). In addition, intracellular GSH is maintained in its thiol form by GSH reductase, which requires NADPH (Sen 1997). GSH participates nonenzymatically and enzymatically in protection against oxidative damage caused by ROS. GSH peroxidase catalyzes the destruction of H2O2 and hydroperoxides (Meister 1995). Thus, NAC is an antioxidant and a free-radical scavenging agent that increases intracellular GSH, a major component of the pathways by which cells are protected from oxidative stress (Arakawa and Ito 2007). Low bioavailability of NAC is one of the major limitations for maximizing its effects on oxidative stress-related diseases. Giustarini et al. (2012) reported that esterification of the carboxyl group of NAC to produce N-acetylcysteine ethyl ester (NACET) would increase the lipophilicity of NAC as the mechanism of increasing its pharmacokinetics. They showed that NACET is rapidly absorbed in rats after oral administration, but reaches very low concentrations in plasma. This is due to a unique feature of NACET: it rapidly enters the cells and transforms into NAC and cysteine (Giustarini et al. 2012). After oral treatment, NACET (but not NAC) was able to increase significantly the GSH content of most tissues in the rat (including brain), and protected them from paracetamol intoxication. To overcome this limitation of NAC, an amide derivative, N-acetylcysteine amide (NACA) has been synthesized to improve its lipophilicity, membrane permeability, and antioxidant properties. Recent studies have demonstrated the blood–brain barrier permeability and therapeutic potentials of NACA in neurological disorders (Sunitha et al. 2013).

Figure 1. Mechanism of action of N-acetylcysteine (NAC). ASC, alanine-serine-cysteine (ASC) transport system; c-GCS, c-glutamylcysteine synthetase; cys, cysteine; glu, glutamine; gly, glycine; GSH, glutathione.

Does NAC cross cell membranes and the blood–brain barrier?

The ability to cross the blood–brain barrier (BBB) by a compound is thought critical to a treatment targeting dysfunction of brain parenchyma. NAC's ability to cross BBB is being disputed, and this controversy likely stems from differential ability of NAC to cross BBB that could be dependent on its dose and administration.

N-deacetylation and a carrier-mediated active transport are the only pathways of compound crossing the blood vessel wall. Different forms of NAC and different routes of administration may result in different concentrations and variable utilization of these mechanisms. For example, after 2 h following oral administration of S-NAC to rats, the highest concentration was seen in the kidney and liver, followed by the adrenal glands, lung, spleen, blood, muscle, and brain (Sheffner et al. 1966). Intraperitoneal or intravenous injection of 14C-NAC resulted in its uptake by most tissues except the brain and spinal cord in mice (Sunitha et al. 2013). In contrast, some studies reported that intra-arterial (intracarotid) and intravenous (jugular) administration of 14C-NAC resulted in good BBB permeability (McLellan et al. 1995).

BBB crossing by 14C-NAC increased following intraperitoneal administration of lipopolysaccharide (LPS). Interestingly, NAC-amide (NACA is an active derivation of NAC) has been measured in brain after oral or interperitoneal administration, but not NAC itself (Samuni et al. 2013). When NAC was replaced with NAC ethyl ester, a dramatic increase in the brain levels of NAC and cysteine was detected probably due to a rapid hydrolysis of NAC ethyl ester (Samuni et al. 2013).

Effect of NAC on the functions of vascular smooth muscle cells

Excessive proliferation of vascular smooth muscle cells (VSMCs) contributes to atherosclerosis, a major cause of cerebrovascular disease. NAC partially inhibits ox-low-density lipoprotein (ox-LDL, a pro-oxidant) and urotensin-(a potent vasoconstrictor) stimulated proliferation of VSMCs. These effects of NAC raise the possibility of a therapeutic benefit to prevent stroke or atherosclerosis progression in patients with hypertension and hypercholesterolemia (N-acetylcysteine 2000). Additionally, NAC inhibited serum PDGF- and thrombin-stimulated extracellular single-regulated kinase (ERK2), c-JUN N-terminal kinase (JNK1), and p38 mitogen-activated protein kinase (MAPK) activation as well as expression of the c-Fos (70%), c-Jun (50%) and JunB (70%) genes, suggesting redox-sensitive mechanisms for protective effects of NAC in patients with major vascular risk factors (Su et al. 2001). Furthermore, NAC almost completely inhabits the Ag II-induced downregulation of AT (Dekhuijzen 2004)-R mRNA (Angiotensin II receptor, type 1) (Ichiki et al. 2001). NAC also blocks serotonin-stimulated superoxide production and ERK-MAPK phosphorylation in VSMCs (Lee et al. 1999). As a result of these multiple mechanisms of action, NAC reduced thickening of the neointima by 39% in rabbit aorta after injury produced by balloon (Ghigliotti et al. 2001). Finally, NAC inhibits cyclooxygenase-2 induction by benzopyrene, an atherogenic component of cigarette smoking (Yan et al. 2000).

