Brain Facts: A Primer on the Brain and Nervous System

Drug abuse has been much in the news recently, with particular focus on the over-prescription and subsequent abuse of opioids. All too often, this abuse results in overdose and even death. In a 6-day period in late August 2017, one city (Cincinnati, Ohio) reported that 174 overdose cases flooded their hospital emergency rooms. The city is suing the pharmaceutical industry, as are counties in West Virginia, California, and New York. Addiction afflicts people around the world, often with chilling consequences. The National Institute on Drug Abuse estimates that the United States spends $700 billion each year on addiction-associated treatments, crimes, and lost productivity.

Addiction is a chronic brain disorder that affects the body through physical and psychological dependence. Intentional, regular use of substances like opioids, alcohol, tobacco, or other drugs becomes an addiction when a person can no longer control his or her use despite negative consequences such as loss of control and harm to themselves or others. One factor fueling addiction is tolerance — when a person’s body becomes “used to” a drug and requires more of it to experience the same effect. Another facet of addiction is withdrawal, when lack of a drug causes the body to react with unpleasant or life-threatening physical symptoms. These may range from moderate headaches or muscle pain to severe tremors or seizures.

A combination of positive factors (pleasurable feelings) and negative ones (avoiding withdrawal) helps to create an addiction. Cues or triggers, such as being in a place associated with drug or alcohol intake or being around other drug or alcohol users, also provoke drug-taking behavior. It is important to realize, though, that drug use does not always lead to addiction. Addiction is complex, and many researchers are working to understand the various interacting influences.

Almost all abused drugs produce pleasure by activating a specific circuit of neurons, the brain’s reward system, which is controlled mainly by the neurotransmitter dopamine. This brain region, called the limbic system, drives healthy behaviors such as eating and socializing, but it is also activated by drugs of abuse. The limbic system helps people experience emotion, which somewhat explains the mood-altering properties of many drugs. In addition, the brain’s reward system generates habits and learned behaviors: When a reward (a delicious food or a high-inducing drug) generates feelings of pleasure, we learn to repeat the actions that led to that reward.

Mimics and Imposters

Drugs of abuse act as imposters that invade our nervous system, mimicking the messages of naturally occurring neurotransmitters in our brain circuits. While some drugs copy the actions of neurotransmitters, others can block neurotransmitter action, and still others alter the way neurotransmitters are released or inactivated. Ultimately, in all cases of addiction, drug use changes the brain’s reward system and other regions involved in judgment and decision-making, contributing to addictive symptoms and behaviors.

Who is susceptible to becoming addicted? A precise answer to this question is still elusive, but we now know a great deal about vulnerability. As with most health conditions, vulnerability to addiction involves internal risk factors, such as certain genes, and external risk factors, such as stress and a person’s social environment. Often, a person’s social environment both contributes to addictive behavior and is shaped by addictive behavior, creating a cycle that is difficult to break.

Much remains to be learned about addiction’s causes, but researchers are intrigued to find common genetic links in many different types of addictions.

Studies that track twins, and other closely related individuals with and without addictions, conclude that about 50 percent of addiction can be traced to genetic factors. Much remains to be learned about addiction’s causes, but researchers are intrigued to find common genetic links in many different types of addictions — those involving a host of illicit drugs, marijuana, and legal drugs such as alcohol, tobacco, and even caffeine. Generally, the genes linked to addiction fall into one of two categories. Some of these genes affect how brain circuits respond to drugs; others influence the way the body metabolizes drugs, which then affects how quickly drugs enter and leave the body. Other biological factors important in addiction are gender and age: Females and males differ in their risk of addiction as well as their response to treatment. Also, while social environment has a significant influence on drug-taking behavior during childhood and adolescence, the influence of hereditary factors is stronger in later stages of addiction, which usually occur in adults.

OPIOIDS

Dating back to prehistoric times, humans have consumed opioids by extracting opium (also known as morphine) from the juice of poppy flowers. The drug heroin is an opioid that is made (illegally) by drying morphine, adding various chemicals, and then heating it until it evaporates and becomes a powder. When injected into a vein, heroin reaches the brain in 15 to 20 seconds. Once there, it is quickly converted back to morphine, which binds to opioid receptors, switching on the brain’s reward system and flooding synapses with pleasure-inducing dopamine. The result is a brief rush of intense euphoria, followed by a few hours in a state of relaxed contentment.

