Introduction

The U.S. is clearly a nation of drug users.   On a per capita basis, our combined legal and illicit drug use exceeds that of any other country.  And for those drugs that are abused (either illegal or prescription), a certain percentage of users become addicted.  In 2015, drug overdose deaths finally managed to surpass automobile accidents as the leading cause of preventable deaths (with opioids being the main culprit).   Over ½ trillion dollars are spent each year combating U.S. drug abuse, with harder-to-measure social and interpersonal costs being equally serious.  Despite governmental efforts, drug abuse and addiction are  societal problems we have yet to get a handle on.

A major problem in dealing with drug addiction is how little we are really sure about.  Like many complex biological and psychological phenomena, it is difficult to come up with a precise definition of addiction that everyone accepts.  Although the brain is definitely involved, there remain mysteries concerning exactly how it is involved.  While addiction clearly has a genetic component, it’s not always apparent how genes provide this susceptibility.  And while many treatments can provide some relief, they often function more as temporary “band-aids” than as long-term “cures”.

This blog posting is the first in a series of four. In this posting, I begin by addressing definitional issues and how scientific thinking about the causes of addiction have changed over the years.  In the second, I get nerdy  and speculate about the critical brain circuitry and where this circuitry might be located (hopefully in an understandable way).  In the third posting, I briefly explore genetic and environmental factors related to addiction.  And in the final posting, I present an overview of some different pharmacological treatments to help addicts cope.

Definition of Addiction.

There are probably as many definitions of addiction as there are experts.  At the same time, there are three addiction characteristics upon which most would agree.  1. An addict has uncontrollable cravings to take the drug.  2.  An addict will continue to take the drug despite experiencing negative consequences.  3.  Once addicted, an addict has great difficulty stopping.

A major problem in defining addiction is that it exists on a continuum. While some drug users are easily identified as addicts and others not, for individuals somewhere in the middle, classification is not always clear.  The question is, where do you draw the line?  I find the definition of Burgess and Shaffer in 1984 both instructive and amusing.  They define addicts as “certain individuals who use certain substances in certain ways thought at certain times to be unacceptable by certain other individuals for reasons both certain and uncertain.”

The Diagnostic and Statistical Manual of the American Psychiatric Association (DSM V) has attempted to resolve the issue, not by defining addiction per se, but rather by operationally defining a disease called substance abuse disorder (roughly comparable to addiction).   To do so, DSM V identifies 11 possible problems that a regular drug user might have.   Different degrees of this disease (mild, moderate, and severe) are then defined by how many of these 11 problems occur.

However, according to DSM V, regular drug use, by itself, does not qualify a person as having substance abuse disorder.  The person must have at least 2 of the cited problems for the mild form of the disorder.  Although unlikely, it is theoretically possible for a chronic drug user to not qualify, an outcome some drug experts find problematic.

Despite definitional problems, the term “addiction” continues to be heavily used by the public as well as by professionals.  While addiction is difficult to define precisely, most of us know it when we see it.

Tolerance and withdrawal

The original idea of how people become addicted was explained by the well-established pharmacological principles of tolerance and withdrawal.  When you first take an addictive drug, body and mental functioning are often disturbed.  However, with continued use, the body makes homeostatic compensations to reduce the disturbance and allow the user to function more normally in the presence of the drug.   As this tolerance to the drug become established, it also causes a given dosage of drug to become less rewarding.   To continue to obtain the desired reward, larger and larger drug dosages must be taken.

Two major types of compensation underly tolerance.  For example, many addictive drugs exert their effects by binding specific neurotransmitter or neurohormone receptors embedded in neuron membranes in the brain.  Under conditions of continued binding, the brain compensates by downregulating (decreasing the number of) these receptors, which makes the drug less effective.  Another type of compensation occurs mainly in the liver where most drugs are enzymatically deactivated and prepared for excretion.  The liver compensates by upregulating the appropriate enzyme(s), further contributing to the drug’s loss of effectiveness.  This “double whammy” causes tolerance, resulting in more drug being required to get the desired effect.

In addition, once the body has established a new homeostatic set-point to allow for functioning in the presence of the drug, the drug must then be present in the body allow for proper body functioning.  If the drug is discontinued, body homeostasis is again thrown out of whack and the person experiences withdrawal.