Role of NAC in atherosclerotic plaque stability

ROS such as superoxide, nitric oxide (NO), and H2O2 can modulate the activities of matrix-degrading proteases, matrix metalloproteinases (MMPs) and contribute to the instability of a vulnerable atherosclerotic plaque (Xu et al. 1999). Ox-LDL activates AP-1 and NF-kB transcription factors, promotes macrophage-mediated matrix disruption in the rupture-prone atherosclerotic plaques (Xu et al. 1999). NAC inhibits the homocysteine-enhanced expression of an ox-LDL receptor, lox-1 in the endothelium (Nagase et al. 2001). NAC can inhibit MMP-9 (gelatinase B) activity and expression in lipid-laden macrophage-derived foam cell by 60% (Galis et al. 1998) demonstrating a potential for antioxidants to stabilize vulnerable plaques. In a rabbit model, NAC reduced angioplasty-induced vascular inflammation, thrombus formation, and laminal damage (Mass et al. 1995). In hypertensive rats, NAC administration was partially protective against peroxynitrite-induced aortic vascular dysfunction related to hypertension (Cabassi et al. 2001). In a rat model with ischemic heart, NAC provided protection to ischemic and reperfusion injury in part by inhibiting adhesion molecules (Cuzzocrea et al. 2000a).

In patients with elevated remnant-like lipoprotein (RLP), adhesion molecules levels decreased after treatment with another antioxidant, a-tocopherol (Cabassi et al. 2001). In cultured endothelial cells, NAC decreased RLP-induced adhesion molecules by 50–70% and repaired endothelium-dependent vasorelaxation (Doi et al. 2000). A clinical trial showed that daily oral NAC administration at 1.2 mg dose increased GSH and decreased plasma vascular cell adhesion molecule-1 (VCAM-1) levels in noninsulin-dependent diabetic patients (De Mattia et al. 1998). In the previous studies, NAC supplementation significantly improved coronary and peripheral vasodilatation by enhancing the effects of NO (Andrews et al. 2001).

Role of NAC in neural cell survival and antiapoptotic activities

Oxidative stress causes encoded cell death or apoptosis in several pathological processes such as aging, inflammation, carcinogenesis, and neurodegeneration (Chandra et al. 2000). Studies of various cell types showed NAC growth-promoting activities. NAC increases concanavalin A-induced mitogenesis and simultaneously reduces apoptosis of B-lymphocytes (Li et al. 1999; Martin et al. 2000). Interestingly, NAC and dithiothreitol (DTT) block apoptosis of endothelial cells by LPS (Abello et al. 1994).

Ox-LDL-induced superoxide production and apoptosis of human umbilical vein endothelial cells (HUVEC) were blocked by NAC (Galle et al. 1999). In contrast with endothelial cells, NAC induced apoptosis and reduced viability of rat and human VSMCs (Tsai et al. 1996). NAC was found to maintain VSMCs in inactive state, and its removal led to their return into the cell cycle (Lee et al. 1998). During investigation of the mechanisms of hyperhomocysteinemia-associated atherosclerosis, NAC suppressed homocysteine-stimulated collagen production and proliferation of VSMCs (Tyagi 1998). Such selective impact of NAC can be useful for blocking proliferation of VSMCs in atherosclerosis and lesions prone to restenosis (Yan and Greene 1998; Shirvan et al. 2000). NAC also prevented tumor necrosis factor (TNF)- and thrombin-induced neuronal cell death (Talley et al. 1995; Sarker et al. 1999). Arabinoside-induced neuron apoptosis and neurotoxicity were inhibited in vitro by NAC through ROS inhibition (Geller et al. 2001), a mechanism that supports survival of neurons. While NAC at low concentrations promotes cell growth, its high doses can lead to apoptosis (Kim et al. 2000).

