Nutrigenomic Targeting of Overall Wellness & Attenuation of Craving Behavior
Brain Repair for Addictive Disorders: Successful, Cost-Effective & Drug-Free Therapies.
 Community Addiction Recovery Association, Sacramento April 17, 2009

I started this process in 1964 so it’s been quite some time. The basis of what I am going to talk about has been termed since 1995 Reward Deficiency Syndrome. We are extending all of that out into unraveling the neurogenetics of happiness. Pseudohappiness came in plant form with marijuana. Reaching the state of happiness by understanding the interaction between the genes involved in bringing about wellness. To go through an understanding of where we came from and where we are going in terms of neurochemistry of the brain and how we ended up looking at this and getting into the idea of nutrition for addiction….

One of the things we have to realize is there are common mechanisms between alcohol and opiates. In the early days the antagonist naloxone affects alcohol. In the drug world how they are treating alcohol and opiates is to use trexan. This was the forerunner to understanding you could treat alcohol with trexan. This was done in 1970. When I talked about why don’t we treat alcoholism with a narcotic antagonist they wanted to shoot me. They thought I was crazy. What does that have to do with alcohol? Why should you take something that is intravenous and give it to people? Of course now it’s the main stay for the treatment of drug and alcohol abuse to use buprenorphine and all those good things.

When you look at how individuals get into the behavior, looking at from chocolate to morphine, loving chocolate as a kid and when you are older you end up having a heroin problem. There is three basic characteristics: genetic predisposition, stresses, and long term abuse.

If you continue to use alcohol and drugs what is going to happen? You are going to change the chemistry of the brain just as if you were born with deficiencies in the brain. You are going to end up changing the neurochemistry of the neurotransmitters which are serotonin, dopamine, norepinephrine, endorphins, epinephrine, and GABA.

When you look at craving behavior, what is it? There are three types of people involved with substances or addiction. The first type is you are born an alcoholic. Alcohol craving behavior is equal to the genes, which is a deficiency of the neurotransmitters, plus the environment. There are always genes and always the environment. You always have them interacting.

The second one is stress. You may not be an addict but your situation is so stressful your neurochemistry is compromised. Your genes may be normal but the environment produces neurotransmitters as if there was a genetic problem.

The third is alcohol toxicity or heroin toxicity or drug toxicity, cocaine, or whatever. What you have is the genes may be normal but by using the substance you change the chemistry in your brain.

Years ago when I first started this thing in the 1960s we had no idea what endorphins were or what the opiate receptors were, which came later. When the endorphins came on the map in 1975 what I thought about was, if you have opiates, the endorphins must be playing a role in alcoholism. We were the first ones to show the endorphins would influence behavior without changing normal thirst. This is water. This is the fluid substance. When you give the rats what creates neurotransmitters it wipes out the drinking. We learned a whole lot about genetically-bred animals, back in the 70s.

This is a C-57 black mouse. This mouse loves alcohol. A DBA mouse hates alcohol. He doesn’t drink it. Then there are C3Hs which are in between. They don’t really know what they want. But, if the C-57 is given a choice between water and alcohol it will choose alcohol. When we looked at the brain, the amount of endorphins in the brains of these animals correlate with whether they like or hate alcohol. So if you hate alcohol you end up with a lot of endorphins. If you are in between you have in between endorphins and if you love alcohol you have very low amounts of endorphins. They are born genetically with very low amounts of endorphins and they love alcohol.

Can enkephalinase inhibitor reduce craving behavior? We reasoned to ourselves, if you are born with low enkephalin all we have to do is raise the enkephalins in the brain to stop the behavior. In those days the word enkephalinase was hardly around. Basically we found that the enzyme that breaks up these endorphins was called carboxypeptidases. You have a chain of 5 amino acids and it’s chopped up. The enzyme that destroys it chops it up. When it is chopped up it means you get no activity. So we did an experiment. We looked at a substance which actually had enkephalinase or carboxypeptidase inhibition. That was D-phenylalanine.