Opioids’ effects vary in strength, toxicity, safety, and how quickly they act. But why do our brains have opioid receptors? Our pituitary gland produces natural versions of opioids called endorphins, which help control motivation, emotion, food intake, and our response to pain. Laboratories produce synthetic opioids, which include heroin as well as prescription pain medicines like codeine, oxycodone (oxycontin), and fentanyl. Much more powerful than other opioids, fentanyl is used by doctors to treat severe pain. However, illegally made and distributed versions are sold on the black market and can be extremely dangerous. Opioids have many medically important uses — suppressing a cough, stopping diarrhea, and relieving pain — but, in excess, they can cause breathing to stop, the usual cause of death in an overdose.

Over the past two decades, the number of overdose deaths involving opioids (both prescription opioids and heroin) has quadrupled. Nearly 100 Americans, from every walk of life, die from opioid overdoses each day. As mentioned above, this opioid-addiction epidemic appears to stem directly from increased use of legally prescribed opioid medications that began in the mid-1980s to treat chronic pain. In fact, about 80 percent of current heroin users say their opioid use began with prescription pain medications; once hooked, they found heroin to be cheaper and easier to get than the prescription medications. Tragically, street heroin can be mixed with other dangerous substances, including high concentrations of fentanyl that can be immediately fatal. Another contributor to this epidemic was the 1995 introduction of a long-lasting version of oxycontin. Researchers now believe that, in medical as well as nonmedical users, addiction rather than abuse is the main driver of the opioid-overdose epidemic.

Treatment

The most effective treatment for opioid overdose is an antidote-like approach using synthetic drugs that block opioid receptors. The “antidote,” naloxone, binds to opioid receptors — without producing a biological effect — and prevents an opioid from binding. If given quickly enough, it can actually reverse a potential overdose caused by heroin or prescribed painkillers. Naloxone can also be used in prevention, to limit cravings in people highly motivated to quit. Doctors sometimes prescribe naloxone to a family member of someone at risk of opioid overdose so they can administer it, and many first responders across the country are taught how to administer naloxone in cases of overdose emergencies.

Drug-based treatment for overdoses can save lives, but other strategies are needed to treat opioid addiction itself and prevent future crises with these highly addictive substances. Two other drugs, methadone and buprenorphine, stimulate opioid receptors, but produce a limited high. They also reduce withdrawal symptoms from other opioids; both drugs have milder withdrawal symptoms of their own. Researchers have found that these therapies can help deter a person from seeking heroin or other abused opioids. Of the two, buprenorphine is safer because its effect is weaker than methadone, and it can be prescribed in an office setting. Psychosocial approaches, including cognitive behavioral therapy and behavioral change focused on positive reinforcement, can also be combined with drug treatments to treat opioid addiction.

NICOTINE

Nicotine is the addictive substance in tobacco. Within 10 seconds of smoking a cigarette, nicotine arrives in the brain (as does any other drug that is smoked). There it attaches to proteins on nerve cells called nicotinic acetylcholine receptors, triggering release of many neurotransmitters. It also releases neurotransmitters outside the brain like adrenaline, a stimulant that raises a person’s blood pressure and quickens their heart rate. In the brain, it creates a buzz of pleasure and energy — due to release of dopamine — followed by a calming sensation and a rapid boost in attention and memory. The latter finding has led to ongoing tests of non-addictive nicotine-like substances as possible treatments for cognitive disorders such as schizophrenia, attention-deficit hyperactivity disorder (ADHD), and Alzheimer’s disease.

Tobacco is the leading cause of preventable deaths in the United States, accounting for approximately 90 percent of lung-cancer deaths, 60 percent of lung-disease deaths, and 30 percent of deaths from heart disease. Despite the well-known health risks of tobacco use, however, about 20 percent of Americans still smoke. Nicotine itself does not cause cancer, but of the thousands of chemicals in tobacco, about 70 are known to be carcinogenic. However, nicotine is responsible for other health risks of smoking, including heart disease and stroke. Like many other addictive substances, nicotine generates tolerance; over time, more and more nicotine is required to obtain the same effect. Also like other drugs of abuse, nicotine activates dopamine-producing reward pathways that induce feelings of pleasure and affect motivation, creating the urge to use more.

