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HOPE FOR The Future How alcohol affects epigenetics

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It’s in the Genes Researchers Probe Alcohol’s Effect on Epigenetics As scientists gain a better understanding of the human genome, one rapidly emerging area of research is the effect of alcohol on epigenetics – external modifications to DNA that turn genes “on” or “off.” Epigenetic changes alter the physical structure of DNA. One example of an epigenetic change is DNA methylation — the addition of a methyl group, or a “chemical cap,” to part of the DNA molecule, which prevents certain genes from being expressed. A recent article in the National Institute on Alcohol Abuse and Alcoholism’s Alcohol Alert reports on a growing body of research showing how alcohol’s influence on epigenetics may be associated with an array of illnesses and disorders. These include fetal alcohol spectrum disorders (FASD), cancer, liver disease and other gastrointestinal disorders, brain development, the body’s internal clock, and immune function. Researchers and clinicians are beginning to explore therapies that might be developed to target the changes occurring through epigenetics.

How alcohol affects epigenetics Alcohol consumption leads to chemical changes within the body that can affect all the epigenetic mechanisms. For one, excessive alcohol consumption interferes with the body’s ability to process and access a chemical called folate. Folate is critical for methylation, a biochemical process that attaches a methyl group to a specific spot on DNA. DNA methylation acts to lock genes in the “off ” position. Chronic alcohol consumption leads to lower-than-normal methylation, or “hypomethylation.” Research also finds that alcohol metabolism leads to an increase in a substance called NADH, which is a byproduct of alcohol metabolism, and through production of reactive

oxygen species (ROS), which are chemically reactive molecules that at high levels can damage cells. Fetal alcohol spectrum disorders Women who drink during pregnancy put their developing fetuses at serious risk for a range of conditions collectively known as FASD. In exploring how epigenetics contributes to FASD, researchers have also begun to investigate two complex enzymes that play a crucial role in cell differentiation during fetal development. One, called polycomb protein, remodels chromatin to turn genes off; the other, called trithorax protein, remodels chromatin to turn genes on. Research suggests that exposure to alcohol may

Researchers and clinicians are beginning to explore therapies that might be developed to target the changes occurring through epigenetics due to alcohol use.

disrupt these two enzyme complexes, altering how cells differentiate during fetal development. Liver disease and the gastrointestinal tract Alcohol affects epigenetics on many levels within the GI tract and liver, where the majority of consumed alcohol is metabolized and cleared from the body. As alcohol enters the liver, it sets off what could be described as a cascade of epigenetic changes that increase the risk of liver disease, liver cancer and immunological problems. In addition, alcohol-associated epigenetic changes may play a role in what researchers call organ “cross- talk” between the GI tract, the liver and other organs. For one, epigenetic changes to genes involved in joining the cells lining the intestines may be partially responsible for “leaky gut,” which allows endotoxins to enter circulation and initiate liver damage. Alcohol-associated cancers As suggested above, alcohol-related changes involved in epigenetics can be linked to the development of liver cancer. In particular, research suggests that some epigenetic changes can transform normal liver cells back into stem cells, which then can develop into liver cancer. In addition, alcohol acts indirectly on a receptor that, when disrupted, is involved in the development of liver cancer. Alcohol’s role in changing DNA methylation patterns, leading to hypomethylation, may be one of the main routes between alcohol consumption and liver cancer as well as other types of alcohol-associated cancers. Changes in brain functioning Alcohol’s epigenetic effects within the brain are complex and intertwined. But increasing evidence suggests that they result in adaptations within the brain that ultimately influence addictive behaviors, including tolerance and alcohol dependence. As seen in other disorders, changes in DNA methylation are one of the epigenetic changes in the brain caused by chronic alcohol consumption. Although researchers still are piecing together the details, findings to date suggest that epigenetic changes in gene expression induced by alcohol consumption may underlie the brain pathology and adaptations in brain functioning associated with

alcohol abuse and alcohol dependence, and may contribute to alcohol relapse and craving. Hope for the future As researchers begin to untangle the exact nature of alcohol’s interactions with epigenetics, they will be able to design better medications to treat or alleviate a wide range of alcohol-related disorders, including FASD, alcohol addiction, cancer and organ damage. In addition, researchers can now analyze DNA methylation patterns for the entire human genome. This work could yield comprehensive maps of DNA methylation changes in alcohol-associated cancers. Those maps then could potentially be used to develop pharmacological treatments that target epigenetic markers and develop new markers for cancer detection and prognosis. 