When we looked at this substance surprisingly we found that D-phenylalanine raised the endorphin levels and that was a significance difference in the brain. Now we have a substance that raises endorphin levels. The next question was, can it actually reduce craving behavior? So, we showed if we take mice that love alcohol and gave them a chronic dosage of D-phenylalanine it reduced their drinking and in fact you made them look like a DBA. You knocked out their drinking.

That was the beginning of where we were going. I thought at that moment we had found the drug to treat alcoholism. I was a pharmacologist. I started to talk to pharmaceutical companies. They didn’t like the name D-phenylalanine. That sounded too natural. I said, “What about hydrocinnamic acid?” Oh, they said, that’s good. That is really the metabolism of it. Well, it didn’t work so I said I’m not going in that direction but I realized that if you have DL-phenylalanine you have something nutritional so why not go that direction.

Let’s talk about stress for a little. Everybody knows that stress is a problem. This was shown with some work we did with some people in Ohio, we showed that stress lowers brain endorphins and increases craving behavior. So it’s as simple as this. If I split this room in half and everyone over here you take your clothes off and you will jump into ice cold water. And here on the other side you can keep your clothes on and do your little thing, it doesn’t matter. Then after the first group swam and came out cold and if you were a rat you don’t like to swim. It would be like having your hands behind your back. That would really stress you out. Then you take a look at what happens and if we put you in a room with all the alcohol you want, this group would drink the alcohol like crazy and this group wouldn’t drink it that much. That is what happened with the rats. When you swim a rat and look into the brain for endorphins you end up with lower. After stress the endorphins go down. Females know it in terms of when they have labor the endorphins go down from the pain and the stress.

The third set of types was toxicity. If you drink alcohol or use heroin, your endorphins in the brain are going to go down. We experimented with hamsters. We had 8 hamsters. We called them Sleepy and Dopey and Happy and Sneezy … we had the 7 dwarfs. And the last one was Ken. When you look at the pictures after one year, 12 months, every day we would study them, we found if this is what the normal endorphin looked like here is what happens after a year. It is wiped out. This would be equivalent to drinking like maybe a bottle of rum a day. That is a lot. If you are drinking a lot you are going to wipe out your endorphins.

They found the exact same thing in humans. They found that when humans, in Italy, when alcoholics and looked at their brain endorphin levels it was down by at least a third compared to the non-drinkers. I reviewed that paper and I liked the result but I rejected it at first because there was a smaller amount of controls than in the experimental group. I got back a response from the Italians saying (they didn’t know I reviewed it but they told the journal) they cannot find more controls because everyone drinks vino. OK, so accept the paper. They did get controls.

When you look at the science of genes and substance response you have two very important theories to consider. One is pharmacogenomics and the other is nutragenomics. We all know what the pharmaceutical industry has done to this profession. If you have to make a quick comparison between pharmaceuticals vs nutraceuticals what do you get? First of all, a pharmaceutical is indeed a very powerful agent. It targets one mechanism. It is foreign to the organism so you get an immunological response. The therapeutic index is narrow meaning the toxicity can go up much quicker in a human. And it’s effective but with adverse reactions. On television they are talking about all the different drugs and you sit there at the end laughing, saying “how am I going to take this?!” It requires FDA approval which by now costs $260 million to get a drug through.

If you look on the other side, nutraceuticals, it’s a less powerful agent. There is no doubt that we cannot in the world of nutrition say we are using a very very powerful agent however that doesn’t mean it isn’t effective, and it is more natural, so it targets multiple pathways and certainly the brain is not one neuron, it’s billions, and has multiple pathways through which it’s effective and the interaction and outcome are related to the net effect of how all these things interact. So you have multiple pathways. It’s natural so it’s compatible to the body. It isn’t foreign. The therapeutic index is wide. So we have a  safe means of utilizing a nutritional. It’s effective with little adverse reactions but the effect doesn’t come immediately. It takes time. It’s a building up effect, just like some of the drugs. The FDA’s oversight for claims so you can’t have structural-functional claims and can’t say it’s good for a disease. The cost is low.

