Low D2 receptor levels predispose to enjoying ritalin
Reprinted from The American Journal of Psychiatry.Copyright @ 1999 American Psychiatric Association.
1. Prediction of Reinforcing Responses to Psychostimulants in Humans by Brain Dopamine D2 Receptor Levels Nora D. Volkow, M.D., Gene-Jack Wang, M.D., Joanna S.Fowler, Ph.D., Jean Logan, Ph.D., Samuel J. Gatley, Ph.D., Andrew Gifford,Ph.D., Robert Hitzemann, Ph.D., Yu-Shin Ding, Ph.D., and NaomiPappas, M.S.
Objective: This study assessed whether brain dopamine D2receptor levels, which show significant intersubject variability,predict reinforcing responses to psychostimulants in humans. Method:[11C]Raclopride and positron emission tomography were usedto measure D2 receptor levels in 23 healthy men (mean age=34 years,SD=7) who had no drug abuse histories in order to assess if therewere differences between the subjects who liked and those whodisliked the effects of intravenous methyiphenidate (0.5 mg/kg).Results: Subjects who liked the effects of methylphenidatehad significantly lower D2 receptor levels (mean=2.72 Bmax/Kd,SD=0.3) than subjects who disliked its effects (mean=3.16, SD=0.3).Moreover, the higher the D2 levels found, the more intense weremethylphenidate's unpleasant effects. Conclusions: Theseresults provide preliminary evidence that D2 receptor levels predictresponse to psychostimulants in humans and that low D2 receptorsmay contribute to psychostimulant abuse by favoring pleasant response.(Am J Psychiatry 1999; 156:1440-1443)
One of the most challenging problems in the neurology of drugaddiction is understanding why some individuals abuse drugs, whereasothers do not. It has been hypothesized that low levels of dopamineD2 reptors predispose subjects to use drugs as a means of compensatingfor the decrease in activation of reward circuits activated by thesereceptors. However, the data supporting D2 receptor level involvementin predisposition to drug addiction are controversial, and the involvementof D2 receptor levels in the reinforcing responses to drugs inhumans has not been demonstrated. In the present study, we used[11C]raclopride and positron emission tomography (PET) to determineif there were differences in striatal D2 receptor levels betweensubjects who reported the effects of methylphenidate (a psychostimulantdrug that, like cocaine, blocks the dopamine transporters) as pleasantand those who reported them as unpleasant and to assess whetherD2 receptor levels predict behavioral responses to methylphenidate,which differ markedly among subjects. Although raclopride bindsto both D2 and D3 receptors, the striatal concentration of D3receptors is very low, so that the PET measurements mainly reflectbinding to D2 receptors.
The differences in response to methylphcnidate between subjectswith high and low D2 receptor levels can be explained by the hypothesisthat there is an optimal range in which D2 receptor stimulationcan perceived as reinforcing; too little may not be sufficient,but too much may be aversive. Thus, it is possible that in subjectswith high D2 receptor levels, a small dose of methylphenidatemay be perceived as pleasant. If D2 receptor levels modulate sensitivityto physiological reinforcers , then one could postulate that lowD2 receptor levels would predispose a subject to use drugs asa means of compensating for decreased activation of reward circuits.Alternatively, low D2 receptor levels could predispose individualsto psychostimulant abuse by favoring initial pleasant drug responses,which have been shown to predict future drug use, and/or highD2 receptor levels may protect against drug abuse by favoringunpleasant drug responses.
