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Anyone familiar with the difficulties of addiction knows that staying clean is the primary difficult in beating drugs.  I view relapse as interplay of two factors: the cravings for a drug and the ability to resist the craving.  Some people have  very severe cravings.  Other people continue to relapse despite having relatively mild cravings for drugs.  They either are not motivated to stay clean and/or they cannot resist any type of impulse.  This category includes younger people, those with ADHD or another type of psychiatric problem, and those who are mandated into treatment against their will.

In this article, I want to focus on cravings.  A craving is a hunger for a drug.  In the disease of addiction, the appetites for food and water get hijacked into appetites for the drugs.  As anyone who has been on a diet know, our appetites change and can be related to factors other than the last time we ate.  What makes us “hungry” for the drug?

As a clinician, I recognize three general categories of cravings: exposure related, stress related and cue related.  If a former heroin user takes painkillers for a medical condition or if an alcoholic takes cough medication with alcohol, they will have cravings for their substance of choice.  These are examples of exposure related cravings.  An example of stress related cravings is when some one experiences a fight in the house or stress at work and wants to get high.  Cue-related cravings are often the most pervasive and long lasting.  This means when we see people, places, things or images related to substance use, we want to get high.  Routines may also be cues.  A person who always has a cigarette after dinner will miss this cigarette in particular. 

Other articles on this board have focused on the central role of dopamine release in the Nucleus Accumbens or pleasure center of the brain.  A drug exposure leads to an increase in dopamine and endorphin, which is intrinsically pleasurable.  This is why we get high.  We want to repeat the experience.  This is why we develop an addiction.  However, can we explain the mechanism of all the different types of cravings solely by looking at dopamine?

I have made certain assumptions about dopamine and endorphin and cravings.  These are supported by scientific evidence even if the assumptions represent gross oversimplifications. 

The first assumption is that a dopamine/endorphin surge for any reason leads us to want another surge.  Since the addict knows the drug gives him this feeling, he will crave the drug after experiencing any dopamine surge.  This is true even when such surges occur from causes other than using drugs.

The second assumption is that any reduction in baseline dopamine/endorphin activity levels will make us more irritable and depressed.  It will also make it more difficult to resist any dopamine/endorphin surges and subsequent cravings.  The person with low activity levels will therefore have more intense cravings.

It is easy to explain exposure related cravings.  Every one knows that the use of a drug usually increases our desire for more of the drug.  The first drink leads to the second and than to the third.  The release of dopamine/endorphin in the brain rewards us and leads us to repeat the drug using behavior.  If the dopamine/endorphin release were blocked, we would not have the desire to continue using.  This is the secret behind the use of naltrexone which helps with control of opiate, alcohol, marijuana and overeating.

What about stress-related cravings- why does it make us want to use?  The biology of stress is complex with multiple areas of the brain and body involved.  In fact, acute stress increases dopamine levels.  This does not make sense if we think of dopamine only in terms of causing pleasure and euphoria.  But it makes perfect sense if we consider that the main role of dopamine is to help us learn.  We always want to learn from a stressful situation.

Chronic stress produces many changes in the brain as well.  It turns out that the increased release of dopamine leads to an increase breakdown of dopamine.  This means that after a period of time, dopamine levels are less and dopamine activity is reduced.  We are burned out and feeling depressed and irritable.  

Therefore, in chronic stress we do not feel well.  We are less able to resist the other types of cravings.  In addition, when there are periodic exacerbations of stress, we again have small releases of dopamine and our cravings are stimulated.  It’s a one-two punch for relapse. 

If we could increase dopamine activity, we can minimize this effect.  This may be the mechanism underling bupropion's (Wellbutrin's) effectiveness in reducing cravings for tobacco, food and other drugs.  It also explains why patients who take stimulant medication for ADD do not often abuse other drugs.

Cue related cravings may occur in the absence of stress.  However, there is still dopamine release in the Nucleus Accumbens.  The mechanism of this requires the understanding of a whole different nerve tract.  This tract comes from the prefrontal cortex.  

The prefrontal cortex is where the executive functions of the brain are located.  Complex actions are initiated and impulsive tendencies hopefully are inhibited.   Nerves originating here travel to the Nucleus Accumbens and release a neurotransmitter called glutamate.  The glutamate stimulates the dopamine releasing cells and causes them to release more dopamine.  This means that thoughts themselves can release dopamine.  This concept is of utmost importance when we consider the various causes of addiction and other psychiatric disease (see abnormal glutamate)

When we experience cue-associated cravings, multiple areas of the brain are active including those involved with memory.   A person will think of a drug and the memory of the drug and other factors leads to a surge in glutamate and a subsequent surge in dopamine.  These surges will often make them feel better  So the thoughts of the drug stay in their head, it makes them feel better and makes them want to use the drug.

This is the reason underlying a phenomenon long appreciated by clinicians.  Often, a patient will seem to get high just thinking about a drug.  A heroin user, in withdrawal, will have noticeably less withdrawal while preparing their injection.  Other patients seem to get high just talking about a drug.

The strength of the glutamate/dopamine circuit can be modified by other influences.   Seratonin, GABA, natural cannabinoids, and the hypothalamus influences all can affect the strength of the reaction 

In sum, the glutamate/dopamine interaction is a source of strength behind cravings.  If we could mute this action, we could reduce intensity of this mechanism, we can reduced triggered cravings.  This is the idea behind Campral, topiramate(Topamax), Depakote, gabapentin, Accomplia, Zofran and the Prometa protocol.

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Stuart Wasser MD
March 10, 2006