(He shows a colorful crystal x-ray of a dopamine molecule). Doesn’t it look happy?

In 1987 I was always engrossed with the idea there must be a gene or multiple genes that can affect our craving behavior for drugs. Why do some people have this risk and why don’t others? Why is there a black C-57 mouse compared to a DBA mouse, one that hates alcohol and one that loves alcohol? It has to be genetic. So we embarked on a study. I don’t have time to tell you all the stories we went through but all I can say is after many many trials I would go to bed at night and say, “Oh my God I’ll be dead by the time we figure this out!” and finally we hit what we call the dopamine jackpot. Basically that is what everybody is looking for is the dopamine jackpot. We found it in the dopamine D-2 receptor gene. It is on chromosome 11.

When we talk about genes we need to talk about a big word called polymorphism. Who knows what it means? Nobody? Oh, a couple of people! It is a genetic variation. In the human genome 99.9% of one is the same as another human. That .1% difference brings the difference from billions down to only about 300 million base pairs. In 300 million base pairs don’t you think there could be variations? That variation is called the polymorphism. There is a normal gene and there is an abnormal gene. When we say abnormal that doesn’t always translate to being a deficit. There may be some benefits to having a variation. But, it is a variation.

When we look at the dopamine D-2 receptor gene this is the so-called “normal” A2 allele. An allele is the genotype. When you have this extra bar it now says it’s A1. In our first study we found that 79% of severe alcoholics that died, 80% of them having cirrhosis of the liver, we took the DNA out of the brain had this, the A1 allele, and 21% had that, the A2 allele. A very big difference. The question is, why did the nonalcoholics have it at all?

This was done in 1990 and published in JAMA. What that translated to was this is the normal A2 receptor in the neuron in the limbic system, in the part of the brain dealing with emotions right at the nucleus accumbens. What we are talking about is a genetically dependent decrease in the number of receptor sites. Those that are there are filled. The resulting decrease in neuronal activity is read by the brain as craving and stress. In other words if the number of D2 receptors are low and that correlated with the A1 form of the dopamine D2 receptor gene, then your craving behavior goes up. So, if you have an A1 gene form and we know, not just from our work but from many many much more work after that, one third or 33% in America alone carry this form of the A1 allele which means you have 100 million people in the United States at risk for addictive behavior. That is how big it is.

When we first reported this we could have been strung up on a cross. Individuals who carry the A1 allele of the dopamine D2 receptor gene have a lower density of the D2 receptor compared to individuals who carry the D2 A2 allele. A decreased number of D2 receptors in the reward pathways of the brain result in anger, anxiety, and the craving for substances such as cocaine, alcohol, nicotine, that increase the release of the neurotransmitter dopamine in the brain.

Reward behaviors generate from the limbic system. So what do we have? Basically as humans we have typical life motivational drives like hunger, thirst, and sex. The neurotransmitters that control and make these things happen physiologically normal are serotonin, opioids, GABA, dopamine, norepinephrine, acetylcholine, glutamate, and leptin. There are probably others but those are the main ones.

When we coined the words Reward Deficiency Syndrome what we were looking at was compulsive behavior, addictive behavior, impulsive behavior, and personality disorders. All these behaviors are tied in to genes and if we just look at the D2 receptor gene if you carry the A1 allele variant it associates with all these behaviors.

From 1990 when we first discovered this til right now in 2009 there are 2,800 papers on this.

