Meth and the Brain: The Pleasure/Reward Circuit’s Role in Addiction
Joel Stegen, CADCA

Methamphetamine is a highly addictive drug. As with all drugs of abuse, it stimulates the area of the brain responsible for motivation and reward, and fools the brain into thinking that meth use is important for survival. Methamphetamine is so highly addictive because it stimulates this area of the brain more intensely than any other addictive drug.

In order to understand how methamphetamine addiction occurs, it is first necessary to understand how the part of the brain affected by methamphetamine is designed to work normally.

All mammals have common structures in their brains that regulate motivation. These structures are located in an area of the brain called the limbic system. The limbic system is involved in determining whether behaviors are beneficial or detrimental to survival. There are two types of motivation that this system is responsible for producing. Aversive motivation is triggered by situations that are biologically detrimental or dangerous. The limbic system associates detrimental situations with physical or emotional pain or discomfort so that the organism avoids the behavior that has produced the pain. Appetitive motivation is triggered by situations that are biologically beneficial or advantageous. The limbic system associates beneficial situations with pleasure or a sense of well-being so that the organism is likely to repeat the desired behavior.

Behavior Chart 1
This is a diagram that represents different areas in the brain and their corresponding roles. When an organism behaves in a way that may be beneficial or detrimental, the behavior is analyzed in the Ventral Tegmental Area or VTA for short. The VTA weighs the pros and cons of a given behavior and decides if it is worthy of repeating or avoiding. If the behavior is notable, it sends a signal to the Nucleus Accumbens, which produces feelings of pleasure or pain depending on the situation. The Hippocampus is responsible for storing memories, and the Amygdala associates emotion with the memories that are stored. Together, they link the pleasure or pain that the Nucleus Accumbens is producing with the memory of the behavior, producing a strong emotional memory. Later, when the opportunity to repeat the behavior arises, the three areas of the brain originally involved in storing information about the behavior all send signals to the prefrontal cortex, which is involved in planning and decision making. The nature and intensity of the previously stored experience strongly influences the decision to repeat it or avoid it.

The prefrontal cortex is the only structure in the above diagram that participates in rational, cognitive processes. It is part of the cerebral cortex. The VTA, Nucleus Accumbens, Amygdala and Hippocampus are all part of the limbic system and its related structures, which govern instinct rather than rational thought. The interaction between these two areas of the brain explains how instinctive urges influence rational decisions.

The following table illustrates how the motivation/reward circuit influences behavior:

  Behavior Effect Conditioned Response Conditioned Behavior

  Drinking a Pint of Tequila


Vomiting / Hangover

Smell of tequila turns stomach

Avoid tequila

  Eating a Meal Pleasure of taste / fulfillment of
being full

Smell or sight of food creates
food craving
Acquire food and eat

  Having Sex Pleasure of sex / euphoria of
orgasm / fulfillment afterward
Sexual opportunities evoke
arousal and excitement
Pursue sex

Note that behaviors that are biologically detrimental are reinforced with pain, and behaviors that are biologically beneficial are reinforced with pleasure.

The brain chemical responsible for generating feelings of pleasure in biologically beneficial situations is the neurotransmitter dopamine. Methamphetamine works the way it does because it is structurally similar to dopamine and interacts with dopamine neurons by fooling the brain into thinking it is dopamine.

Methamphetamine Molecule
Dopamine Molecule


Behavior Chart 2
Here we have the motivational system in the brain again, but now with methamphetamine use as the behavior that is being processed. Remember that the two crucial areas for processing motivation and associating it with pleasure or pain are the VTA and the Nucleus Accumbens. The neurons in these areas are dopamine neurons. Meth directly stimulates these areas so that huge amounts of dopamine are released upon use. The VTA’s ability to accurately assess the situation is obliterated by an unnaturally loud message that says “this behavior is vitally important to survival”. It also sends a signal to the Nucleus Accumbens telling it to produce a pleasure signal to reinforce the behavior, but this is hardly necessary at this point because meth is also directly stimulating this area, and huge amounts of dopamine are creating an intense euphoria that will be associated with this behavior as an emotional memory. Because the signals are so loud, it does not take long to condition the behavior. Later, when no drug is present, situations which present opportunities for use (internal or external triggers) cause the motivational system to send a very loud signal to the Prefrontal Cortex. This is how, even in the face of grave consequences, the rational part the mind decides that it’s a good idea to use. Use creates stronger reinforcement, and the cycle goes on and on, making rational choice less and less possible.