As researchers begin to untangle the exact nature of alcohol’s interactions with epigenetics, they will be able to design better medications to treat or alleviate a wide range of alcohol-related disorders.

NIDA ‘Future’ survey finds declining teen substance use

FORWARD MOVEMENT A recent survey of American middle and high-school students found that students’ use of most substances in 2015 continued its flat or downward trends of recent years—many dropping to the lowest levels in the history of the survey. These mostly positive results, gathered by University of Michigan for its annual Monitoring the Future survey, provide some cause for optimism about long-term trends, according to researchers. For example, fewer 12th graders than ever (17.2 percent) reported binge drinking five or more drinks on a single occasion in the past two weeks, and fewer than ever (37.7 percent) reported being drunk in the past year.The MTF has been conducted annually since 1975. Positive trends Teenage smoking has seen a downward trend year-over-year, according to the study. Among high school seniors, 5.5 percent reported daily cigarette smoking, down from 6.7 percent a year ago and 24.6 percent at its peak in 1997.This decline in cigarette use means that, for the first time, fewer seniors are daily cigarette smokers than are daily marijuana users. Use of inhalants, traditionally a concern in the youngest age groups, was at its lowest levels ever, and the drop in lifetime use of these substances since last year’s survey was significant among 8th and 10th graders (9.4 percent and 7.2 percent, respectively, down from 10.8 percent and 8.7 percent last year). Similarly, teens’ use of synthetic marijuana has

decreased in all grades surveyed since 2012, when the survey first started tracking use of these drugs. Non-medical use of prescription pain relievers was down significantly from five years ago and heroin use was at its lowest levels in the history of the survey —a positive note in the current opioid crisis that continues to strongly affect other age groups. However, non-medical use of the prescription stimulant Adderall remains high: 7.5 percent of 12th graders and 5.2 percent of 10th graders reported non-medical use of the medication. Marijuana use still remains high among teens, who may be vulnerable to the drug’s long-term, adverse effects on brain development.

A cautionary note Along with the encouraging results, the researchers also sounded a cautionary note in regard to teens’ use of marijuana and e-cigarettes.The study noted that marijuana use by teens use has remained relatively stable over the last decade, despite concern that wider availability and softening attitudes towards the drug would lead to increased use. However, marijuana use still remains high among teens, who may be vulnerable to the drug’s long-term, adverse effects on brain development. Six percent of high school seniors use marijuana daily or almost daily, which could have detrimental impacts on their current functioning and their future prospects. Also, surveys indicate increasing numbers of teens think marijuana use is not a health risk, indicating a lack of awareness of the harm it can do to the developing brain. The researchers also expressed concern that use of e-cigarettes remains high, with 9.5 percent of 8th graders, 14 percent of 10th graders, and 16.2 percent of 12th graders using these devices. While more information is needed on the health implications of e-cigarettes, the nicotine in many e-cigarette fluids can be addictive, and their vapor may contain other chemicals that might be harmful to the lungs.There is also concern that vaping may “re-normalize” smoking behavior and lead to traditional cigarette use among youth who start using e-cigarettes.

Teen substance use is still a problem In spite of the optimistic tone of the report, the researchers stress that the problems and consequences of adolescent substance use in America have not diminished. Far too many 8th, 10th and 12th graders continue to use drugs regularly or try them, possibly paving the way for substance use disorders, since adolescence is the period of greatest vulnerability for the brain changes underlying addiction. The researchers call for continued support of evidence-based prevention programs, training health care providers to identify and treat youth with substance use disorders, and empowering young people with the knowledge and resources to live healthy lives. 

Non-medical use of prescription pain relievers was down significantly from five years ago and heroin use was at its lowest levels in the history of the survey—a positive note in the current opioid crisis that continues to strongly affect other age groups.

“The concept of addiction as a disease of the brain challenges deeply ingrained values about self-determination and personal responsibility.” – Dr. Nora Volkow, Dr. George Koob, Dr. AThomas McLellan

Fighting for the Brain Disease Model Model can complicate messaging in treatment plans

Fighting public opinion can be an uphill battle, sometimes even a futile one. Despite years of progress and scientific advancements, researchers and treatment providers still find themselves having to convince the general public that substance use disorder is a disease. But it’s a message that can often complicate treatment plans as much as it seeks to inform.