The area in the brain is the limbic system. That is where your emotion resides. I’m not going to go into all the structures but the most important structure is the nucleus accumbens. Years ago when I used to go to conferences, say in the 1980s, what they used to have were endorphin conferences, GABA conferences. Dopamine conferences. Serotonin conferences. Norepinephrine conferences. Leptin conferences. Nitrous oxide conferences.  How do you have a brain that is isolated and here is the endorphins, this is dopamine. There is something called the cascade that we developed. Don’t get scared but basically it looks like this:

Serotonin in the hypothalamus stimulates the endorphins and enkephalin that projects out and goes to a substance called GABA in the substantia nigra that holds the dopamine in place so just the right amount of dopamine comes out in the reward side of the brain which is called the nucleus accumbens. And, it happens again right at that site so you get double protective mechanisms. The net result of the interaction of all these neurotransmitters is dopamine. It sounds simple and it is. People have to understand that while there is much interaction going on and multiple genes and multiple pathways the net result is dopamine.

A guy by the name of Lee in China put together a neural network of 396 genes that all impinge on dopamine being released. 395 genes getting you to be happy. Getting you to get to the pleasure state. The dopamine molecule is the pleasure molecule and guess what – the anti-stress molecule. So how would you feel if you had all you needed so nothing could bother you, you were protected against all stress and all you have is euphoria? You may not like that but some people will.

The various things that have been associated with reward deficiency syndrome include under addictive behavior: severe alcoholism, severe smoking of pot; under impulsive: attention deficit disorder, Tourette syndrome, autism,; under compulsive behavior: aberrant sexual behavior, pathological gambling,; under personality disorder: conduct disorder, antisocial personality, aggressive behavior. They are even now finding kids who are doing Internet gaming. This is expanding into a lot of behaviors. It just goes on and on.

When reward chemistry figures into those with the DrD2 gene and those without the gene. If you have a normal circuitry in the brain that is a non-addict, shows a healthy number of receptor sites. Varying circuitry shows reduced receptor sites. Addictive behavior is linked to low receptor numbers and the DrD2 gene A1 allele.

When you look at a brain map, a P300 wave of individuals and you really see that this is a normal brain, here is a brain with chemical imbalance: It’s depressed, all of this shows up. When you are depressed and you end up taking drugs like cocaine you get a double fried egg. Your brain is fried. We published this study in Clinical EEG. A guy by the name of Friend who was a reporter for USA Today was going to take it and put this on the front page and the editor said wow, we all know that. We don’t have to show this. This would have been a great thing to show the teenagers. Not that it would have stopped them but it at least would have made them think.

I am not promoting anything but there is a nutrient complex called Synaptamine which is amino acids and herbals and it is basically substances that can change the neurotransmitters and cause release of dopamine though we have not done the final experiment, and it can keep the dopamine in the synapse, which we have done. Synaptamine is a dopamine agonist that has safely and effectively reduced craving behaviors. What we have here is presynaptic reward circuits. When we use Synaptamine it lights up the brain that has dopamine. That is with a nutritional, not a drug.

There have been other clinical trials of Synaptamine with aberrant behaviors and every one of these behaviors have been affected positively by Synaptamine. That includes drug hunger, stress, weight gain, withdrawal from drugs, focus, happiness, carbohydrate craving, appetite, late night snacking, energy, hypertension, body mass index, smoking, sleep, interpersonal interaction, digestion, and mood.

The populations used in these clinical studies are substance abusers, alcoholics, cocaine addicts, narcotic users, ADHD, obesity, eating disorders, children of alcoholics. In one of the experiments we did we showed that 50% of the children of alcoholics coming from very severe alcoholic parents who have been incarcerated or who have been through multiple rehab have the A1 allele.

One year outpatient recovery program for both federal and municipal court system in Las Vegas the relapse rate was only 7%. It reduces craving behavior.

10 month outpatient recovery program for DUI offenders in the Cambridge Treatment Program in San Francisco alcoholism relapse 17%, stimulant relapse 46% but 46% for cocaine is pretty good. Stress has been reduced. Depression has been reduced. Anger has been reduced. Drug Craving and the building up to leave is reduced. Self confidence up. Energy up. Restraint so you don’t complain up. Wellbeing up. Recovery score up.

