I often ask my patients who have relapsed why they restarted their drug use. Sometimes, the reasons for the relapse seem easy to understand. There was some particular stressor or or some turn of events that the person could identify.. These cravings were easy to understand But often, the person has no clue. They found themself using before they knew it. It was akin to a knee-jerk reflex and the person had relapsed before they knew what was going on. I had also asked the patient if there were a lot of cravings- sometimes there were. However, sometimes they were using with their first craving, it was that intense.
How does it come about that such a "reflex" to relapse develops? To understand why this happens, one needs to understand normal functioning of the brain. Imagine a lab rat placed in an unfamiliar maze with the smell of food emanating from wherever the goal is. Outwardly, they sniff around and move quite slowly. This belies lots of internal brain activity; the brain is ferociously active and involves the analytic parts of the brain including the prefrontal cortex and nucleus accumbens. The neurotransmitters,glutamate and dopamine, are released in the accumbens which provides the motivation to seek out the food. This pathway involves multiple neurological connections with various parts of the brain and is a relatively slow process.
As the rat, learns the maze, he moves more, and his brain becomes less active. The behavior still needs to be motivated but it is no longer motivated by the accumbens. Rather a nearby area, called the posterior striate cortex (PSC), which also releases glutamate and dopamine, motivates the behavior. In comparison to the accumbens, the connections between the stimulus (smell) and the effect (movement) are fewer. The behavior is accomplished faster and with less brain activity. It is also accomplished more automatically and with less conscious thought.
Human learning is chock full of comparable examples. When we first learn a sport, each skill is thought out, and than practiced over and again until hopefully it becomes automatic. A major league shortstop does not have time to think about catching a line drive- he has to react quickly. The better athletes among us are those who can get these skills learned efficiently and reproduce them consistently- it is why we practice. As we repeat the behavior over and over and see good outcomes, we imprint the behavior into our PSC. The motivation for the behavior has moved from our accumbens to the PSC. These behaviors now are a reaction to a stimulus (the ball coming at us) and we act without thinking.
Of course, we did not evolve to play ball, rather the ability to make these adaptations helped make our hunting, gathering and survival skills more efficient.
So how does this relate to drug cravings. A person looking forward to a good movie, or a pay check at the end of the week, or a good grade for work well done, is certainly motivated by the benefits they are anticipating. However, it is a conscious, analytic motivation involving the relatively cumbersome accumbens. A non-addict thinking about the pleasurable aspects of a drug (or another addictive behavior) will also be motivated by the accumbens. However, it has been shown that by the time an addiction has been set in, that motivation has moved to the PSC.
An alcoholic, who is shown pictures of an alcoholic beverage, will release dopamine in the PSC. This motivates alcohol seeking behavior. Even if alcohol is not obtained, the desire to use alcohol, or craving, is similarly caused by the dopamine release. In fact, it has also been shown that the greater the amount of dopamine released, the more intense the cravings will be. A similar finding is seen when a heroin addict is shown a needle or a compulsive food addict is shown a plate of cookies. We therefore see this dopamine release in response to a trigger that causes a behavior (the cravings is the behavior). Even when we don't use the drug, the cravings can persist as long as 20 minutes and can keep recurring throughout the day. Even if the trigger is subliminal (below the awareness of the person) it has been shown to lead to dopamine release and cravings. I have termed this the "I want" reflex.
The drugs have taken advantage of an evolutionary adaptation. Behaviors that have been shown to be beneficial though multiple episodes of expression and reward eventually get imprinted into the PSC so they can be performed quickly and automatically for the benefit of the person. However, drugs cause such a release of dopamine that they fool the brain into treating them as beneficial behaviors. Drug using behavior may be imprinted after only a few expressions of the behavior. Unfortunately, once, imprinted, they are extremely persistent and difficult to get rid of.
Even though we have this drive to use drugs or act inappropriately, there are still other parts of our brain that are supposed to help us inhibit inappropriate behavior. Unfortunately, a separate abnormality found in the addicted brain is a deterioration of these self control parts of the brain.
Any medication that minimizes the release of dopamine or gluatamate in the PSC will reduce the intensity of cravings. Topiramate stabilizes glutamate levels as does N-acetyl cystine. Ondansetron (zofran), in ultra low doses only, has been shown to reduce the release of dopamine. All these medications have shown the ability to reduce cravings.