Setting the Record Straight Earlier this year, three of the nation’s leading drug experts wrote a paper seeking to explain, once and for all, how substance use affects the brain in the same way as similar diseases. In an article published in the New England Journal of Medicine, NIDA Director Dr. Nora Volkow, NIAAA Director Dr. George Koob, and Treatment Research Institute founder Dr. AThomas McLellan say they hope to reaffirm the brain disease model while simultaneously addressing common misconceptions about addiction. “The concept of addiction as a disease of the brain challenges deeply ingrained values about self-determination and personal responsibility that frame drug use as a voluntary, hedonistic act,” the authors write. The authors argue that public skepticism about the brain disease model comes from researchers’ inability to articulately describe the relationship between changes in neurobiology and the behaviors associated with addiction. Although countless scientific studies have proven the brain disease model to be accurate and effective, the authors admit more work may be needed to change public perception. “A more comprehensive understanding of the brain disease model of addiction may help to moderate some of the moral judgment attached to addictive behaviors and foster more scientific and public health–oriented approaches to prevention and treatment,” the authors write.

“You have to emphasize the responsibility on the part of the person, but you also have to explain why the behaviors are happening.” – Bob Rohret, MARRCH executive director

 Scientific studies attest that a person’s brain chemistry can be altered as a result of addiction.This fact can provide a needed explanation as to why continued use can still be a problem for people who clearly desire to get clean. “When you start to apply an explanation of why certain behaviors occur,” Rohret says, “it provides people some comfort in understanding why they’re doing what they’re doing.” Mixed Messages But as confident as many in the medical community are about the nature of substance abuse disorder, the idea that addiction is a disease presents something of a double-edged sword for treatment providers. “The messaging has to be sort of finessed,” says Bob Rohret, executive director of the Minnesota Association of Resources for Recovery and Chemical Health (MARRCH). “You have to emphasize the responsibility on the part of the person, but you also have to explain why the behaviors are happening.” Rohret says treatment providers have to inform those in recovery about the nature of their disease, while also making sure knowledge of that disease doesn’t become a crutch or an excuse for inaction. When presented correctly, Rohret says patients should understand their addiction and responsibility toward it in much the same way someone with heart disease may understand their affliction. Although they cannot change the biological makeup of their body immediately, they can make behavioral changes and take actionable steps that lead to more positive outcomes.

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Learning to Drink

Study finds alcohol changes the brain from the very first drink

“ Drugs of abuse basically hijack the normal learning and memory processes. ” - Dr. Dorit Ron University of California - San Francisco

Preventing escalation

The NIAAA-funded study did not establish a relationship between initial use and addiction, or even problematic drinking. But the hope is that further understanding of how alcohol affects the brain initially could lead to better treatment and prevention efforts down the road. “If we can control that step, we may be able to prevent further escalation,” Dr. Ron says. More research is needed to determine which other components of the brain are affected by initial alcohol exposure. Dr. Ron says she believes the changes that occur during first exposure could be reversed with prolonged abstinence from alcohol. But she said the more a person drinks, the harder it is to reverse those changes as the brain forms stronger connections to drinking.

One drink is all it takes. That’s what one research team found when studying how even the first exposure to alcohol can affect a person’s brain. A team from the University of California - San Francisco exposed mice to alcohol and then studied the synapses (connections) in their brains.The team found that even the first drink produced significant changes in the brain’s biological structure, calling the changes a “learning event.” “This is basically the first step,” says Dr. Dorit Ron, one of the chief researchers. “You are basically placing a memory trace.” Dr. Ron says the entire study was based on the idea that “addiction, and not just alcohol addiction, is thought to be a maladaptive form of learning and memory.” In essence, the study showed that first exposure to alcohol primes the brain for further use and lays the foundation for future “learning.” “Drugs of abuse basically hijack the normal learning and memory processes,” Dr. Ron says. “The behavior becomes habit.”

