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Mechanisms of Addiction
Richard Gracer, M.D.


Drug addiction is a complex process that involves many of the basic systems that regulate our emotions and perceptions. These processes are closely regulated and are interlinked. The brain is not static. The nervous system is constantly changing. Most of these changes are merely the evanescent daily variations that make up our thoughts and memories. With severe or chronic stimulation, such as with chronic pain, there are longer lasting changes that affect the function of many brain circuits and through them many other facets of body function.

These changes are called “neuroplasiticity”. The pathology seen in drug addiction is really an exaggeration of normal brain functions. As with chronic pain, some of the changes that occur can be long lasting and even in some cases may be permanent. Drug addiction is therefore a brain receptor disease and not a strictly social/moral problem. While the social aspects of this disorder are important and should not be minimized, it is these changes that must be understood and modified as part of successful treatment of this disorder.

Homeostasis, Tone, and Neural Function

The ability of the body to maintain its normal function under a wide spectrum of conditions is called homeostasis. Most of these biologic mechanisms rely on competing actions that keep each other in check. The easiest analogy to help understand this is to think of the major muscles that flex and extend the elbow. The biceps muscle causes flexion while the triceps causes extension. When we want to flex the elbow, the nervous system relaxes the triceps while at the same time it activates the biceps.

Of course there are a multitude of other modifying factors that make sure that the movement is smooth. It is important to note that at no time is the triceps muscle completely flaccid or the biceps contracted at full strength. When the arm is still, both muscles have some activity balancing each other and maintaining position. The concept that both systems are working at the same time and that the relative activation of each determines the final result is called tone.

In the central nervous system (CNS) processes work in a similar way. There are a large number of complex pathways that interconnect, modulating, and balancing each other. There are basic chemicals called neurotransmitters that are released by the nerve cells and that act upon receptor sites, resulting in the various actions that we make and feelings that we experience.

Receptors that effectuate the pain relief and euphoria that one feels with taking opiates or the effects of any of the other addicting substances such as alcohol, cocaine, amphetamines, and even nicotine are found in many parts of the spinal cord and brain. Pain relief from opiates, for example, comes from stimulation of the mu (also called the morphine) receptor. Each of these classes of drugs also stimulates other receptors in many parts of the brain that regulate many other functions. It is their effects on these other areas that lead to addiction.

GABA and Glutamate

The simplest level of control in the CNS is the play for a balance between relaxation and excitation. The two major players are GABA (gamma amino butyric acid), the relaxation neurotransmitter and glutamate, the excitation neurotransmitter. They act on neurons (this is what nerve cells are called) that when fired release “modulating” neurotransmitters, including serotonin, dopamine, and norepinephrine. Some neurons decrease and others increase the firing of other neurons. These in turn modulate specific pathways in the brain that result in the complex variety of feelings, cravings, and pleasure that make up our personality and that therefore determine our behavior and mood.

Nerve cells usually have a negative charge inside and a positive charge outside the cell wall. When the inside charge gets below a certain point the nerve “fires”, which causes the release of one or more of the modulating neurotransmitters. These in turn stimulate other neurons to fire, etc. These receptor sites are part of the cell wall of each neuron. When the GABA receptor is stimulated it opens a gate that allows chloride ions, which have a negative charge, to flow into the cell. This increases the normal negative charge inside the cell, making the cell less likely to fire. When the glutamate receptor is stimulated, it allows positively charged sodium ions into the cell which decrease the normally negative interior cellular charge and therefore make the cell more likely to fire. It is this balance that determines whether the cell fires or not.

The GABA receptor has several sites where different compounds can “dock”, causing it to activate. The benzodiazepine class of drugs (including Ativan, Valium, Librium, and Ambien), alcohol, opiates, cocaine, and amphetamines all activate specific sites on the GABA receptor. This also causes a relative decrease in glutamate activity resulting in relative relaxation of the central nervous system.

These drugs also stimulate neurons that release dopamine in the pleasure centers of the brain (nucleus accumbins in the meso limbic area). Additionally, in some people after alcohol is converted to acetaldehyde as part of normal metabolism, this substance combines with neurotransmitters in the brain to form compounds called tetrahydroisoquinolines (THIQ’s). These provide powerful stimulation to the mu receptor, similar to opiates and which are themselves addicting. The overall effect is to cause pleasure, relaxation, and even euphoria.

Under normal conditions this system is activated by natural substances, such as endorphins. In normal people, pleasurable events such as a fine meal, laughter, sex, and hearing good music cause an increase in the dopamine levels in these brain areas. The part of the brain which is responsible for these feelings and emotions is called the limbic system. When dopamine is released in the limbic system, specifically into the nucleus accumbins, one feels pleasure.