Role of NAC in cell signal cascade

The effects of NAC are most commonly attributed to its capability to scavenge ROS and elevate cellular GSH levels. However, the redox state is the principal mechanism through which ROS are integrated into cellular signal transduction pathways. As NAC affects redox-sensitive signal transduction and gene expression both in vitro and in vivo, its functions on cell signaling should also be considered.

The Rel homology domain (RHD) is a protein domain found in a family of eukaryotic transcription factors that includes a nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and a nuclear factor of activated T cells (NFAT). Some of these transcription factors appear to form multiprotein DNA-bound complexes (Wolberger 1998). NF-κB represents proteins sharing RHD that bind to DNA as homo or heterodimers (p50/p65) and activate a multitude of cellular stress-related and early response genes, such as genes for cytokines, growth factors, adhesion molecules, and acute-phase proteins (Sheffner et al. 1966). NAC exerts an effect on NF-κB, which has a cardinal role in regulation and expression of stress response genes under inflammatory and oxidative challenges. Interestingly, NAC affects other signal transduction pathways to expression of various genes. It can directly modulate the activity of common transcription factors both in vitro and in vivo (Samuni et al. 2013).

Oxidative stress is an effective inducer of NF-κB, and NAC treatment suppressed its activation in cultured cells in vitro and in clinical sepsis also reducing subsequent cytokine production. NF-κB is naturally bound to its inhibitor (I-κB) that prevents its nuclear translocation. Dissociation of I-κB following its phosphorylation by specific kinase of NF-κB (IKK) allows NF-κB transport to the nucleus. (Samuni et al. 2013).

Misfolded proteins and neurodegenerative diseases

The alpha-helix structure of proteins is related to their function. When a protein becomes toxic, an extensive conformational change occurs and it will change to the beta-sheet (Reynaud 2010). Note that the beta-sheet conformation also exists in many functional native proteins such as the immunoglobulins. The transition from alpha-helix to beta-sheet is characteristic of amyloid deposits. Misfolded proteins appear when a protein follows the wrong folding pathway or energy-minimizing funnel, and misfolding can happen spontaneously (Reynaud 2010). As millions of copies of each protein are made during our lifetimes, sometimes a random event occurs and one of these molecules follows the wrong path, changing into a toxic configuration. This kind of conformational change is most likely to occur in proteins that have repetitive amino acid design, such as polyglutamine in Huntington's disease (HD). Under normal circumstances, proteins that have problems achieving their native configuration are helped by chaperones to fold properly. Chaperones can prevent protein misfolding by using energy (ATP). Despite chaperone actions, some proteins still misfold. Accumulation of misfolded proteins can cause disease such as amyloid diseases; Alzheimer's, Parkinson's, and HD have similar amyloid origins. Regardless of the type, the risk of getting any of these diseases increases dramatically with age (Unnithan et al. 2012). With aging or mutations, the fine balance of the synthesis, folding, and degradation of proteins will decrease resulting in the production and accumulation of misfolded proteins. Postmortem tissues from patients with neurodegenerative diseases demonstrate protein-misfolding stress and reduced proteasome activity. This broad-spectrum effect of proteotoxic stress has led to the term “proteinopathies” for neurodegenerative diseases. Unnithan and his team believe that toxic-related proteinopathies with GSH loss could have good response to NAC by reversing this GSH loss and preventing this toxicity (Unnithan et al. 2012).

Effect of NAC on diseases of the central nervous system

Oxidative stress plays a critical role in neuronal dysfunction and death in various neurodegenerative diseases, including spinocerebellar disease (SCD), myoclonus epilepsy of the Unverricht–Lundbor type (ULD), Alzheimer's disease (AD), Parkinson's disease (PD), tardive dyskinesia (TD), and Down's syndrome (DS) (Arakawa and Ito 2007) (Table 2).

Table 2. Clinical trials in neurological disorders.