Withdrawal symptoms are, in many ways, the opposite of the drug effects.  Since addictive drugs make you feel good, withdrawal makes you feel bad.  During withdrawal, the brain’s autonomic regulation of body physiology begins to malfunction.    So, until your body can re-establish its pre-drug homeostasis, you experience symptoms of withdrawal.  The intensity of withdrawal and how long it takes, depends on the drug and the degree of tolerance achieved.   Sometimes it can take a month or more of drug abstinence for withdrawal symptoms to subside.

Although withdrawal symptoms vary somewhat from drug to drug, in all cases withdrawal results in a dysphoric, anxious, hyperactive, and unhealthy state.  And in all cases, a very easy way to make the unpleasant withdrawal symptoms go away is to take the drug.  According to this idea, once you’ve reached the stage where significant withdrawal can occur, you are now addicted.

This perspective of addiction was likely developed from studying alcoholics, and perhaps heroin addicts, where it seemed to have some utility.  While withdrawal occurs to all drugs of abuse, alcohol withdrawal generally has the most serious consequences.  For example, the withdrawal from alcohol by a chronic alcoholic is called delirium tremens (DT’s).  It is not only very unpleasant, in extreme cases, particularly in older, long-term alcoholics, it can be fatal (usually through heart attack or stroke).  However, the DT’s are quickly alleviated by taking a drink of alcohol.  Thus, an alcoholic was viewed as being addicted in order to prevent the DT’s.

However, the tolerance/withdrawal explanation has some problems.  One problem is that after withdrawal is complete and brain receptors and body physiology have pretty much returned to normal, all withdrawal symptoms subside except for one:  the compulsive desire to take the drug.  Some experts argue that once addicted, you are addicted for life.

Another problem is that some non-addictive drugs  (such as antidepressants) can cause marked tolerance and decidedly unpleasant withdrawal.  But after withdrawal is complete, they do not result in an addictive desire to take the drug.  It’s also problematic that marijuana, a drug with addiction potential, does not have withdrawal symptoms for many users.  (Marijuana users do develop tolerance. However, during abstinence, the very gradual release of THC into the blood from its storage in body fat produces a unique “built-in” tapering effect that minimizes withdrawal symptoms.  In fact, when addicts are trying to quit other addictive drugs, gradually reducing the dosage is sometimes used to help them cope with withdrawal.)

While the desire to avoid withdrawal can certainly influence an addict’s day-to-day drug use, the hard-to-control desires that remain after withdrawal is complete must be due to something else.

Brain Reward Circuitry

One of the great discoveries of modern neuroscience is that rewarding stimuli (e.g. food, drink, warmth, sex, social interactions, and drugs) are thought by many neuroscientists to be experienced as pleasurable and rewarding through activation of a common reward circuitry in the brain.  Critically important to this circuitry are ventral tegmental neurons in the midbrain that release dopamine into the nucleus accumbens in the forebrain via part of an ascending fiber tract called the mesolimbic/mesocortical pathway (See Figure 1 below).  Other parts of the mesolimbic/mesocortical pathway (not shown below) deliver dopamine from ventral tegmental neurons to parts of the amygdala (important in emotional responses), prefrontal cortex (the executive part of the cortex that makes conscious decisions about what you should be doing and when you should be doing it) and, to some degree, the hippocampus (important in memory formation).  All addictive drugs , either directly, or indirectly, are now thought to promote this dopamine release in varying degrees.  Moreover, non-addictive neuroactive drugs  (like most antidepressants and cannibidiol (CBD) ) do not.

There are changes in the areas that receive dopamine input as a result of chronic drug use that last for some time.  For example, in regular cocaine users dopaminergic synapses in the nucleus accumbens are strengthened (making the nucleus accumbens more sensitive to dopamine).  There is also a strengthening of glutaminergic input into the ventral tegmental area, altering the ability of other brain areas (such as the prefrontal cortex and amygdala) to activate the reward circuitry.  Accompanying changes in the reward circuitry are also changes in the functioning of the prefrontal cortex and amygdala.

These dopamine-related changes have been proposed to underly the neurological basis of addiction.  While they are almost certainly involved in the development of an addiction, they may not be sufficient, by themselves, to explain long-term addiction.  The problem is that the reward circuitry, and associated areas, also influence many other areas of the brain.  Consequently, important changes underlying long-term compulsive drug use may actually occur elsewhere as well.

In the next post, I present an idea about what that might entail.