1 year analysis of the combination IV Synaptamine complex and oral combination, in a drug rehabilitation clinic for court-ordered DUI clients in Denver, Colorado, 600 subjects studied, and this is what we published. Anxiety reduced. Cravings reduced. Depression reduced. Fatigue much reduced. Concentration is up. Lack of energy down. Crisis down.

90 day obesity study with outpatients using Synaptamine complex in a bariatric clinic in Shreveport, Louisiana. Patients lost an average of 25 pounds compared to 10 pounds for the controls. 18% relapse among experiemtntal compared to 80% of controls.

4 year study involving the antiobesity effects of Synaptamine in an outpatient bariatric clinic. For two years they were put on Optifast, and two years on Synaptamine (FenCal). After two years on FenCal the patients regained only 14.6% compared to controls who gained 46% using Centrum vitamin as the placebo. You know you can gain weight fairly easily so Synaptamine helped. And even craving for sugar was reduced tremendously.

For healthy volunteers Synaptamine improves attentional processes, for ADHD. A statistically significant amplitude enhancement of the P300 component of the event-related potentials was seen after Synaptamine as well as improvement in cognitive processes. So through this nutrient it increased focus and attention.

Nutrigenomic studies with the DrD2 gene and chromium using anthropometric measures of those carrying the DrD2 A1 allele do not respond to treatment. If you casrry the A1 allele and these people in this program are allowed to walk out and you tell them don’t use sweets, they don’t listen. They love sweets. If you tell people who carry the A2 allele they listen to you and you get effect from chromium. So chromium is quite effective but it depends upon your genotype. And, that is called pharmacogenetics. You can look at genes and see if you will get a response. It’s actually called nutrigenetics. Because you are using a nutrient, not a drug.

Here you have the A1 allele and there is no change in body weight, a 0 percent change in kilograms but with the A2 allele look at the change. This is over 100 people double blinded. Everything is down. Chromium works but it depends upon your genes.

Now we have a paper that is just being published in the journal of Medical Hypothesis. What we are saying is the way you need to get to obesity is to understand that there are multiple pathways that are going to impinge upon obesity. In the paper we do a gene map of the genes involved and the different pathways. We have a gene map on pleasure pathways. We have a gene map on stress pathways. A gene map on energy metabolic pathways. One on immune. One on endocrine pathways, which all impinge on your obesity risk. So these genes, these polymorphisms, these genetic variants, and multiple genes, not just the DrD2 gene, all affect your risk for obesity.

It came to us about two years ago and I mentioned this the last time I was here, that we were going to do DNA customized nutritional genetics for wellness and the name we gave it is LG839. That is when I was born. That’s the name. You can’t get it anywhere. But, here it is. There is an Advances in Therapy article, PubMed, peer reviewed,  2008. showing metabolic immune measures. Another article in Gene Therapy and Molecular Biology (I was a busy boy last year) showing effects on both BMI (body mass index) and weight showing that treatment compliance with DrD2 A1 allele – the individual does not drop out when you give him Synaptamine two fold over when you have the A2 allele, in terms of better treatment. This isn’t the first time it’s been done. LG839 reduces the BMI.  Both weight and BMI are reduced when you look at five genes across pathways that are involved in reducing risk. We look at the genes and change the ingredients according to the polymorphisms. We target the polymorphisms with nutrition.

Are human nature genes tied to happiness? I just found this out very recently. There is a whole world of social science, and a whole world of biology. I had an interview with a guy by the name of James Fowler who is in the Social Science Department at the University of San Diego who has done some fantastic work on the  s of genetics.