Trial	Status
N-acetylcysteine for neuroprotection in Parkinson's disease (NAC for PD)-NCT01470027	Recruiting participants
Intravenous N-acetylcysteine for the treatment of Gaucher's disease and Parkinson's disease. NCT01427517	Completed (Holmay et al. 2013)
N-acetylcysteine (NAC) for children with Tourette syndrome. NCT01172288	Recruiting participants
The role of N-acetyl-l-cysteine (NAC) as an adjuvant to opioid treatment in patients with chronic neuropathic pain. NCT01840345	Not yet open for participant recruitment
Single-port thoracoscopic sympathicotomy in complex regional pain syndrome type I (CRPS). NCT01886625	Not yet open for participant recruitment
A clinical trial of a vitamin/nutriceutical formulation for Alzheimer's disease. NCT01320527	Completed. Pilot Study is published (Remington et al. 2009)
NAC-003 P.L.U.S. program (Progress through Learning Understanding and Support). NCT01370954	Completed. Final results not yet published
Biomarker validation for Niemann–Pick disease, type C: safety and efficacy of N-acetylcysteine. NCT00975689	Completed (Fu et al. 2013)
Overcoming membrane transporters to improve CNS drug delivery—improving brain antioxidants after traumatic brain injury (Pro-NAC). NCT01322009	Recruiting participants
Efficacy mechanism of N-acetylcysteine in patients with posttraumatic stress disorder. NCT01664260	Not yet open for participant recruitment

Spinocerebellar disease

SCD is a diverse group of rare, slowly progressive neurological diseases, often inherited but of incompletely understood pathophysiology, which affect the cerebellum and its related pathways. Several studies have found evidence of oxygen-mediated damage in SCD (Arakawa and Ito 2007). If free-radical species play an important role in cerebellar degeneration in SCD, then NAC may be therapeutically effective. However, there have been no basic or clinical studies aside from one report of 18 patients with SCD who received NAC (Eldridge et al. 1983). Despite varying degrees of ataxia, dysarthria, and oculomotor disturbance among the patients, all claimed subjective improvement with NAC. The most severely affected patient was treated with NAC for 26 months, leading to a marked improvement in the eye movement control (Eldridge et al. 1983).

One case report described NAC administration in a patient with olivopontine cerebellar atrophy (OPCA) who had difficulties with balance and walking, progressive speech disruption, and diminished proprioception and pain sensitivity. A marked improvement in dysarthria and balance was seen 1 month after using NAC. By 3 months, the patient could discriminate between hot and cold, and had regained some touch and position sense (Yang et al. 1984). NAC was also administered in a case of Friedreich's ataxia, a multisystem disorder, for 8 months with an improvement in proprioception and a slight decline in ataxia (Yang et al. 1984).

Ataxia-telangiectasia (AT) is a complex multisystem disorder characterized by ataxia, ocular telangiectasia, immunodeficiency involving both T- and B-cell functions, 50- to 100-fold increased cancer incidence and increased sensitivity to ionizing radiation (Woods and Taylor 1992). Three siblings aged 7, 11, and 13 with AT, confirmed by chromosomal analysis and lymphocyte radiation fragility testing, had questionable improvement in their condition after 3 months of receiving NAC. When two patients were taken off NAC for a period of 2 weeks, rapid deterioration in their conditions ensued including a return of copious drooling in the youngest patient (Eylar et al. 1993; Sölen 1993).

Myoclonus epilepsy of the Unverricht–Lundbor type (PME-ULD)

PME-ULD is an autosomal recessive disorder that typically develops between the ages of 6 and 15 years with stimulus-sensitive myoclonus and tonic colonic seizures followed by progressive cerebellar syndrome (Lehesjoki and Koskiniemi 1998; Arakawa and Ito 2007). A Florida family with four siblings with PME-ULD received treatment for 20 years with phenytoin, phenobarbital, carbamazepine, and other anticonvulsants without benefit (Lehesjoki et al. 1993). After starting NAC, improvement in myoclonus was reported in the least affected patient such that she has been able to walk unaided for several days at a time. Objective measurements of improvement included some normalization of somatosensory evoked potentials (Lehesjoki et al. 1993).

Tardive dyskinesia

The basal ganglia are exceptionally vulnerable to free-radical overload because they are rich in dopamine as well as other catecholamines. By blocking dopamine receptors, neuroleptics may cause dopamine buildup in the basal ganglia, which then increase free-radical production. NAC decreased disease severity in both in vivo and in vitro TD models suggesting that further clinical trials may be warranted (Galili-Mosberg et al. 2000; Sadan et al. 2005).