The graph below illustrates the intensity of the stimulation meth use creates:

Limbic System Dopamine Levels
During activity that is not necessarily important for survival, the average person has a dopamine level of about 100 units in the limbic system, which is the reward center of the brain. Seeking food is important to survival, so the VTA creates a nice pleasant feeling of contentment in response to eating by increasing dopamine levels to 150. From a biological standpoint, propagation of the species is crucial to survival, so the pleasant feeling after sex is the result of even higher levels of dopamine. Cocaine creates significantly greater euphoria than sex by increasing dopamine levels to 350, which is outside of normal biological values. You’re body can’t create levels this high without drugs. Meth increases dopamine levels to 1250, which creates a euphoria that dwarfs all of the others. It is not hard to see how eventually behaviors that don’t result in meth use become extinct, and drug seeking and using behaviors become the only things that motivate an individual.(1)

Not only does methamphetamine increase the dopamine levels in the reward circuit more powerfully than cocaine, it also does so for a longer period of time because the half-life elimination of methamphetamine is much longer than that of cocaine. Five hours after peak concentrations of drug have been reached, a dose of cocaine is metabolized to the point that only 5% of the original dose remains in the bloodstream. A similar dose of meth is eliminated much more slowly, so that 80% of the original dose is still present after 5 hours.

Having the motivational system overwhelmed like this eventually results in motivational toxicity, where rewards that would normally motivate a person cease to be effective because methamphetamine has directly stimulated the reward system and has conditioned meth use over all other survival instincts. This is why meth addicts will choose their drug over family, career and health.

Mechanism of Action
In order to understand meth’s mechanism of action, we need to cover some basic neuron anatomy. Neurons, or nerve cells, communicate with each other by sending and receiving small electrochemical impulses. The receiving fibers of a neuron are called the dendrites. The sending fiber of a neuron is called the axon. As you can see, neurons have many dendrites and one axon. The axon sends its signal to a receiving dendrite by releasing chemical messengers called neurotransmitters into the space between the axon and the dendrite. This space is called a synapse.

Neuron Diagram Synapse Illustation

The illustration on the right shows the junction between two neurons. There is a small amount of space between the two neurons. This space is called the synapse.

Here is a schematic diagram of a synapse. The axon, or sending part of the neuron, sends a signal to the dendrite, or receiving part of another neuron. The signal is sent chemically by dopamine molecules. Dopamine filled pockets in the cell called vesicles move toward the surface of the cell membrane and allow their contents to be released into the synapse. The dopamine molecules float across the synapse and make momentary contact with dopamine receptors on the surface of the receiving cell. This triggers a chemical process that causes the cell to fire. Dopamine is then pulled back into the sending cell by reuptake pumps and absorbed back into the vesicles so that it can be used again. Methamphetamine works by taking advantage of its similarity to dopamine. First, methamphetamine attaches itself to the reuptake pumps. It actually binds to them more powerfully than dopamine, and will push dopamine out of the way to get to them. Meth then gets transported into the cell masquerading as dopamine. The neuron thinks the meth is dopamine, so it tries to absorb it into the vesicles. When it does this, meth actually causes the vesicles to dump massive amounts of dopamine into the cell.

Synapse Schematic Figure 1 Synapes Schematic Figure 2

Meth temporarily changes the structure of the reuptake pumps when it is taken into the cell. As a result, the reuptake pumps now work in reverse, pumping the free dopamine out of the cell and into the synapse. Because of the meth’s interaction with the reuptake pumps, dopamine can’t get back into the cell to be recycled, so large amounts of it build up in the synapse very quickly.