In the social science world, they are studying things like attachment, friendship, marriage, relationships, sexuality, politics, criminality. When you look at the biological side, RDS and dopamine resistance. By the way we have come up with a new name. Have you ever heard of insulin resistance? We now are saying what we are studying is dopamine resistance. So sensitivity to dopamine is down like sensitivity to insulin is down. Dopamine resistance. When you look at dopamine resistance you find substance use disorder, alcoholism, stimulant dependence, nicotine, carbohydrate dependency, gambling, sex, Internet gaming, juvenile delinquency. All of these have been studied with different genes and if you take the DrD2 A1 allele you get some very interesting stuff.

First of all you have genes and politics. James Fowler’s group wrote a paper in a very good journal, the Journal of Politics, in which he looked at the partisanship from voting records and the Dopamine D2 recessive gene. He found out if you carry one of the A1 alleles you have no attachment. You don’t belong to any political party. If you have  ??? that is when you belong. Dopamine D4 gene is tied to ideology and friendship. Friendship is very wrapped up in happiness. You cannot be happy unless you have friends.

The dopamine D4 variant is called the R7 allele. It is the gene that ends up causing novelty seeking. You increase your friends and as you increase your friends you become more liberal.

Birds of a feather flock together. Ever hear that statement? Research in social networks from James Fowler’s group recently found that the A1 allele is common among friends up to three degrees of separation. So that means an A1 guy is friends with another A1 guy and they are friends with another A1 guy and friends with another A1 guy. It’s amazing.

Someone by the name of Blum’s group at Wake Forest found recently that the A1 allele was present in 100% of males and females that marry each other in families with very serious RDS behaviors over five generations. Well, that fits!

Over five generations every male and female who got together had the A1 allele.

You have in the brain dopamine, serotonin, norepinephrine,  all affect happiness. If you carry the A1 allele you have a 71% chance of having one of the addictive, impulsive, compulsive  behaviors. DNA-directed targeting of polymorphisms of RDS: pleasure pathways, energy, stress, endocrine, immune, these are the gene pathways that we have developed in the lab and are ready for market. Obesity risk. fibromyalgia. ADHD, anxiety, addiction, and a gene pathway for happiness. Nutrigenomic processes to reduce dopamine resistance. We swab and collect a sample from patients’ cheeks and send it for genotyping, the lab sends the information to the manufacturer, we code it and dispense it to the patient. What do we get? dopamine release. Happiness.

This is something being published in Gene Therapy which we have developed, which is the happiness gene map, which shows all the interactions of all the multiple genes and the end result is DrD2, releasing dopamine. That is what gives you happiness. It follows the reward cascade. There is the serotonin, there is the endorphins, there is GABA, and there is dopamine, it’s all interactive. And it follows the reward cascade that we developed in 1989. It’s working out pretty good.

This is the schematic of happiness. Gene polymorphisms affecting your inner constitution, how you feel, while this side of things includes parents, childhood friends, training, works, associates, social status, love partner, education, the social elements, and all are affected by the environment and by DNA coding. These can influencer RNA expression and change your genes.

 

All this influences risk of love styles, whether you are romantic, whether you have erotic fantasies, it’s all genetic. Kindness, compassion, morality, criminality, cravings, anxiety, coping skills, sprituality. There is a God gene! DrDT4 BM2L. Pleasure genes. Optimism genes. Gratitude. Temperament. All these genes can affect, and you can affect, the outcome with nutrigenomic intervention. You can have good health, normalize pleasure, stress, energy, you get your endocrine system back, you get your immunological system back, through reduction of dopamine resistance, and what have you got? Happiness! The dopamine molecule.

My girlfriend Marg and I went to a show with Leonard Cohen. So Leonard inspired me and I got home and I wrote a song for this conference:

No leaving you.

I have been trying to leave you.

Every evening, by closing the book

Every morning, when I work, there is more

I’m talking about my buddies

For all to look

Stand back, nothing to ignore

Because termination of our arduous work on addiction

will only come

When we find the answer

And close the door.

Thank you, Leonard!