We all want to be healthy happy people. In order to be happy, we need the hormones and neurotransmitters that control our moods to be working optimally. Serotonin, nor-epinephrine and dopamine are among the more important chemicals in our brain that need to be balanced. Increasingly, the role of glutamate is also being recognized as crucial to our emotional health. These chemicals all need to be running at an optimal levels; too much or too little will wreak havoc with our emotions.
There is an important neuro-physiology concept call TONE. A nerve left completely alone will still fire at a certain rate. It will release a certain quantity of neurotransmitter. This steady baseline secretion of transmitter is call tone. Many processes will transiently increase or decrease nerve activity from baseline. The nerves have evolved to adapt to any outside stimulation in order to return activity as close to baseline as possible. Nerve adaptation is the reason people become tolerant and physically dependent on drugs with chronic exposure.
Despite the tendency to maintain baseline activity, it is part of normal physiology that there will be transient increases in activity and neurotransmitter release. This is especially true with dopamine. Periodic pleasures, such as orgasm or good food, will transiently increased dopamine. In fact, such periodic increases in dopamine are likely necessary for optimal emotional health.
It is not only experiencing pleasure that release dopamine; even the anticipation of a pleasurable activity will increase dopamine. This makes perfect sense for the survival of the organism and species. If I anticipate finding a good meal or having sex, I will have a dopamine surge in my brain. I will therefore maintain this thought in my head. This will motivate me to perform the activities necessary to secure that meal or sexual encounter.
I enjoy eating, reading, doing crosswords and spending time with my family. I look forward to playing tennis. Whenever I look forward to these activities, the dopamine surges in my brain. If we did not look forward to something we could be clinically depressed.
An important area involved with anticipation may be located in a nerve tract that originates in the prefrontal cortex and goes to the medial Nucleus Accumbens. The prefrontal cortex (PFC) is the area of the brain where complex behavior is initiated. The nucleus Accumbens (NAC) is the pleasure center of the brain where dopamine is released. This is where the drugs of abuse work.
This nerve tract releases glutamate in the NAC. The glutamate interacts with a specific types of receptor ) that results in a greater release of dopamine. and greater response from the dopamine released. This makes a thought pleasurable and important and it allows us to stay focused on that thought. Without the nerve tract, we would not look forward to anything, we would be unmotivated
Glutamate is essential for addiction behavior. Studies have demonstrated that the rodents born with genetic defects that prevent certain types of glutamate responses are unable to become addicted.
The release and interactions of glutamate and dopamine in this fashion motivates our behavior. They are the reasons we look forward to doing the things we like to do. Undoubtedly, this nerve connection is, and will continue to be, the subject of intense research.
We all look forward to doing a variety of fun and pleasurable activities. What about the addict? A typical young man will look forward to a possible sexual encounter. However, the average young male addict will be comparably less interested in sex as the average male non-addict. Imaging studies show a decrease in metabolism in the relevant brain areas. In many situations, we see that the person who is addicted, or in early recovery, is not interested in a lot things. They often describe a boredom or fatigue. It is not a fatigue where they sleep; rather, they just are not interested in doing anything. It is a situation similar to depression. Many people will try to engage the addict in non-drug activities as a way of helping them heal; however, they are biologically not able to motivate themselves.
Lab rats can be trained to anticipate reward. Their brains can be studied during these behaviors. Glutamate and Dopamine surges in the NA are part of this process in normal rats. However, rodents who were addicted to cocaine and are now in recovery have less of a surge of glutamate with non-drug rewards They just can’t get excited about any reward ( such as food) that is not drug related.
In the lab, this nerve tract can be artificially enhanced by drugs (not approved in humans. What is really amazing is when glutamate activity is artificially normalized in addicted rats, their addictive behaviors resolve. They have become more involved in anticipating non-drug activities and seem to have less time and or focus for drug related activities.
he previously mentioned glutamate dysfunction in the brain is associated with less activity of the target cells in the NAC. This is not healthy. We need to have optimal activity in this area for optimal emotional health. We will be depressed and irritable. We will want to relieve this situation.
