Read Time: 20 minutes
Readers of a certain age might remember the public service announcements from the late 1980s showing a frying egg with the tagline: “This is your brain on drugs.” Although these commercials were effective at delivering the message that drugs are harmful to the brain, the comparison is very simplistic, and some consider it no more than a “scare tactic”.1
For many people, addiction can be difficult to understand. After all, why do people risk so much, perhaps even their own lives, just to get high? Understanding how drugs affect the brain can help shed some light on this mystifying behavior.
Rather than “frying” all of the brain’s circuits at once, most drugs have very specific effects on the way the brain functions. This article is a brief survey of how various drugs affect the chemistry of the brain. This will help reveal why even though someone who is high on cocaine acts very differently than someone who is abusing heroin, both individuals may find it close to impossible to give up their drug habit, even if they desperately want to.
To understand how different drugs—with their diverse mechanisms of action and varied effects—can all lead to addiction in those who abuse them, it helps to know a little bit about how the brain works.
Neurotransmitters: the Messengers of the Brain
The brain is the most complex organ in the human body2 and has even been called “the most complex object in the known universe”.3 Around 100 billion individual nerve cells, or neurons, form a complex network that has over 100 trillion (100,000,000,000,000) connections, or synapses.
Information travels around this network 24 hours a day, allowing the brain to direct all the conscious and unconscious activities in the body. Everything from composing a symphony to deciding what to eat for dinner requires complex calculations carried out in the brain.
The brain uses chemicals called neurotransmitters to carry information from one neuron to another at junction points known as synapses. Neurotransmitter signaling is a crucial part of all the brain’s functions, and changes in neurotransmitter signaling can alter the way people think, feel, or perceive the world around them.
Important neurotransmitters in the human brain include:
Messages in the brain usually travel from the presynaptic neuron to the postsynaptic neuron. This occurs when the presynaptic neuron releases neurotransmitters into the synapse, which then attach to special proteins on the surface of the postsynaptic neuron called receptors.
Neurotransmitters and receptors fit together in specific combinations like a lock and key. Other specialized proteins, called transporters, move neurotransmitters from the synapse back inside the neuron to turn off signaling.
Medications and illicit drugs that affect the brain alter neurotransmitter signaling in several different ways:
- Imitating neurotransmitters—Drugs like opiates and marijuana have chemical structures that are similar to natural neurotransmitters. Because they fit into the receptors, these drugs act like neurotransmitter “imposters”.
- Causing neurotransmitter release—Drugs like methamphetamine cause neurons to release neurotransmitters into synapses when they would normally be inactive.
- Preventing neurotransmitter signals from switching off—Certain drugs, like cocaine and many antidepressants block transporters so that neurotransmitters stay in the synapse and continue to activate receptors longer than normal.
All of the different ways drugs affect neurotransmitters have the effect of changing the information being processed by the brain. Drugs prescribed by a doctor, such as painkillers or antidepressants, can be used to “correct” imbalances in brain chemistry that may contribute to an individual experiencing physical or emotional distress. On the other hand, those who abuse drugs are altering the way their brains work in ways that may be temporarily pleasurable, but potentially dangerous in both the short- and long-term.
Drugs Hijack Communication in the Brain
The brain is a finely tuned machine, and individuals who abuse drugs upset its delicate balance. These outside chemicals can flood or supplant the brain’s natural circuitry, resulting in effects ranging from confusion to death. Several classes of drugs and the neurotransmitter systems they affect are described below.
Stimulants are drugs that increase the activity of a few specific neurotransmitters in the brain. Prescription stimulant medications are mainly used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy. They function similarly to the illicitly abused stimulants like methamphetamine and cocaine, though, and all ultimately result in increased levels of the neurotransmitter dopamine in the brain. Stimulants are also sometimes referred to as “speed,” “uppers,” or “study drugs”. Well-known prescription stimulants include:
- Methylphenidate (Ritalin).
- Amphetamine + Dextroamphetamine (Adderall).
- Lisdexamfetamine (Vyvanse).