Taking addicting drugs on a regular basis results in constant stimulation of the GABA receptor, which over time causes these receptors to become less sensitive to stimulation and to actually decrease in number. When this occurs, the usual things that cause dopamine release and therefore give pleasure are no longer strong enough be effective. In addition, when there is no exogenous stimulation, the dopamine levels in the limbic areas become low, causing one to feel agitated, anxious, and dysphoric (depressed, unhappy). In extreme circumstances the person can have a seizure. This is what addiction really is at the most basic level. The addicted individual needs the drug to just feel “ok”. This powerful desire to get the drug is called “craving”.

When the GABA receptor is chronically stimulated by drugs, the number of them decreases and the actual receptor areas on the cell change to a form (called alpha-4) that is not sensitive to the normal substances that stimulate it (endorphins and enkelphins). When the drug is no longer available, the receptor is under activated and the glutamate system is over activated. The results are the typical symptoms of drug withdrawal; anxiety, muscle aches, stomach cramps, sweating, agitation, and even seizures.

The body’s ability to make endorphins is decreased and the GABA receptors are insensitive. These two problems must be addressed before the cravings subside. Over time there is a gradual increase in the number of GABA receptors and the receptor type slowly returns to the normal alpha-1 type. This may take a very long time and in some cases, it may never return to normal. This results in long-term cravings and the frequent failures of patients in programs in which this critical problem is not treated.

For opiates, buprenorphine fills the receptors and treats the cravings. For alcohol and stimulants, there has not been a good way to stop the cravings until the PROMETA protocol from Hythiam became available. This protocol regenerates the alpha one type receptors, resulting in a dramatic decrease in cravings for both of these addictions. Research is planned to see if a similar strategy will work for opiate addiction and smoking cessation.

The Two Forks of Brain Dysfunction in Drug Addiction

What I have described above are effects on two separate systems. Sanjay Sabnani, the research coordinator at Hythiam, Inc., the company that has studied and perfected the PROMETA protocol mentioned above, has conceptualized what I have described above as consisting of two separate “forks”.

The First Fork: The Dopamine System, the “Reward Circuit”

The first is the dopamine system, also called the “Rewards Circuit”, which is responsible for stimulation of the pleasure centers in the limbic system. This is modulated by the balance of GABA to glutamate, but is directly stimulated by addicting substances. This is further complicated by another type of receptor called the NMDA (n-methyl, d-aspartate) receptor. This receptor is activated when there is increased brain glutamate activity. It is an important factor in the development of chronic pain and when stimulated causes increased pain and a variety of other symptoms that complicate treatment of these patients.

In drug withdrawal the NMDA receptor is also stimulated. With NMDA stimulation there is decreased activity in the reward circuit. This results in cravings for the addicting substance to calm this system and increase dopamine activity in the pleasure center. Strategies to decrease cravings, dependence, and addiction and to diminish the effects of the reward circuit in the brain, thereby deterring the desire for drugs and medication must modify NMDA activity.

Campral is a medication used in alcoholism that blocks the NMDA receptor, thereby decreasing cravings. Another approach is to use anticonvulsant medications, which decrease overall neuro-stimulation and irritability. Topiramate has shown positive effects in preventing relapse in the treatment of alcoholism.

A common cough medication, dextromethorphan, also blocks the NMDA receptor. I have found this useful for the treatment of chronic pain.

The Second Fork: GABA Dysregulation and Effects in the Neo-Cortex

I have already described the basic workings of the GABA system. In this section I will give an overview of some of the complex effects that this system mediates. In addition to the modulation of the rewards circuit, this system is very important in the neo-cortex, the part of the brain where judgment and emotional control are controlled. (The cortex is the part of the brain that distinguishes humans as thinking beings and the neo-cortex is a center for sophisticated thought processes.)

This part of behavior is crucial to being able to maintain abstinence and indeed to being able to function comfortably in society. The level of GABA activity determines how relaxed we are. Some level of anxiety can be a beneficial, allowing sharp attention and giving energy to function at a high level in important situations. It is also important to be able to relax and rest, but too much GABA activity results in inattention, forgetfulness, poor judgment, and with more stimulation, lethargy, sleep, and then coma.

There is a large area of normality, but the extremes of this spectrum cause severe problems. On one side is coma and on the other is seizure. When an addicted person takes their drug, the GABA system is stimulated. In withdrawal, it is inhibited causing anxiety, panic, or even seizures. Persistent thoughts will not stop. There is no rest. There is also a disruption in the normal judgment areas of the brain leading to poor decisions. These are important factors for cravings and the ability, or inability, to resist them.