Subjects who reported the effects of methylphenidate as pleasant,as most cocaine abusers do, had receptor levels similar to thosepreviously reported cocaine abusers. Thus, these results bringto light the possibility that low receptor levels in cocaine abusersmay have antedated their cocaine use and may have contributedto their cocaine abuse. However, even if this possibility wereto be corroborated, the fact that the subjects who liked methylphenidatehad D2 receptor levels similar those found in cocaine addictsbut were not drug abusers suggests that additional variables areinvolved the vulnerability to drug abuse. These results are highlysuggestive of an involvement of D2 receptor levels in the perceptionof the reinforcing effects of psychostimulants. These resultsagree with those from studies in laboratory animals indicatingthat D2 receptor levels mediate reinforcing responses to drugsof abuse. This is evidenced by decrease in the reinforcing effectsof alcohol and morphine in mice who lack D2 receptors (D2 receptorknockout) and by the decrease in the reinforcing effectsof cocaine in animals given drugs that block D2 receptors. Whilethe studies on the effects of D2 receptor antagonists in the reinforcingeffects of psychostimulants in humans have not been as conclusiveas those in laboratory animals, they have shown a decrease inthe subjective ratings of pleasant sensations and of the cravinginduced by cocaine. The lower efficacy of D2 receptor antagonistsreported in human studies may reflect the fact that the dosesused were lower than those used in laboratory animals. Althoughanalogue scales for self-reports of drug effects have been shownto be reliable and consistent across studies and to predict administrationof drug in human subjects, this study would have benefited hadthese measures been corroborated by other behavioral instruments-e.g.,the Profile of Mood States. This is the first evidence in humansshowing an association between D2 receptor levels in brain andthe reinforcing responses to psychostimulants. Further studiesare required to determine the involvement of D2 receptors in thepredisposition to drug abuse.
Journal of Neurochemistry, 2001, 78, 1094-1103
Over Expression of Dopamine D2 receptors reduces alcohol self-administration
Panayotis Thanos, Nora Volkow, et al.
Review of study: The study showed that rats who prefer alcohol decreased theiralcohol intake when a gene for the DRD2 receptor was injected into their nucleus accumbens. The gene expressed itself with increasedreceptor activity on PET scan for a few days and the animals showed decreased drinking during those day and increased drinking when the effectof the gene wore off. This all suggested that decreased DRD2 receptorhad a role on alcohol intake in these rats. This study confirmsprevious studies and shows the role of the receptor level in alcoholintake, all consistent with Hypoism.
Study Links Binge Eating to Mutation in a Gene
By THE ASSOCIATED PRESS
OSTON, March 19 — Binge eaters who say they cannot help it may have a point.
A study suggests a gene may contribute to the cause of binge eating in some people. Researchers said they hoped the finding would point the way to a pill that could bring appetites under control. The Swiss-German-American study makes the strongest case yet that a genetic mutation can cause an eating disorder, the researchers say. Researchers generally believe that eating behavior is complex and cultural in its causes. "Willpower is not always important to reduce weight," said Dr. Fritz Horber, the leader of the binge eating study at the Hirslanden Clinic in Zurich. "Some people can by willpower. Some cannot, and I think these patients have a hard time." The study is in Thursday's New England Journal of Medicine. Researchers have been trying to understand the reasons for an epidemic of obesity, which raises the risk for heart disease, diabetes and many other ailments. Abundant high-calorie foods and sedentary habits are widely blamed for the surge. However, some researchers have also begun to link several genes to obesity. Increasingly, eating problems are thought to stem from a subtle interaction of lifestyle and multiple genes. Probably the most common eating disorder, binge eating strikes up to four million Americans, according to the National Institutes of Health. Binge eaters, who are usually but not always overweight, frequently and compulsively stuff themselves, often in secret, and feel ashamed afterward. In the study, the researchers focused on a gene previously linked to obesity. Known as the melanocortin 4 receptor gene, it makes a protein by that name that helps stimulate appetite in the brain's hunger-regulating hypothalamus. If a mutated gene makes too little protein, the body feels too much hunger. The researchers considered 469 severely obese white adults, a quarter of them binge eaters. The disorder was much more common among the 5 percent with the mutated gene. Eric Ravussin, a Louisiana State University researcher on obesity genetics, said that without more biochemical proof, he remained "a little bit skeptical" that the mutation — and not others nearby on the same chromosome — are the syndrome's precise cause. But Dr. Joel Habener, a diabetes expert at Boston's Massachusetts General Hospital who was one of the writers of an accompanying editorial, said the Swiss-led study demonstrated either the "genetic cause or a very strong association." Dr. Habener agreed with the researchers, who said future drugs acting like the melanocortin 4 receptor protein might compensate for the genetic defect.
Below are the actual abstracts from the NEJM. These are seminal and predictive papers of the first definitive demonstration of a genetic mutation causing a clinical addiction, as predicted by the Hypoism paradigm years ago. Moreover, they show the unconscious and compelling nature of the behavior associated with the mutated gene. This differentiates Hypoism from all current addiction paradigms.