Common illicitly abused stimulants include:
- Methamphetamine (crystal meth).
In the brain, dopamine is involved in several important behaviors including:
- Arousal (the state of being awake or alert)—Boosting dopamine levels increases energy, wakefulness, and attention while decreasing dopamine causes fatigue and drowsiness.
- Motor (movement) control—The death of dopamine-producing neurons in patients with Parkinson’s disease causes symptoms such as shaking, stiffness, and difficulty walking.
- Reward and motivation—Activities that promote survival including eating food, having sex, socializing with friends, or hugging a puppy, all increase dopamine levels in the brain’s reward circuitry.
Dopamine is an important neurotransmitter for keeping people awake, focused, motivated, and coordinated. However, when someone abuses stimulants, the unnaturally elevated levels of dopamine in their brain can cause hyperactivity, insomnia, anxiety, increased risk taking, and euphoria.
Also, because these drugs unnaturally stimulate the brain’s reward and motivation circuitry, they are often abused in a “binge” pattern. In a binge, individuals will consume all of the available stimulants in one sitting, often neglecting eating or sleeping. Because the brain’s reward center is more strongly activated by stimulants than normal, healthy activities, the brain prioritizes drug use over almost any other behavior.
Opioids are a group of natural and synthetic drugs that activate opioid receptors in the brain, spinal cord, and digestive tract. Opioid medications are also known as opiates or narcotics and are used as painkillers, cough suppressants, and anti-diarrhea medications. Well known opioids include:
- Oxycodone (OxyContin).
Normally, opioid receptors are activated by chemicals called endorphins. Endorphins are produced naturally in the brain and pituitary gland when the body is exposed to pain or other stressors such as an injury, childbirth, or intense exercise (runner’s high). In the brain, endorphin signaling has several roles, including:
- Altering pain perception—Opioid signaling reduces pain sensations centrally – mitigating pain signaling within the brain without affecting the injury itself. This is different from many over-the-counter pain relievers such as aspirin or ibuprofen, which reduce swelling and inflammation at the site of the injury to achieve their analgesic effects.
- Producing feelings of wellbeing—Endorphins cause more dopamine to be released in the reward and motivation circuits of the brain, which produces positive feelings. Opioid drugs mimic these endorphins but cause much more dopamine release in the reward pathways, creating a strong euphoric high.
- Decreasing respiration—There are many opioid receptors in the areas of the brain stem that unconsciously control breathing. Endorphin signaling in these neurons helps to slow breathing in situations that might otherwise lead to hyperventilation – such as feeling pain or being under stress. Because opioids can activate these receptors more strongly than endorphins, individuals who overdose on these drugs could stop breathing and die.
The brain’s system of endorphins and opiate receptors is a survival tool that helps people in dangerous situations from being overcome by pain or fatigue. Medically, opioids are an important treatment for people who have severe pain that cannot be controlled with other medications.
Individuals who abuse illicit or prescription opioids do so because these drugs have unnaturally large effects on the opioid system, including the reward pathway. Because opioid use can initiate much higher dopamine release in the nucleus accumbens rather than endorphins, they produce a euphoric high that is difficult to achieve through natural means.
By simply swallowing, snorting, or injecting these drugs, abusers can get all the feel-good effects of endorphins without having to break a bone or run a marathon. Also, because opioid users can control how much and how often they take the drug, they can get a more intense, longer-lasting high than is possible with natural endorphins.
Many different types of legal and illegal drugs are classified as depressants. Dependent on the specific type of depressant medication, the prescription pharmaceuticals in this broad class may also be referred to as sedatives, tranquilizers, and hypnotics.
Substances classified as depressants include:
- Alcohol—Technically called ethyl alcohol or ethanol, this is most widely used and abused recreational drug in the US.4
- Barbiturates—These drugs are used as surgical anesthetics and seizures. Historically, they were used to manage anxiety and insomnia, though their use for these applications has been largely supplanted by newer, safer medications.
- Phenobarbital (Luminal, goof balls).
- Amobarbital (blue devils).