Treatment

Nicotine is so highly addictive that, even though most smokers want to quit, few succeed. For some smokers who are highly motivated to quit, some drug treatments (pharmacotherapy) can help. Nicotine packaged into gum, skin patches, lozenges, nasal sprays, or inhalers can sidestep the use of cigarettes or chewing tobacco. Nicotine replacement products provide users with lower overall nicotine levels than they get with tobacco use, totally eliminate exposure to smoke and its deadly contents, and relieve withdrawal symptoms. Buprenorphine, used to treat opioid addiction, can also help smokers quit by simulating nicotine’s effect on dopamine.

One of the newest treatments for nicotine addiction is varenicline, approved by the U.S. Food and Drug Administration (FDA) in 2006 for tobacco-cessation treatments. Varenicline is a nicotine mimic that attaches to a special type of nicotinic acetylcholine receptor — one that is thought to be responsible for conveying nicotine’s addictive properties. Doctors consider varenicline the best single-drug option for nicotine addiction, and it is even more effective when combined with counseling and behavioral therapy. For example, smokers are twice as likely to quit if the advice comes from their medical provider. Other useful resources are motivational tools such as cessation hotlines, websites, and social media that promote tobacco-free living.

ALCOHOL

Alcohol, although legal like tobacco, is also addictive. Together, alcohol abuse and alcohol addiction are a serious and costly national health issue. Aside from secondary behavioral impacts such as drunken driving, sexual assault, and domestic violence, a primary chronic health problem is associated with alcohol addiction: cirrhosis, a late-stage of scarring of the liver. The annual U.S. cost of alcohol abuse and addiction is estimated at $250 billion.

Ethanol, the addictive ingredient in alcoholic drinks, has tricky effects on our bodies. Ethanol is water-soluble so it easily enters the bloodstream and quickly travels to the brain. With just a drink or two, ethanol acts as a stimulant. At higher blood levels, however, it acts as a depressant, causing intoxication, sleepiness, and even “blackouts,” or short-term memory loss.

Ethanol targets gammaaminobutyric acid (GABA) receptors, which drive the brain’s inhibitory system. In this capacity, ethanol calms anxiety, weakens muscles, and delays reaction time. Ethanol also blocks the N-methyl-D-aspartate (NMDA) type of glutamate receptors, which alter mood and impair memory, both common features of intoxication.

Finally, ethanol can stimulate the brain’s pain-relief circuits, fueled by natural opioid molecules. This accounts in part for ethanol’s feel-good effects in many people. It is also a diuretic — a substance that pulls water from body tissues and can cause dehydration.

Binge drinking — excessive alcohol consumption in a short period of time — slows heart rate and causes breathing difficulties — usually the underlying cause of death in alcohol overdose.

Chronic, heavy ethanol use can also change brain structure. People with alcohol use disorder (formerly called alcoholism) can have an unsteady gait, tremors, and slurred speech; these symptoms result from damage to the cerebellum, a brain region important for movement and balance. They also suffer from memory loss due to the degeneration of neurons in the areas of the brain that govern learning and memory.

When does alcohol drinking become alcohol addiction? Federal surveys have found that nearly 9 in 10 Americans have drunk alcohol at some point in their lives, and an estimated 15 million have an alcohol use disorder, which might develop into addiction. As is true of addictions overall, about half the risk of alcohol addiction is thought to be linked to genetics. Yet, given that not all people who choose to drink become addicted to alcohol, it is clear that both genetic and environmental factors contribute to alcoholism. Currently, no single factor or combination of factors can predict the risk of developing an alcohol use disorder, although having a parent or grandparent with an alcohol use disorder is a good predictor. For this reason, neuroscientists often study genetic and environmental factors separately, designing some experiments to understand drinking behavior and others to investigate general issues related to motivation. Researchers often use animal models in these types of studies.

Treatments

Most people with a problem with alcohol use can benefit from some form of treatment before their use becomes a dangerous addiction. Treatments include behavioral therapy such as individual counseling, group therapy, and support groups. Some medications (disulfiram, naltrexone, and acamprosate) are used to treat alcohol addiction, and researchers can now use genetic testing to try to optimize therapy for individual drinkers.