The anticipation of using drugs seems to be one of the few things that is able to overcome this baseline inhibition of glutamate/dopamine action. However, drug cravings may use other pathways, (see The disease of Addiction:tale of 2 circuits,
To sum up, hypo-function of the PFC to NA tract results is a general lack of motivation and sets the stage for obsessing about drugs. It seems reasonable that gambling, sex and other non-substance addiction disorders may have a similar pathology. I believe this abnormality constitutes one of the core pathologies involved with the disease of addiction
At the present time, there are no drugs to treat this problem. In animals, manipulation of brain physiology with directly infused drugs has reversed the abnormalities. However, these treatments remain limited to the lab bench. I believe that time will repair this circuit to some degree. The brain has the ability to restore itself towards normal. This process can take months or longer. In certain types of substance use (such as opiate and perhaps marijuana and alcohol) I believe that this process might be accelerated with the use of naltrexone. (see article)
Recently, opioid dependence come into the front and center of our public awareness as so many people, young and old, rich and poor and from both politically connected and disaffected families, develop opioid addiction and die from overdose. Those who are advocating for more treatment keep emphasizing that ADDICTION is a disease and not just a poor choice.
Many people don’t understand or accept this. It seems like a slogan or an excuse. After all, where is the disease located in the brain? Can we point to it on a scan or a lab test? We should be able to demonstrate what part of the brain is not working well.
Many others don’t believe in a disease concept because, for most of us, drinking or using marijuana seems like a choice. We can easily say no to those things and it is hard to comprehend that others cannot. Certainly, even addicts, when suitably motivated, can say no to drugs. (Many temporarily stop using when threatened with jail or other serious consequences). So why should it not be considered a choice?
Not so fast. If I asked you if you whether you wanted to have a piece of cake after finishing an overly large meal, you might or might not say yes, but many would say no without a second thought. If I asked you, if you wanted that cake after 24 hours of not eating, your hunger would make that choice more difficult. You might still say no but you would think of that cake repeatedly and even obsessively. You might not steal bread after 24 hours of not eating, but what if you haven’t eaten in 72 hours?
No fair you say. Food is a necessity and we die without it. Drugs are different. However, the urgency and hunger that occurs when we need food is caused by certain MOTIVATION circuits in the brain. These circuits are similarly activated in drug addiction.
The main role of these circuits is to motivate us to act and react to our environment. All our behavior requires motivation: going to work, running away from danger, putting food in our mouth, taking a shower and even shifting our weight to maintain our balance. These behaviors are motivated by dopamine release in one of the older parts of the brain called the striate cortex. If there is no activity, we would stop interacting with the environment. We might lie in bed, not bathe, not eat and barely move. We would die. There are two different (though somewhat overlapping) circuits involved in this function.
The GOAL DIRECTED CIRCUIT drives complex behavior like going to school, doing housework or planning a trip. It requires coordination of several brain structures: hippocampus (memory), amygdala (emotion), prefrontal cortex (executive control) and finally a nerve connection with the ANTERIOR striate cortex. (the glutamate nerve tract between the prefrontal cortex and the nucleus accumbens discussed in the prior article) It is a complex and relatively cumbersome process that involves multiple nerve connections.
It is relatively slow. While I’m considering whether I want that cake, you might automatically grab it without thinking. Your quick behavior has netted you a piece of cake and I have lost a source of nutrition.
When a behavior is found to be beneficial to the person, we often repeat it. When it is repeated (and rewarded) enough it becomes habitual and we do it without thinking. In the brain, the motivation for that behavior moves from the ANTERIOR striate cortex to the POSTERIOR striate cortex. It is now part of the HABIT CIRCUIT. For instance, when a professional shortstop hears the crack of a bat, he is reacting without thinking, in order to catch that line drive. Years of practice, with rewards for successful plays, have switched the motivation for this behavior from the goal directed circuit, where he has to think about it, to the habit circuit.
Stimuli, like sound, sight and smell will quickly go to the switching station of the brain (called the tegmentum) and then right on to the POSTERIOR striate cortex. There is no conscious thought. just reaction. Motivation to use drugs, because of the drug’s hugely rewarding effects on our brain, quickly make this transition. Activity is this area will then increase drug using behavior. Therefore, when we are exposed to a drug trigger, the behaviors occur without higher brain input and we find ourselves acting without being aware of out behavior.
Negative emotions such stress and depression as well as pain all contribute to a relative increase in activity in the habit circuitry compared to goal directed circuitry. They increase the risk for relapse
Drug use also leads to abnormal endorphin biology. This is true for all drugs and addictive behaviors, not just opioid drugs. This abnormal endorphin biology increases activity in the hunger center (lateral hypothalamus) which will, in turn, activate the habit circuit. This adds a true hunger to our drug seeking behavior. We are now craving (hungering) for the drug. Perhaps we should think of the circuit as the HABIT/HUNGER CIRCUIT. This is also why we crave more when we are have not eaten.