- Secobarbital (Seconal, red devils).
- Tuinal (Secobarbital + Amobarbital, rainbows)
Benzodiazepines—Also known as benzos, these drugs are used to treat anxiety and panic attacks, as well as to manage acute seizures in emergency situations. Examples include:
- Diazepam (Valium).
- Alprazolam (Xanax).
- Lorazepam (Ativan).
Non-benzodiazepine sedatives—Often referred to as “z-drugs” because many of the drug names begin with the letter “z,” these medications are considered to be safer (milder effects and lower addictive potential) than benzodiazepines and are used to treat insomnia. Examples include:
- Zolpidem (Ambien).
- Eszopiclone (Lunesta).
- Zaleplon (Sonata).
Although these different drugs are very different chemically, all of them ultimately increase the activity of a neurotransmitter known as gamma-aminobutyric acid (GABA). Alcohol, barbiturates, and benzodiazepines all bind at different sites on the surface of the GABA receptor to activate this type of inhibitory signaling.
Activated GABA receptors inhibit, or decrease, the firing of individual neurons, and GABA signaling is critical to maintaining a healthy level of brain activity. Insufficient levels of GABA can cause restlessness, insomnia, anxiety, and seizures due to abnormally high levels of neural overactivity.
Many people abuse sedatives because they reduce anxiety, help them to relax and, in some cases, to help them sleep. These drugs can also indirectly affect the reward pathway and cause a euphoric high, especially when taken in high doses.
However, excessive GABA signaling from depressant abuse can cause problems if brain activity is reduced too much. These negative side effects include:
- Difficulty breathing
- Slurred speech.
- Memory loss.
In extreme cases, critical functions such as breathing might stop, causing death.
Cannabinoids are chemicals that bind with cannabinoid receptors in the brain. They are found naturally (in marijuana or cannabis), but may also be laboratory-made (synthetic cannabinoids, Spice/K2).
Although illegal in many parts of the country under federal law, cannabinoids are very popular recreational drugs that produce effects such as:
- A euphoric high.
- Distortion of perception.
- Memory impairment.
Cannabinoid receptors were first discovered in the 1980s using tetrahydrocannabinol (THC) and other cannabinoids found in the marijuana plant. It took another decade of research before scientists discovered the natural brain chemical counterparts – called endocannabinoids – that naturally bind to these receptors. In 1992, researchers discovered the first endocannabinoid in the brains of pigs, which they called “anandamide” from the Sanskrit word for bliss.5
Endocannabinoid signaling is complex and slightly unusual because these are retrograde neurotransmitters. That means endocannabinoids are released by the postsynaptic neuron and their receptors are on the presynaptic neuron, so they send information in the reverse direction of most neurotransmitters.
Although scientists are still learning precisely what these chemicals do, they are involved in many brain processes including:6
- Energy balance—Endocannabinoid signaling is important in brain pathways controlling hunger and energy metabolism in the body.
- Sensory perception—Many brain cells in the areas of the cortex that process sight, sound, hearing, and touch have cannabinoid receptors.
- Learning and memory—The hippocampus, an area involved in learning and forming short-term memories, is rich in cannabinoid receptors.
- Coordination—Endocannabinoids are important for the function of the cerebellum and basal ganglia, areas of the brain involved in balance and motor control.
In the brain, endocannabinoids are created only in specific neurons where they are needed and only for the amount of time they are needed, which can be as short as a few minutes.7 In contrast, THC and other cannabinoid drugs are ingested in relatively large amounts and indiscriminately activate receptors all over the brain.
This is why natural endocannabinoids are essential for forming clear memories and maintaining a normal appetite, while cannabis abusers often find themselves craving junk food and forgetting mundane things like where they parked.
Why Do Drugs Feel Good?
Most addictive drugs produce an intense euphoric high that abusers seek. This is because these drugs either directly or indirectly increase dopamine signaling in the limbic system, which includes a part of the brain that is involved with reward and motivation—the nucleus accumbens.