Wheeler, et al. Journal of Neuroscience 2013.

Studies show that the brains of drug addicts look different than those of people who don’t use drugs. This MRI scan reveals a mouse’s thinning cortex, the part of the brain associated with higher-level functioning, following exposure to cocaine. Researchers found that changes in brain shape and volume were most pronounced when animals were exposed to cocaine in adolescence, suggesting the impact drug use has on brain development.

MARIJUANA

Also known as weed or pot, marijuana comes from the dried leaves, flowers, stems, and seeds of the Cannabis plant. The plant contains the mind-altering chemical tetrahydrocannabinol, or THC, which distorts perception and alters a person’s sense of time, space, and self. Within minutes of smoking a marijuana “joint,” THC travels from the lungs to the blood and then into the brain. Eating foods containing THC can also create a high, usually within an hour of ingestion. Although the federal government deems marijuana illegal, in recent years several states have passed laws legalizing it. This has substantially increased documented recreational use of marijuana in the United States.

Marijuana is not harmless. Neuroscientists have discovered that regular marijuana use is linked to abnormal neurobiology in brain regions related to reward, cravings, and thought control — all are key players in addiction. Marijuana use during the teen years can have long-lasting effects on thinking, memory, and learning. Although cannabis-use disorders have been less studied than other addictions, some known harms include higher stress levels due to craving and withdrawal, inability to think clearly, missing school or work, and risky behaviors while intoxicated. As with other addictions, heavy marijuana use seems to increase vulnerability to drug use in susceptible people, through physical changes in the brain circuits of reward systems. In some users, long-term marijuana use has been linked to schizophrenia.

Our brains make a natural form of THC called anandamide, which acts through cannabinoid receptors in the body that help coordinate movement. This may explain why people’s driving is impaired after smoking marijuana. The hippocampus, involved in memory and learning, also contains many THC receptors, possibly explaining the effects of marijuana on short-term memory. While relatively little research has been conducted on the role and usefulness of marijuana in treating medical conditions, some studies suggest that another active compound in marijuana called cannabidiol, or CBD, which does not produce a high, can control epileptic seizures, relieve pain and inflammation, and possibly even treat mental illness and addictions.

Many people with post-traumatic stress disorder (PTSD) self-medicate with marijuana to cope with anxiety, stress, and insomnia, and a few research studies appear to validate this strategy. These studies show that marijuana might reduce anxiety, improve sleep, and erase trauma-related memories in people with PTSD, but it is unknown whether this is due to CBD, THC, or some other ingredient. More research is needed to explore these findings. Similarly, marijuana has been widely regarded as a treatment for reducing nausea associated with chemotherapy. However, 2017 information from the National Cancer Institute (NCI) says there is currently too little evidence to recommend using cannabis to treat this side effect of cancer therapy.

PSYCHOSTIMULANTS

Psychostimulants are chemicals that excite the brain. They give a temporary boost to physical and/or mental function, earning some the nickname “speed.” One very common psychostimulant is caffeine, and another is nicotine. While both are legal and commercially available, nicotine is highly addictive and can create secondary problems as the main ingredient in cancer-causing cigarettes and chewing tobacco.

Other psychostimulants are in commonly prescribed medications that are sometimes abused recreationally. For example, doctors prescribe amphetamine (Adderall) and methylphenidate (Ritalin or Concerta) to treat ADHD and the sleeping disorder narcolepsy, but these drugs have migrated to the black market and are widely sold illegally. Amphetamines, including methylphenidate, are frequently abused by high school and college students. One study determined that, by their senior year, two-thirds of college students had been offered prescription stimulants and one-third had used them non-medically to increase focus and enhance concentration.

Illegal psychostimulants that are made in makeshift drug labs and sold on the street include cocaine and methamphetamine, or “meth.” Abusers sometimes smoke these — in particular, cocaine (crack) and crystal methamphetamine (crystal meth) — producing a rush of euphoria and feelings of power and self-confidence. Typically, the effects are short-lived, prompting repeated use and physical harm to various organs, including the heart. Meth, in particular, is quite destructive to the brain itself, as it generates harmful substances called free radicals that destroy dopamine neurons.

NIH.