Sanjay describes what he terms, “The Anxiety to Acquisition Circuit”. He states:

“The brain is designed to increase anxiety until you require a solution. It also provides ways to get rid of the anxiety that’s created. Maybe you eat or work out to provide a psychological solution. Sometimes it’s difficult to perceive why or when these things happen. For instance, I have always had a tough time emotionally on Sunday evenings. I’m under mental duress because I can’t take action for Monday but I also can’t enjoy my weekend.

When you get anxious like this, the ability to sleep disappears. But if you think about how you can solve various problems or deal with difficult situations, your brain sort of turns the screws off and your anxiety is reversed. Then you can sleep. This demonstrates the process involved in activating this anxiety to acquisition circuit. And there’s no other circuit like this; typically it’s disregarded. ”

The following diagram illustrates the GABA spectrum:

More GABA stimulation                    less GABA stimulation
Spectrum of GABA activity


Genetic Factors


The receptor sites are coded on our DNA. Each of us has our own genetic makeup and therefore we each have different proteins on our brain receptors. For example, it is estimated that there are approximately 100 different variations of the morphine receptor. This is why some people can take a given medication with good effect while others get nauseated. Our hair and eye color are another example of this type of genetic variation. These genetic differences are called single nucleotide polymorphisms (SNP’s). This means that a given DNA site can be filled with a variety of different combinations. As a result the proteins made by the cells are a bit different. They all work, some better than others.

In one person opiates may fit on the GABA receptor more easily than on someone else’s. If one person has a GABA receptor that only responds to high stimulation from an addicting substance to produce euphoria or who has a pleasure center (the nucleus accumbins in the limbic system) that is relatively insensitive to dopamine, there is a greater chance of addiction than in those who take lower doses. For example, someone who can really “hold their liquor” is much more likely to become an alcoholic than another person who can only drink one drink without getting ill. This person with low response actually gets seduced into thinking that their drinking is not a problem because they don’t feel drunk and they can drink much more than others. Peers provide verbal reinforcement on their excessive drinking, i.e., “Joe can drink so much, isn’t that cool?”

Another critical area of genetic variation is in the way the liver detoxifies drugs and toxic substances. There are a series of complex enzymes systems called the cytochrome system that process these compounds allowing for excretion through the kidneys or stool. Many of the metabolites that are produced have active drug effects, sometimes more powerful than the original medication that was taken. At other times the drug itself is actually inactive while the metabolite is the active drug. Variations in this complex system are another reason for different responses to medications and also the reason for most drug interactions.

Effects on Depression

This same type of variation is also responsible for why depression is commonly an inherited trait. In fact, depression and drug addiction are interrelated. This is why it is so important that both of these conditions be treated together. Depression itself is very complex. There are two basic types that must be treated in very different ways. The more typical major depression is a common problem that effects up to 30 percent of the population. It is treated with SSRI drugs such as Prozac, Zoloft, and others such as Wellbutrin.

The other less common type is bipolar disease in which patients alternate between severe depression and a euphoric state called mania. This problem starts early in life and is probably the most common type of depression seen in teenagers. There are variations that are not as extreme with rapid “cycling” between the states and where the manic state may be seen as extreme irritability. Bipolar disease may comprise as much as 15 percent of all depressed persons. This disease is not easily diagnosed. In fact, the average patient sees four physicians over a period of 10 years before having the correct diagnosis made, even though more than 1/3 of these patients seek medical help within the first year of symptom onset. Over 20 percent of these people attempt suicide at least once; many of them succeed.

This distinction is important to make because the treatment is very different for bipolar disorder than for unipolar depression. Using an SSRI to treat a depressed bipolar patient often triggers an episode of mania and may be the reason that there is an increase in the chance of suicide in younger patients treated with these antidepressants.

In addicted patients, the bipolar type of depression is common. They often use addicting substances to self medicate for such symptoms as anxiety, worry, guilt, fatigue, or pain. They eventually become physically dependent. If the underling bipolar syndrome is not properly treated, the chance of successfully treating their substance abuse is very low. Bipolar disease and substance abuse are genetically linked. Family history of either problem is an extremely important factor in assessing risk for the other.

Future Treatments

The human genome has been completely mapped. The DNA site (called a locus) for each enzyme and process can be tracked. This is how polymorphisms can be determined. In only a few years we will know which type of enzyme or receptor site (which SNP we have) we have for any important locus. With a DNA sample, it will be possible to tell which medication will work for any given patient for any specific purpose and perhaps more importantly which treatments to avoid.

This has already allowed certain high risk cardiac patients to know what type of vitamins they need to minimize their risk and whether others have a propensity for osteoporosis. It will not be long until we will know the physical and chemical reasons why a given person may suffer from depression or substance abuse. This knowledge along with appropriate psycho/social treatment, treatment of underlying hormonal and nutritional problems, as well as dealing with legitimate pain issues should yield much better long term results.