Down syndrome

Down syndrome is known to involve increased systemic oxidative stress (Busciglio and Yankner 1995). The 50% overexpression of super oxidase dismutase (SOD) on chromosome 21 contributes to heightened fluxes of superoxide in all tissues. However, DS is not manifested until after birth, as the mother's antioxidant defenses might guard the fetus until delivery. Children with DS are also at significantly increased risk of Alzheimer-type dementia (Lehesjoki et al. 1993). Although NAC protects neuronal migration in DS models in vitro (Behar and Colton 2003), further clinical trials should help to clarify whether supplementation of NAC from birth can delay the beginning of Alzheimer-type dementia in DS patients.

Multiple sclerosis

There is a marked increase in expression of TNF in active multiple sclerosis (MS), and a correlation exists between cerebrospinal fluid levels of TNF and the severity and progression of disease (Sharief and Hentges 1991). With cytokine activation, free-radical production increases and this has been demonstrated in MS (Glabiński et al. 1993). NAC inhibits the toxicity of TNF and in an animal model of MS, it inhibited the development of MS-like pathology (Lehmann et al. 1994).

Ten patients with MS were treated with NAC for a period of up to 16 months. Due to relapsing–remitting course in many MS patients, it is difficult to determine efficacy of NAC in a small sample without concurrent controls. However, two MS patients with longstanding inability to speak coherently had a rather dramatic improvement in speech shortly after they started to take NAC. Controlled trials are needed to ascertain if NAC can decrease the number of exacerbations in MS (Stanislaus et al. 2005).

Huntington's disease

Mitochondrial dysfunction is a major event involved in the pathogenesis of HD. In 2000, Butterfield and his team tried to create an animal model of Huntington's disease by nitropropionic acid (3-NP) injection to rats. 3-NP is an irreversible inhibitor of complex II in the mitochondria (Fontaine et al. 2000). They reported that rats injected with 3-NP exhibited increased oxidative stress in both striatum and cortical synaptosomes. Treatment of these rats with a free-radical spin trap agent, 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO) in a dose of 30 mg/kg, i.p., daily or with NAC (100 mg/kg, i.p., daily) starting 2 h before 3-NP injection protected against oxidative damage. Furthermore, both DEMPMPO and NAC treatments significantly reduced striatal lesion volumes (Fontaine et al. 2000). In 2012, Sandhir and his team evaluated the role of NAC in preventing mitochondrial dysfunction in a 3-NP-induced HD model in rat (Sandhir et al. 2012). They found an increased generation of ROS and lipid peroxidation in mitochondria of 3-NP-treated animals. Endogenous antioxidants (thiols and manganese-SOD) were decreased in mitochondria of 3-NP-treated rats. 3-NP-treated animals showed increased cytosolic cytochrome c levels and mitochondrial swelling. Increased expressions of caspase-3 and p53 were also observed in 3-NP-treated animals. Increased neural space, neurodegeneration, and gliosis accounted for most histopathologic findings in these rats. These findings were accompanied by cognitive and motor deficits. NAC treatment was capable of reversing 3-NP-induced mitochondrial dysfunction and neurobehavioral deficits in this study (Stanislaus et al. 2005), thus suggesting a beneficial effect of NAC in HD.

Amyotrophic lateral sclerosis

Linkage of familial amyotrophic lateral sclerosis (FALS) with mutations in the gene encoding superoxide dismutase (SOD1) support the role of free radicals in the progression of ALS (Rosen et al. 1993). Levels of SOD1 are reduced in patients with FALS, but are often normal in sporadic ALS. In two patients with sporadic ALS, SOD1 activity was normal, but GSHpx and GSH reductase activities were markedly reduced. In these patients, NAC treatment may have modified the course of the disease as one patient (duration of treatment 12 months) has remained stable with an increase in grip strength. The second patient has only marginally progressed during 17 months of treatment with NAC. Louwerse et al. (1995) reported a double-blind trial of NAC in 111 patients with ALS. Patients with limb onset but not bulbar onset of ALS had a 50% decrease in the 1 year mortality rate after beginning NAC treatment (Cray et al. 1980; May and Gray 1985; Louwerse et al. 1995).

Parkinson's disease

Multiple neuronal systems are involved in sporadic PD. Alpha-synuclein-immunopositive Lewy neurites and Lewy bodies are the cardinal histopathology in PD. Lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Anteromedial temporal mesocortex is involved too. Neural degeneration in substantia nigra, which is a common finding in sporadic PD, could be a coincidental finding rather than a casual finding (Braak et al. 2003). Increased lipid peroxidation and dramatically decreased GSH levels have been reported in PD (Arakawa and Ito 2007). Some published reports have mentioned that GSH levels were reduced by 40% in substantia nigra compared to controls (Sian et al. 1994).