Behaviors that improve the chances of survival, like eating, having sex, and socializing with friends cause an increase in dopamine levels in this area. This increase in dopamine feels good and motivates people to repeat those actions.
Stimulants flood the whole brain with dopamine, including the nucleus accumbens, which causes intense pleasure in abusers and motivates them to repeat this behavior. Likewise, studies have shown that drugs that affect other neurotransmitter systems, such as alcohol,8 opioids,9 and cannabinoids,10 also cause dopamine levels to rise in regions of the brain involved in pleasure, especially the nucleus accumbens.
Experiments in animals have shown that drugs such as alcohol, amphetamine, cocaine, and morphine cause 2 to 10 times more dopamine to be released in the nucleus accumbens than natural rewards.11 This means that the motivation to use these drugs repeatedly is very strong, even if an individual knows that drug use is unhealthy and causes other problems such as losing a job or getting arrested. It also means that drug use takes priority over the desire for other healthy activities that originally provided a feeling of satisfaction or happiness.
Brain chemistry in the nucleus accumbens also shows the link between addictions to drugs and behavioral addictions. Research has shown, for example, that dopamine levels rise in the reward center when individuals with gambling addictions make bets, and that drugs that restore the normal neurotransmitter balance in the nucleus accumbens reduce both cocaine cravings in drug addicts and gambling urges in compulsive gamblers.12
How Drugs Change the Brain
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The brain and its networks have the ability to change and adapt, a property called plasticity. Plasticity is important for normal brain development and learning, as well as recovering from brain injuries and strokes. Plasticity is also the reason that long-term exposure to drugs produces abnormal changes in the brain.
The brain will attempt to correct network activity that is much higher or much lower than normal levels. If an individual is regularly flooding their brain with opioid or endocannabinoid signaling by abusing drugs, the brain makes attempts to counteract these changes and bring them back to natural levels. Like a thermostat in a house, which works to keep the temperature from getting too hot or cold, plasticity allows the brain to keep neurotransmitter signaling from getting far from normal levels.
This adaptation by the brain leads to 2 important consequences of drug abuse: tolerance and withdrawal.13
Individuals who abuse drugs often find that they need to take larger and larger doses of a drug over time to feel the same high. This is known as tolerance, and it is the result of the brain adapting to counteract the effects of abnormal neurotransmitter signaling caused by the drug.
One example of this is seen with long-term opioid abuse, which results in abnormally high opioid receptor signaling. The brain attempts to compensate for this imbalance by reducing the number of opioid receptors on the surface of neurons.14 Over time, this “pruning back” of receptors results in a reduced potential to experience the full spectrum of pain relief and euphoria that these drugs produce in a more “drug naïve” individual. Interestingly, circuits that control some of the more negative effects of opioids—including respiratory depression—do not develop tolerance as quickly. This phenomenon is known as asymmetric tolerance.15
An opioid abuser who develops asymmetric tolerance is at great risk for overdose. Why? When an individual has become tolerant to the effects on the reward pathways, it will take a lot to feel high. Meanwhile, the area of the brainstem that controls breathing has yet to develop an equal tolerance level, so there is a high risk of overdose and respiratory arrest.
People who regularly abuse a drug may find that they feel sick or experience other negative symptoms when they stop using the drug suddenly. This phenomenon is referred to as a withdrawal syndrome. Many of the symptoms of withdrawal are caused by the same brain adaptations that lead to tolerance.
The brain of a person who abuses sedatives such as alcohol for months or years has an imbalance caused by too much GABA receptor activation. GABA signaling reduces overall neuron firing and slows down many networks in the brain. The brain tries to counteract this imbalance by decreasing the baseline amount of GABA being released as well as by increasing glutamate signaling to boost overall neuron activity.16 This adaptation works well as long as the person keeps using alcohol or sedatives. Logistically, this cannot occur indefinitely. Inevitably, the onset of withdrawal arrives at the point which the abuser stops taking these drugs for a certain amount of time. Without them, the brain will be over-stimulated – potentially resulting in anxiety, delirium, and even seizures. (This is the main reason that attempts to detox from alcohol and sedatives should take place under close medical supervision).