NEJM, Volume 348:1085-1095, March 20, 2003, Number 12
Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene
I. Sadaf Farooqi, M.D., Ph.D., Julia M. Keogh, B.Sc., Giles S.H. Yeo, Ph.D., Emma J. Lank, B.Sc., Tim Cheetham, M.D., and Stephen O'Rahilly, M.D.
Background Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype–phenotype correlations.
Methods We determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity. Family studies were undertaken to examine cosegregation of identified mutations with obesity. Subjects with MC4R deficiency underwent metabolic and endocrine evaluation; the results were correlated with the signaling properties of mutant receptors.
Results Twenty-nine probands (5.8 percent) had mutations in MC4R; 23 were heterozygous, and 6 were homozygous. Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia; homozygotes were more severely affected than heterozygotes. Subjects with mutations retaining residual signaling capacity had a less severe phenotype.
Conclusions Mutations in MC4R result in a distinct obesity syndrome that is inherited in a codominant manner. Mutations leading to complete loss of function are associated with a more severe phenotype. The correlation between the signaling properties of these mutant receptors and energy intake emphasizes the key role of this receptor in the control of eating behavior in humans.
Binge Eating as a Major Phenotype of Melanocortin 4 Receptor Gene Mutations
Ruth Branson, M.B., Ch.B., Natascha Potoczna, M.D., John G. Kral, M.D., Ph.D., Klaus-Ulrich Lentes, Ph.D., Margret R. Hoehe, M.D., Ph.D., and Fritz F. Horber, M.D.
Background Obesity, a multifactorial disease caused by the interaction of genetic factors with the environment, is largely polygenic. A few mutations in these genes, such as in the leptin receptor (LEPR) gene and melanocortin 4 receptor (MC4R) gene, have been identified as causes of monogenic obesity.
Methods We sequenced the complete MC4R coding region, the region of the proopiomelanocortin gene (POMC) encoding the melanocyte-stimulating hormone, and the leptin-binding domain of LEPR in 469 severely obese white subjects (370 women and 99 men; mean [±SE] age, 41.0±0.5 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 44.1±2.0). Fifteen women and 10 men without a history of dieting or a family history of obesity served as normal-weight controls (age, 47.7±2.0 years; body-mass index, 21.6±0.4). Detailed phenotypic data, including information on body fat, resting energy expenditure, diet-induced thermogenesis, serum concentrations of leptin, and eating behavior, were collected.
Results Twenty-four obese subjects (5.1 percent) and one control subject (4 percent) had MC4R mutations, including five novel variants. Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and body-mass index with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2 percent of obese subjects without mutations (P<0.001) and 0 percent of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. No mutations were found in the region of POMC encoding melanocyte-stimulating hormone.
Conclusions Binge eating is a major phenotypic characteristic of subjects with a mutation in MC4R, a candidate gene for the control of eating behavior.
Food Addiction Neurotransmitter/Hormone PYY:
From Newsday: Study Finds Appetites Reduced by Hormone
By GINA KOLATA
single infusion of an intestinal hormone made people eat less for the rest of the day, regardless of whether they were fat or thin, researchers are reporting today.
The hormone, PYY (for peptide YY 3-36), is of particular interest because it appears to be the intestine's signal of satiety and because overweight people normally make less of it than thin people. Researchers are trying to learn whether some people grow fat because they do not produce enough of it and thus get only a weak chemical signal to stop eating.
In the study, whose results appear today in The New England Journal of Medicine, 24 volunteers, half of them overweight and half of them lean, received PYY or a saltwater placebo at 8:30 a.m. An hour and a half later, they were ushered in to a buffet lunch. On average, those who had received PYY ate 30 percent less.
"It was dramatic," said the principal investigator, Dr. Stephen R. Bloom, a professor of endocrinology at Hammersmith Hospital at Imperial College School of Medicine in London. "We haven't had anyone who didn't get a result."
The obese subjects ate only 1,810 calories for the rest of the day, compared with 2,456 for those given a saltwater injection. The thin subjects ate 1,533 calories after they had the hormone infusion but 2,312 when they had saltwater.
Dr. Bloom emphasized that the findings were preliminary. PYY is an experimental substance; no doctor can prescribe it. And the researchers have not yet tried to find out whether people lose weight if they get PYY infusions day after day. But obesity researchers say the work, which began just two years ago, is encouraging.
"It's part of the moving front of research that's adding new and potentially important molecules into the pathways that control body weight," said Dr. Jeffrey Flier, an obesity researcher who is chief academic officer at Beth Israel Deaconess Medical Center in Boston.