Methamphetamine abuse can reduce the number of dopamine receptors in the brain, disrupting mental functions.

In the brain, psychostimulants work by flooding the brain’s reward system with dopamine, the “usual suspect” in most addictions and many psychiatric disorders. Most psychostimulants act and wear off quickly, leading to a quick high and then an unpleasant “crash” that encourages more use and can be overwhelming, both physically and mentally. Meth is especially addictive, entering the brain very quickly and staying there longer than other psychostimulants. People who continue using psychostimulants develop a tolerance, needing more and more to get high. Over time, these drugs damage the body’s ability to release normal amounts of dopamine, causing a range of health problems, starting with a lack of drive to engage in activities that were once pleasurable.

Neuroscientists are working hard to figure out how to prevent and treat addiction to psychostimulants. In the course of their work, they have learned a great deal about the brain’s normal function in motivated behavior. For example, in addition to increasing dopamine in the reward system, psychostimulants act in the prefrontal cortex to promote arousal and quicken our thinking. Studies show that low doses of psychostimulants (much less than taken in drug abuse) actually improve the brain’s executive function (as in some ADHD treatments), helping with impulse and emotional control, planning and organizing, and productivity. Such low doses do not lead to tolerance and addiction, but high doses can impair brain function.

Treatments

Currently the best treatments for psychostimulant addiction are cognitive-behavioral therapy and motivational incentives, both of which help steer users away from situations that trigger drug use. So far, no effective drugs have been approved for cocaine or meth addiction. However, now that scientists better understand how psychostimulants work in the brain, they are pursuing treatment strategies that target many neurotransmitters separately to quell cravings and withdrawal symptoms. The neurotransmitter systems include serotonin, glutamate, and GABA. Still-experimental meth treatments focus on entirely new targets, such as the brain’s immune cells (microglia) and oxytocin — the latter is sometimes called the “love” or “happiness” hormone because men and women release it during orgasm and mothers secrete it during childbirth and breastfeeding.

DESIGNER DRUGS AND CLUB DRUGS

Designer drugs such as “bath salts” and “spice” (synthetic marijuana) are synthetic legal substances with psychoactive effects. They look like illicit drugs but can often be bought legally because the people who make them continually tweak their chemical structures to evade drug laws. We now know that these drugs can cause serious, permanent damage in many brain regions. Like designer drugs, club drugs are also synthetic psychoactive substances that look like legal drugs and are named for their use by youth at dance parties and all-night raves in crowded, high-energy surroundings. Examples of club drugs include 3,4-methylenedioxy-methamphetamine (also known as MDMA, Ecstasy, or Molly), rohypnol (“roofies”), GHB (gamma hydroxy-butyrate), and ketamine. Designer and club drugs can be stimulants — such as Ecstasy — or depressants like rohypnol, GHB, and ketamine.

Ecstasy is a widely used recreational drug with similarities to both the stimulant amphetamine and the hallucinogen mescaline, which occurs naturally in the peyote cactus and has effects similar to lysergic acid diethylamide (LSD). When swallowed, Ecstasy works within 30 to 45 minutes, and its effects last for several hours. It initially boosts levels of neurotransmitters, especially serotonin, then temporarily depletes their levels in the synapses. Chronic Ecstasy use leads to long-term changes in areas of the brain critical for thought, memory, and pleasure. Researchers think this harm is a result of long-term damage to serotonin circuits.

Rohypnol and GHB are both depressants, and mimic benzodiazepines like Valium. They are also known as “date-rape” drugs, as people have used them to facilitate sexual assault by slipping pills into drinks, sedating and incapacitating unsuspecting victims. Ketamine, called “Special K,” is also a depressant that is legally used as a veterinary anesthetic. When used recreationally, ketamine takes effect within about 10 minutes, putting users in a trance-like state. Its hallucinogenic effects last one or two hours. Recently, scientists have found a totally unexpected use for ketamine: treating depression. Ketamine alters signaling of the neurotransmitter glutamate, a non-traditional target for antidepressant medications. Perhaps most interesting are its very rapid effects, which occur within minutes to hours instead of the weeks required for other current antidepressant treatments. For this reason, neuroscientists consider ketamine a potential breakthrough, especially in people for whom no other treatments have been effective.