This level of stimulation creates intense euphoria. Very strong pleasure signals are being created. These signals are actually so strong that they can overwhelm the receiving cell and kill it. The body has a remarkable way of minimizing the damage, however. The brain can no longer control the amount of dopamine in the synapse because meth has hijacked this process. It can, however, turn down the intensity of the signal by reducing the number of receptors the dopamine comes in contact with. This process is called down regulation, and it involves actually absorbing many of the receptor proteins into the cell so that it is less sensitive. In meth use, this process happens very quickly, and is part of the reason why tolerance develops so rapidly. This adaptation reduces cell death, but not without a cost. When you remove the methamphetamine, dopamine release plummets for a couple of weeks, but eventually returns to normal.

Synapse Schematic Figure 3 Synapse Schematic Figure 4

These normal levels of dopamine, however, are trying to stimulate a down regulated dendrite with very few receptor sites on it. The neuron senses this and begins to create new receptors, but it takes 18 to 24 months for enough of them to grow back to restore normal sensitivity. Even though the receptors on dendrites grow back, the extensive damage that occurs during meth use causes many connections to be lost. Some of the deficits from these broken connections may never completely resolve.

Normal Brain Scan These images are from SPECT scanning technology to study dopamine activity in the brain. The red areas have the highest concentration of dopamine transporters, followed by the green areas and then the blue areas. The meth user here is 4 months clean. You can see that there is very little dopamine activity in comparison to the normal brain on the left. (2)   Meth User Brain Scan


This image is the result of a study at the Laboratory of Neuro-Imaging at UCLA, where they compared 100’s of SPECT scans of meth users to 100’s of SPECT scans of normal brains. With this data they were able to come up with composites representing the average meth user’s brain and the average non-drug using person’s brain. They then compared the average difference in brain tissue volume of meth user’s vs. non-users. If this were a normal person’s brain, it would be all blue. The parts of the brain governing emotion, reward and memory were the most damaged. This explains the profound depression, emotional lability, and anhedonia (the inability to feel pleasure) that newly clean meth users struggle with. Significant deficits in cognition, memory, judgment and concentration exist during this time as well. (3)   Eroding the Mind Diagram

Primary Neurocognitive Deficits Associated with Long-Term Meth Use:
  • Attention / Psychomotor Speed
  • Learning & Memory
  • Executive Functions
    • Resulting in:
      • Poor judgment
      • Lack of insight
      • Poor strategy formation
      • Impulsivity
      • Reduced capacity to determine consequences of actions
The good news is, it gets better over time. Here are 3 different SPECT scans of dopamine activity in 3 different brains.(4) As you can see, there is a well-defined area of high dopamine activity in the normal brain (the red area). The meth user who is one month clean has almost no red in the image, and a 14 month clean meth user has dopamine activity comparable to the normal subject. It is important to note that it is the subject in the middle who is at the greatest risk of relapse. Life seems dull and gray with dopamine levels that low, and it’s going to be a long time before this person gets fulfillment from normal activities that don’t involve drug use. Studies have been done using SPECT technology while conducting interviews with subjects. When a meth user is asked to talk about drug use, the limbic system lights up like a Christmas tree. The reward circuit turns up the dopamine to influence planning behavior and motivate the subject to perform the behavior they have been conditioned to perform. Thoughts of using are just about the only thing that will get a 1 month clean meth user’s brain to glow red on this scan. Remembering that red feels good, and the lack of it feels depressing or painful, it is not hard to understand why relapse is so prevalent among the newly clean.

Brain Scan of a Normal Brain Brains Scan of a Meth Abuser 1 Month Clean Brain Scan of a Meth Abuser 14 Months Clean


REFERRENCES
1. Richard A. Rawson, PhD, FRONTLINE online article “Meth and the Brain,” Posted February 14, 2006
2. Volkow, N.D., et al. Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. American Journal of Psychiatry 158(3):377-382, 2001.
3. Laboratory of Neuro-Imaging at UCLA
4. Volkow, N.D., et al. Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. American Journal of Psychiatry 158(3):377-382, 2001.