Predicting behavior

A new study also suggests that the earlier a person starts drinking, the stronger those connections may become. Researchers recently set out to identify which substance people use first in their lives and found the majority of people try alcohol before any other substance.The team also looked at how a person’s age when they start drinking affects substance use later in life. Researchers say the earlier someone starts drinking, the more likely they are to use more than one illicit substance, and they’re also more likely to develop an addiction. “It’s a very nice predictor for polysubstance use,” says Dr. Adam Barry, the study’s chief author. “The later you delay, the closer you are to 21, the less likely you are to be alcohol dependent or dependent on other substances.”

“ Alcohol consumption among youth doesn’t occur in a vacuum. ” - Dr. Adam Barry, Texas A&M University

 strategies that prevent drug use and then applying those in an alcohol setting.” Curbing use Researchers acknowledge there’s a difference between a first sip and a first binge drinking event. But they say age at first use of any kind is still a good predictor of behavior later in life. To combat problematic drinking, Dr. Barry says educators need to address all factors of a child’s life, not just the substance itself. In keeping with new guidelines from the National Institute on Drug Abuse, Dr. Barry and his team recommend beginning substance education as early as third grade. “Alcohol consumption among youth doesn’t occur in a vacuum,” Dr. Barry says. “It’s really just trying to find evidence-based

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Too Much? From the Office of Dr. Study cites concern over doctors' prescribing habits

Family physicians are the largest prescribers of opioid pain medications, even outpacing pain specialists, according to a recent study published in the journal JAMA Internal Medicine. The findings reinforce the need for prevention efforts that focus on prescribing behaviors of physicians as well as patients who are at risk of overdosing, the researchers say. “Overprescribing is a national concern, and mitigation efforts should not be oversimplified or targeted to a select few prescribers, or to regions of the country, or to patient populations or communities,” says Victoria Richards, associate professor of medical sciences at Quinnipiac University School of Medicine, in a HealthDay article on the study. According to the advocacy group Physicians for Responsible Opioid Prescribing, many prescribers underestimate the risks associated with opioids – especially the risk of addiction – and overestimate their effectiveness.

Prescription rates vary

painkiller prescriptions per person as those in the lowest prescribing state. Yet, health conditions that cause people pain do not vary much from place to place and do not explain this variability in prescriptions issued. These latest findings add fuel to those who advocate for stricter oversight of narcotic pain medication. Approximately

44 people die each day from prescription opioids, and opioid- related deaths have tripled since the 1990s. More than 80 percent of these deaths are accidental or unintentional, according to the CDC, which estimates that up to 60 percent of opioid overdose deaths occur in people without a prior history of substance abuse.

Another indicator of the need for more scrutiny of prescribing practices is that prescribing rates for opioids vary widely among states, says the Centers for Disease Control and Prevention (CDC). In 2012, health care providers in the highest-prescribing state wrote almost three times as many opioid

Who is prescribing painkillers? In 2013, 15.3 million family practice physicians and 12.8 million internal medicine physicians wrote prescriptions for narcotic pain medication, researchers found in studying Medicare Part D drug coverage claims.The study also found that nurse practitioners wrote 4.1 million prescriptions for narcotic painkillers while physician assistants ordered up 3.1 million.The research, led by Dr. Jonathan Chen of Stanford University, focused on prescriptions for narcotic painkillers containing hydrocodone (drugs such as Vicodin), oxycodone (Oxycontin and Percocet), codeine and others in the opioid class. In studying prescriptions written by 808,020 American doctors in 2013, the researchers found that pain management specialists and anesthesiologists wrote the most prescriptions for opioids. On average, individual pain doctors ordered 900 to 1,100 prescriptions for painkillers in 2013, and anesthesiologists wrote nearly 500. By comparison, each family physician wrote an average of about 160 prescriptions. Because there are many more family doctors than specialists, as a group, their number of painkiller prescriptions was higher than for any other provider category—more than 15 million prescriptions collectively, followed by internal medicine physicians at just under 13 million. In total, these two groups wrote more than half of all opioid prescriptions in the country. Pain specialists, including those involved in the more invasive sub-specialty of interventional pain management, accounted for about 3.3 million prescriptions.

CDC issues draft guidelines In the wake of growing concern over the excessive use of prescription opioids, the CDC recently issued a draft Guideline for Prescribing Opioids for Chronic Pain.The document provides recommendations regarding when and how these drugs are used for chronic pain: selection, dosage, duration, follow- up, and discontinuation; and assessment of risk and addressing harms of opioid use. However, the Guideline is not a federal regulation; adherence to it will be voluntary, the CDC notes. 

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