Decreased GSH levels may be due to mitochondrial dysfunction and oxidative stress. Oxidative stress will increase the accumulation of toxic forms of alpha-synuclein (SNCA). Simon and his team hypothesized that supplementation with NAC could protect against SNCA toxicity. They found that in transgenic mice, NAC increases the SN levels of GSH within 5–7 weeks of treatment; however, this increase was not sustained at 1 year. Despite this transient effect, they found that the loss of dopaminergic terminals at 1 year associated with SNCA overexpression was significantly attenuated by NAC supplementation (Clark et al. 2010).

Dopaminergic neuronal death in PD is accompanied by oxidative stress and preceded by GSH depletion. Earlier studies confirmed that mice have age-dependent loss of dopaminergic neurons in pars compacta of the substantia nigra (Jiang et al. 2005). This neuronal loss is accompanied by increased nitrotyrosine formation, nitrosylated a-synuclein, and microglial activation. These changes are considerably reduced in mice that received NAC. Martinez et al. hypothesized that treatment with a sulfur-containing antioxidant such as NAC may provide a new neuroprotective therapeutic strategy for PD (Schapira et al. 1990; Martínez et al. 1999). Generation of hydrogen peroxide by monoamino oxidase (MAO) and ROS production by catecholamines in the substantia nigra are other precipitating factors in PD (Martínez et al. 1999). Moreover, the substantia nigra in PD patients is rich in iron and in neuromelanin, two other sources that may mediate the formation of ROS. Clinical trials using antioxidants such as vitamin E (The Parkinson Study Group 1993; Pappert et al. 1996) and vitamin C for the treatment of PD have been reported (Reilly et al. 1983). However, no benefit has been found, possibly because of the poor ability of antioxidants to penetrate the BBB. On the other hand, NAC may cross the BBB (Martínez et al. 1999; Farr et al. 2003), and NAC exerts a preventive effect in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD (Pan et al. 2009). One ongoing randomized clinical trial to evaluate the role of NAC as a neuroprotective agent in PD is currently recruiting participants (NCT01470027, http://www.clinicaltrials.gov). Further controlled trials involving administration of NAC or GSH precursors or in combination with other antioxidants are needed (Martínez et al. 1999).

Alzheimer's disease

AD is a multifactorial disease. There is both direct and indirect evidence of free-radical involvement in AD. Increased levels of lipid peroxides in the temporal and cerebral cortex, and decreases in GSH in cortical areas and the hippocampus have been reported in AD (Adams et al. 1991; Jenner 1994; Lohr and Browning 1995).

Most clinical trials of antioxidants for the treatment of AD have employed either tocopherol (a class of chemical compounds which many have vitamin E activity) or selegiline (also known as l-deprenyl, an irreversible and relatively selective MAO-B inhibitor). NAC has been tested in some murine models of AD, and these studies provided supportive evidence that administration of NAC blocks oxidative damage in AD (Tchantchou et al. 2005; Tucker et al. 2005). Adair et al. (2001) administered NAC in a blinded placebo-controlled trial in patients with AD. In patients with clinically diagnosed AD, treatment with NAC failed to alter the primary outcome measures. However, the results may still support future testing of NAC in AD. First, all subjects tolerated the drug well, experiencing only minor and transient adverse effects. Second, the group taking NAC showed positive effects on some secondary outcome measures. Further testing of NAC in patients with AD may determine whether it provides more benefit than vitamin E and other antioxidants (Adair et al. 2001).

Beneficial effect of NAC after focal cerebral ischemia

Cerebral ischemia alters the mitochondria leading to increased ROS generation (Morris et al. 2011). Initiation of the ischemic cascade affects not only neuronal signaling but also several humoral mediators and diverse humoral pathways including opioids, NO, adenosine, bradykinin, catecholamines, heat-shock proteins, heme oxygenase, tumor necrosis factor-alpha (TNF-α), angiotensin, and prostaglandins (Vasdekis et al. 2013).