There are other promising anti-obesity molecules, Dr. Flier said, but PYY is particularly intriguing.
"This one has the compelling feature that it's been tested in animals, it's been tested in humans, it seems to work in the same concentrations in obese and lean humans, and the levels in the blood are low in obesity," Dr. Flier noted.
Dr. Bloom said he began his study of PYY because he was saddened by the obesity he saw every day in his clinic. "Medically, it's a disaster to be obese," he said, adding that the condition exacts social and emotional costs as well: "The rate of suicide is doubled, they are unhappy, they have a lower average wage, they don't get married. They are unhappy people dying of nasty complications, and it's particularly sad because society tries to blame them."
In the quest for treatments to counter obesity, Dr. Bloom went on, "our research team asked the question, What is the best way to restrain appetite?" The researchers tried filling patients up with water or with bulky, low-calorie foods like cabbage, without success. When they tried infusing nutrients directly into the bloodstream, the subjects were as hungry as ever.
Dr. Bloom concluded that satiation "is neither from the food in circulation after it is absorbed or from the fullness of the gut." Those observations led him to PYY, a hormone released by the intestine after a meal. He learned that fat people make less of it than thinner people and that the hormone makes thin people eat less. Rats also eat less when they get it, and they lose weight. Obese people who had gastric bypass operations, which mysteriously result in a loss of appetite, have "sky high" PYY levels, Dr. Bloom said.
Researchers have long noted that one reason people find it so hard to lose weight is that the body has many ways to thwart them.
"Most of us are the same weight year after year," Dr. Bloom said. "We might be overweight, but we are the same weight year in and year out. Yet every day you are faced with this or that amount of food. You don't measure it, you just naturally regulate your food intake."
When people try to lose weight, said Dr. Rudolph Leibel, an obesity researcher and co-director of the diabetes center at Columbia University's College of Physicians and Surgeons, they eat less and the body sends out signals that it is hungry, among them the hormone ghrelin, made by the stomach. If people ignore them and manage to shed some pounds, the body responds by lowering its metabolic rate, making it easy to regain the weight.
My letter to the editor:
Re: Study Finds Appetites Reduced by Hormone
Hypoism states that, in general, people born with defects in the feedback mechanisms that regulate the use of any instinct will use the instinct excessively. If the defect is severe enough the person will become addicted to that instinct. Some of these defects involve specific neurotransmitters used in the feedback mechanism while other relate to defects in the control mechanism itself (the decision-making apparatus). The net result of these defects are drug use and drug addictions (addictive drugs are chemical substitutes for the natural neurotransmitters) and/or use or addiction to the various instinctive behaviors. Moreover, because these regulatory mechanisms work below the level of consciousness, and were designed that way by evolution, they cause people to act out these behaviors against their will all the time appearing to be willful to both outside observers and the person involved in the behavior. In this case it's the intestinal neurotransmitter PYY and its role in the regulation of the feeling of appetite and the behavior of eating food. Thus, the dilemma of understanding addictions in regards to "free will" and "choice" over the history of mankind.
This elegant experiment again validates and confirms the Hypoism hypothesis of instinct regulation and addiction formation. It's too bad we are wasting so much time missing the forest for the trees and thus not changing the entire behavioral paradigm so we help people with this inborn biological and genetic disease.
Another article from the MSMBC web site, 10/23/03:
WASHINGTON, Oct. 23 — U.S. and Japanese researchers said on Thursday they had found a genetic mutation that causes obsessive-compulsive disorder and other mental illnesses and said some patients had a second mutation that made their conditions worse.
THE RARE FINDING could make it easier to discover good treatments for the disorder, one of the top 10 leading causes of disability worldwide.
Dr. Norio Ozaki of Fujita Health University School of Medicine in Toyoake, Japan and colleagues at several U.S. institutions — including the University of Pittsburgh and Yale University — worked on the study, published in the journal Molecular Psychiatry.
The gene is called the human serotonin transporter gene, hSERT, and helps control how the body uses serotonin, a message-carrying chemical or neurotransmitter linked with mood.
Some anxiety drugs and antidepressants target serotonin, but the researchers said patients with the mutations are not helped by these drugs. “In all of molecular medicine, there are few known instances where two variants within one gene have been found to alter the expression and regulation of the gene in a way that appears associated with symptoms of a disorder,” said Dr. Dennis Murphy of the National Institute of Mental Health, who worked on the study.