One measurable anatomic abnormality, consistent with this change in the disease of addiction, is an increase in the size of the POSTERIOR striate cortex.
In addition, the brain structures of the goal directed circuit are more sensitive to harm. The inflammation, injury and deprivation of drug use take a high toll on them. This leads to weakening of our motivations for purposeful and complex behavior. We also reduce our ability to inhibit our impulses. We can’t just say no. Consistent with this abnormal function, we see a measurable decrease in the size of the hippocampus, amygdala and in the nerve tract to the ANTERIOR striate cortex
The result is an imbalance between these two circuits and too much activity in the habit circuit relative to the goal directed circuit. Impulsivity, hunger, cravings are all increased and complex reasoning and impulse control are decreased. This is caused by real brain abnormalities due to damage to underlying brain structures. In other words- it is a medical disease.
Most of our medications help correct this imbalance by weakening the habit circuit and therefore reducing cravings. Opioid maintenance may work by suppressing the hunger component. Counseling and 12 step, yoga and other physical activities strengthen the goal directed circuit. Appropriate nutrition and enough sleep are also important. With time and appropriate treatment, the abnormalities noted above have been found to correct. Most people can recover.
I recently became aware of a large body of research that has been under heavy study in the basic labs but whose implications are only starting to be realized by the clinical medical establishment. The short version is as follows: neurons and neurotransmitters are not the only players in our brain when it comes to addiction, pain, anxiety, and depression. The inflammatory cells are also quite important.
In fact neurons constitute an extremely small fraction of total cells in the brain. There are cells which insulate them and help them with nutrition called oligodendrocytes. Then there are immune cells called astrocytes and microglia. They occur in every cubic millimeter of the brain.
Under normal conditions, the immune cells maintain a certain level of activity while they prune nerve connections, get rid of excess cell waste and absorb excess neurotransmitters from the local environs. However, in the setting of foreign invaders like viruses or bacteria OR if there is local cell damage, they activate to deal with the excess need. Certain receptors, referred to as toll-receptors, can bind to a wide array of foreign substances and innate cell debris. Unlike the classical receptors, which are highly specific for certain compounds, these toll receptors bind to multiple substances.so that a wide variety of threats can be handled.
Unfortunately, ALL opioids, including methadone, as well as alcohol, cocaine and most stimulants bind and activate these receptors. (Suboxone stimulates this process and inhibits this process by different mechanisms; it is unclear what the net effect is) This increased activity in the immune cells results in their spilling a variety of inflammatory molecules into the extra-cellular fluid. They also send out signals recruiting more inflammatory cells. This creates a abnormal environment around the neuron which can change how it functions. We refer to this process as neuroinflammation. The neurons alter the numbers and types of neuro-receptors on their membranes and begin to conduct more impulses with less stimulation.
In some ways this is good, as glutamate & dopamine release required for motivation, action, and learning is increased.. However, it does result in bad consequences in that increased transmission of these signals will also cause depression, anxiety, and irritability. In some patients, these bad effects may become greater than any relief resulting from the drugs. Additionally, this has also been shown to be the main mechanism behind Opioid Induced Hyperalgesia (or increased pain from opioids). The result is pain magnification and symptoms of neuropathy.
This can explain while methadone or Suboxone maintenance fails to work for so many. It shows why opioids fail to adequately treat pain so often (leading to the new CDC recommendation to avoid them in chronic pain treatment) Of course, the drugs are not usually blamed for the pain or the associated emotional issues. The immediate effect after taking a drug is temporary improvement of these symptoms; however opioid induced inflammation may be leading to an overall increase in pain, fatigue and emotional distress in many, or even most, patients. It could be the single most important issue maintaining long term addiction tendencies.
The good news is that we now have so many more biologic targets to address in order to reverse the above abnormalities. In fact, many generic drugs we use for a variety of other indications, including certain antibiotics, circulation drugs and anti-depressants have been found to reverse or slow this process. The bad news is that there are no large scale clinical trials to test their effectiveness due, in part, to the fact that their generic status will keep companies from making a profit from research.
Naltrexone (Vivitrol) has been found to reverse these abnormalities and reduce inflammation. It is already being used in a variety of inflammatory and auto-immune diseases with benefit. Small scale studies have shown that it reduces pain and improves depression in many. It is even possible that dose manipulations or use of specific subtypes of naltrexone will allow it to be used in those currently receiving opioids where it may increase pain relief and treat associated emotional symptoms.