Neural damage following stroke is promoted by a massive release of excitatory neurotransmitters such as glutamate that acts on the N-methyl-d-aspartate (NMDA) receptor and other receptor subtypes (Cuzzocrea et al. 2000b). Animal studies have shown that glutamate receptor antagonists reduce neuronal damage following ischemic stroke and reduce neurotoxicity (Cuzzocrea et al. 2000b). Treatment of mice with nitric oxide synthase (NOS) inhibitors and neuronal (nNOS) gene disruption can protect ischemic brain against NMDA neurotoxicity (Dawson and Dawson 1997; Cuzzocrea et al. 2000b). Most of the toxic effects of NO appear to be a result of the reaction of NO with superoxide to form a very toxic compound peroxynitrite. Cytotoxicity of peroxynitrite is related to its roles in the initiation of lipid peroxidation, inactivation of a variety of enzymes, and depletion of GSH (Cuzzocrea et al. 2000b). Interventions to reduce the generation or the effects of peroxynitrite have showed beneficial effects in a model of cerebral ischemia as well as variety of models of inflammation and shock (Dawson and Dawson 1997). NAC's antioxidant property of being a sulphydryl donor may contribute to the regeneration of endothelium-derived relaxing factor and GSH (Aruoma et al. 1989).

Positive changes in microcirculatory blood flow and tissue oxygenation after the start of NAC treatment were documented in animals (Cuzzocrea et al. 2000b). In a Mongolian gerbil model, NAC treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischemia and reperfusion. Histological observations of the pyramidal layer of cortex showed a reduction of neuronal loss in animals that received NAC. Generally, these results show that NAC improves brain injury induced by transient cerebral ischemia (Harrison et al. 1991). Similar results were obtained in a rat model of cerebral ischemia (Khan et al. 2004). However, no data are yet available on the use of NAC in acute ischemic stroke patients.

Subarachnoid hemorrhage

The pathological production of free radicals and consequent lipid peroxidation are causally related to the development of cerebral vasospasm (Sen et al. 2006). Damage in the endothelium and apoptosis of endothelial cells are also contributing to cerebral vasospasm after subarachnoid hemorrhage (SAH) (Halliwell and Gutteridge 1986; Findlay et al. 1989), while protection of endothelium from apoptosis might attenuate vasospasm (Sen et al. 2006). Intraperitoneal administration of NAC was markedly effective against cerebral vasospasm development following SAH in rabbits. NAC can significantly reduce elevated lipid peroxidation and increase the level of tissue GSH and SOD enzymatic activities. Also, NAC treatment increased the luminal area and reduced wall thickness of the basilar artery. NAC markedly reduced apoptotic index and protected the endothelial integrity (Güney et al. 2010).

Our group reported a 43-year-old woman with Hunt-Hess grade 3 SAH due to a ruptured right middle cerebral artery aneurysm that was coiled and she subsequently developed severe vasospasm. She was treated with oral NAC, 600 mg twice a day, with dramatic vasospasm resolution for 24 h, confirmed by Computed Tomography Angiography and Transcranial Doppler sonography (Friehs 2014). To our knowledge, this is the first report of NAC use and its possible effect on vasospasm in a patient with SAH. We hypothesize that NAC may be a part of the preventive therapy for vasospasm by its multiple complex action mechanisms and the subject deserves further investigation.

Traumatic brain injury

Several experimental studies have found that NAC plays a neuroprotective role by repairing traumatic brain injury (TBI)-induced mitochondrial dysfunction and by increasing the reduced antioxidant enzyme (Xiong et al. 1999; Hicdonmez et al. 2006; Yi et al. 2006). Previous studies focused on NAC modulating oxidative stress in the brain following TBI, but did not examine the influence of NAC on inflammation, which plays an important role in the mechanisms of secondary brain damage after TBI (Morganti-Kossmann et al. 2001). Several experimental studies have confirmed that secondary brain injury can be magnified after TBI by numerous immune mediators including interleukin-1β (IL-1β), TNF-α, interleukin-6 (IL-6), and intercellular adhesion molecule-1 (ICAM-1) (Merrill and Benveniste 1996; Hans et al. 1999; Rancan et al. 2001). In a rat model, cortical contusions induce a concomitant and persistent upregulation of NF-κB, TNF-α, IL-6, and ICAM-1 (Chen et al. 2008). NAC, by increasing the amount of GSH, works as a ROS scavenger resulting in cytoprotection as it also inhibits the activation of NF-κB and TNF-α production by LPS (Hoffer et al. 2002; Akca et al. 2005; Hsu et al. 2006). These results suggest that post-TBI NAC administration may decrease inflammatory response in the injured brain, one potential mechanism by which NAC improves secondary brain damage following TBI (Chen et al. 2008). The use of NAC in humans with TBI has not been reported.