The Addiction Trap
These drug-induced changes in the brain eventually lead to addiction. Individuals who have a drug addiction may have a variety of symptoms, but they all share the key feature of this condition, which is that they use their drug of choice compulsively despite experiencing serious negative consequences from their drug use such as being arrested, being fired from a job, or losing important relationships.
Avoidance of withdrawal symptoms can partially explain why it can be especially difficult for addicted individuals to stop taking drugs on their own.
However, it is adaptations in the nucleus accumbens and the motivation circuits of the brain that are thought to play the biggest part in the development of addiction. Every time an abuser gets high, they bombard the neurons in the reward pathway with unnaturally high levels of dopamine. Just as in other brain regions, these neurons adapt to counteract the repeated overstimulation.
Eventually, the brain adjusts to the intense rewards of drugs, and natural rewards such as food and friends no longer produce a pleasurable response in a drug abuser’s brain (a phenomenon referred to as “anhedonia”). The anticipation of obtaining and using drugs (wanting and craving) becomes the main source of excitement and produces a flow of dopamine that narrows that individual’s focus and excitement to drug use and little else.
This is why many people with addictions often feel life is pointless and empty. Individuals who have reached this stage may also stop feeling good at all when taking drugs; instead, they need the substance in order to feel “normal”.
Once this level of brain adaptation has been reached, taking drugs is no longer truly a choice. The addicted person will be driven to continue their habit as if it is necessary for survival, and drugs will seem more important than almost anything else. The effects of pleasure and motivation, powerful tools to help human survival, have been hijacked for a destructive and unhealthy purpose.
These physical changes in the brain support the idea that addiction is, in fact, a disease and not simply a moral failing. What is known today about the way drugs affect the brain also suggests why the 1980s “Just Say No” anti-drug campaign was not especially successful in preventing drug abuse.17
While using drugs may start out as a choice, physiologic changes in the brain caused by the drug use makes it difficult, if not impossible, for someone who is addicted to make rational decisions about their drug use. Also, individuals decide to first use drugs for many reasons; some want to get high, but others give in to social pressures or are prescribed opioid painkillers by their doctors and begin to misuse them.
By presenting addiction as an issue of morals or willpower, the “Just Say No” campaign did not offer practical tools for people who had already started down the path of drug dependency. It also created a stigma around addiction by sending the message that people could simply stop taking drugs if they wanted to. It is difficult to imagine that anyone really wants to ruin their lives with their drug use, and understanding how drugs affect the reward and motivation circuits of the brain shows us how an individual can lose the power to say “just say no”.
Instead of stigmatizing addiction, we can move forward by increasing the understanding of drug use on the brain and highlighting the ways that someone battling addiction can find recovery and sobriety in the long term.
Addiction does not have to be the end of the road for anyone. There are many drug detoxification and rehabilitation programs available all over the country to help people break out of the addiction trap.
Knowing how drugs affect the brain has provided healthcare professionals with tools that help break the hold of addiction. Benzodiazepines are used therapeutically to prevent life-threatening seizures in people who are addicted to alcohol, while medications like methadone and buprenorphine soothe intense withdrawal symptoms and block the high that comes from abusing opiates, serving as effective tools in recovery maintenance.
Although a happy, productive, drug-free life is possible for those who have become addicted to drugs, the brain adaptations caused by drug and alcohol abuse can be especially persistent.
Most symptoms of withdrawal last only a few days or weeks, but some effects including anxiety, fatigue, insomnia, and anhedonia (absence of pleasure) may last for months or even years. These symptoms are known as post-acute withdrawal syndrome (PAWS) and are thought to be caused by the slow process of the brain undoing drug-induced adaptations.
Some brain changes in the reward and motivation circuitry seem to be permanently affected by addiction.18 Though the vast majority of people recovering from addiction will soon be able to feel pleasure and enjoy life as much as ever, they may always be at risk for relapsing. It seems the brain never completely unlearns the rewarding aspects of drug abuse, so lifelong vigilance is important to prevent relapse.