SECOND GENE INCREASES RISK
The researchers analyzed DNA from 170 people, including 30 patients with obsessive-compulsive disorder, 30 with eating disorders such as anorexia and 30 with seasonal affective disorder — which can cause depression and other symptoms in dark winter months. They also looked at the DNA of 80 healthy people.
A specific mutation in the hSERT gene was seen in two patients with OCD and their families, but not in other patients.
With such a rare mutation showing up, the researchers believe it is likely to be found in other families with OCD and related disorders.
They interviewed relatives of the patients and found 6 of the 7 people with the mutation had an obsessive-compulsive disorder, and some also had anorexia, Asperger’s syndrome, which is a form of autism, social phobia or were abusers of alcohol.
A second mutation was found in hSERT in two patients, giving them a “double dose.” The patients and their siblings had especially difficult to treat versions of OCD, the researchers said.
[© 2003 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content is expressly prohibited without the prior written consent of Reuters.]
My email about this:
Re: Gene found for obsessive compulsive disorder
If you glance down the list of addictions on the home page of hypoism.com you will find OCD, a group of compulsive behaviors associated with addictions to beliefs and behaviors meant to change the feelings that accompany these beliefs. Many OCD patients have other addictions. I said long ago that OCD is one of the symptoms of Hypoism and was caused by the same mechanism that causes all addictions - low activity of a genetic allele related to some neurotransmitter working within the decision-making apparatus. Read the Hypoism definition of the word addiction: The use of substances, people, behaviors and/or beliefs to change how one feels against one's will.
Finally, a couple of these genetic alleles have been identified. A funny thing is associated with having these genes, other addictions: anorexia, asperger's syndrome (a syndrome associated with repetitive behaviors and thoughts), alcohol addiction, and social phobia, an addiction to a belief. The researchers believe they will find other alleles of other genes doing similar things. In fact, Hypoism predicted this years ago. I wrote my first ignored and unpublished paper on this in 1992. Twelve addiction journals refused to publish a review of this hypothesis.
The Hypoism paradigm explains how these genetic alleles cause addictions as well as using this understanding to allow recovery from them. It's quite remarkable that the best current treatment for OCD other than drugs is a kind of behavioral therapy quite similar to the Hypoism recovery outlined in the book, Hypoic's Handbook. In addition to this genetic news today there have been many other scientific neurobiological validations of predictions made by Hypoism, something that only happens and repeatedly happens for a correct paradigm. In the book I predicted these validations as part of the future proof of Hypoism. However, every time I raise the issue that another Hypoism prediction has been confirmed, thus confirming Hypoism, just as current astronomical observations are still confirming Einstein's theories, Hypoism continues to be ignored and censored. Each time one of these confirmation occurs, I write a letter to the editor saying something like, "I already wrote the book about this. How about reading it, let your readers know about it, and start using it?" But that never happens. I would like to ask the readers of this email, why not? Is it because I, Dan Umanoff, M.D., wrote the book, instead of some "expert?" I discuss in my book and on my web site why it is that current experts will never invent Hypoism. It's because they have biased beliefs that exclude Hypoism as a possibility. This is the same thing that happened to Galileo, Darwin, Semmelweis, etc. Every new and real paradigm in medicine must come from someone outside the mainstream because the mainstream is blinded by its outdated bias. I've had this argument in many long and tortuous email exchanges with David Goldman, M.D. chief of genetic research at NIAAA who still has refused to read my book just incase it's correct. What's going on here that makes addictionology and the media keep the public ignorant about the most important advance in addictionology since poppies, Hypoism, while millions of addicts of all kinds and their families are dying and suffering? Do we have to wait interminably until every last detail of Hypoism is proven before we dump the outdated and incorrect addiction paradigm and switch and switch to Hypoism? How many millions must suffer and die before we do this?
2009: Evaluating Dopamine Reward Pathway in ADHD, by Volkow and Wang, et al., JAMA. 2009; 302(10):1084-1091. Low activity of the reward system causes ADHD. Of course, ADHD is part of Hypoism. So, low reward system activity cases Hypoism. That was my hypothesis from the outset, no? Well, there it is. Hypoism is genetic low reward activity, just as I said in 1992.