NAC in psychiatric disorders

Psychiatric disorders have a multifactorial etiology that involves inflammatory pathways, glutamatergic transmission, oxidative stress, GSH metabolism, mitochondrial function, neurotrophins, apoptosis, dopamine pathway, and intracellular Ca modulation (Dean et al. 2011). As NAC plays a role in most of these pathways, its effect on psychiatric disorders has been studied more extensively in the clinical setting.

More than 20 clinical trials have employed NAC as an adjunctive treatment in various psychiatric disorders. These include methamphetamine and cannabis dependence, nicotine and cocaine addiction, pathological gambling, obsessive–compulsive disorder, trichotillomania, nail biting and skin picking, schizophrenia, bipolar disorder, autism, and AD. In most of these studies, NAC had positive effects on clinical outcomes (Gere-Paszti and Jakus 2009; Samuni et al. 2013). A detailed discussion of these results is beyond the scope of this review as it is focused on neurological disorders.

Pharmacokinetics and side effects

With oral NAC doses of 200–400 mg, the peak plasma concentration of 0.35–4 mg/L is achieved within 1–2 h after ingestion. Information on interaction with food is lacking. The volume of distribution ranges from 0.33 to 0.47 L/kg and protein binding is significant being 50% at 4 h after the dose administration.

Intravenously infused NAC rapidly forms disulfides in plasma, which prolong the existence of the drug in plasma for up to 6 h (Sarker et al. 1999). Renal clearance has been reported at 0.190–0.211 L/h per kg; however, up to 70% of the total body clearance is nonrenal.

With oral administration, reduced NAC has a terminal half-life of 6.25 h. It is believed to be rapidly metabolized and incorporated onto proteins. After oral ingestion of 200 mg NAC, the free thiol is largely undetectable, and only low levels of oxidized NAC are detectable for several hours after administration (Cotgreave and Moldeus 1987). The data also indicate that the drug is less than 5% bioavailable from the oral formulation. Further pharmacokinetic data suggest that the drug itself does not accumulate in the body, but rather in its oxidized forms and in reduced and oxidized metabolites (Holdiness 1991; Watson and McKinney 1991).

Pharmacokinetic information is controversial regarding NAC ability to cross placenta or being excreted into breast milk. NAC in the Ames test is negative; however, animal studies on embryotoxicity are equivocal (Ziment 1988). In addition, studies in pregnant women are inadequate. Therefore, NAC should be used with caution during pregnancy, and only if clearly indicated. Its major excretory product is inorganic sulfate.

NAC is generally safe and well tolerated even at high doses. Most frequently reported side effects are nausea, vomiting, and diarrhea. Therefore, oral administration is contraindicated in persons with active peptic ulcer (Ziment 1988). Biochemical and hematological adverse effects are observed, but are not clinically relevant. Drug interactions of clinical significance have been observed with paracetamol, GSH, and anticancer agents (Holdiness 1991).

Infrequently, anaphylactic reactions due to histamine release occur and can consist of rash, pruritis, angioedema, bronchospasm, tachycardia, and changes in blood pressure. In rare circumstances, intravenous administration of NAC can lead to an allergic reaction generally in the form of rash or angioedema. In addition, as with any antioxidant nutrient, NAC at therapeutic doses (even as low as 1.2 g daily) has the potential to have pro-oxidant activity and therefore it is not recommended in the absence of a significant confirmed oxidative stress (Ziment 1988). NAC strongly potentiates the effect of nitroglycerin and related medications, and caution should be used in patients receiving these agents in whom it may cause hypotension (Atkuri et al. 2007).

Conclusions

NAC has a broad spectrum of actions and possible applications across multiple conditions and systems. As a drug, NAC represents perhaps the ideal xenobiotic, capable of directly entering endogenous biochemical processes as a result of its own metabolism. In addition, NAC may cross the BBB. In neurological diseases, there is a potential to explore doses and duration of treatment with NAC to achieve cytoprotection.

Conflict of Interest

None declared.

References available at the Brain and Behavior site.