Addiction IV: Pharmacological Strategies For Treating Drug Abuse/Addiction.


There is no “cure” for drug addiction, however there are drugs currently being used, or being developed, to help addicts cope and to help them quit.  A comprehensive listing is beyond the scope of this post.  Here, I focus more on the strategies than on the drugs themselves.

When employed, results are often mixed, working better for some addicts than others.  Even when there is some effectiveness, compliance is often a problem.  Since some of the treatment drugs are themselves addictive, some people are philosophically opposed to substituting one addictive drug for another. Some critics also argue that treatment drugs are just temporary “crutches.”  Many treatment strategies are also complicated by addicts being addicted to more than one drug.  Nonetheless for some individuals, these treatment drugs clearly improve the addict’s situation.

I am not a clinician so please consult a more comprehensive source or a clinical professional for information/advice about specific treatments.  It’s very sad that around 40 to 60% of recovering addicts relapse within 1 year.  At the end of this post, I provide links to resources which might be helpful.

Different ways that a drug can interact with a receptor.

There are variety of ways a therapeutic drug can interact with brain receptors to produce its effect.  A drug can be a full agonist, partial agonist, neutral agonist (also called a receptor blocker) or an inverse agonist for the brain receptor that both it and the addictive drug utilizes.  A full agonist is capable of causing a receptor system to produce its maximal response, with the others have progressively less capability, with the inverse agonist actually producing the opposite effect.  All of these classes of drugs have been used in the treatment of drug addicts.  Figure 1 illustrates the differences in receptor responsiveness to these different classes of drugs.

Fig 1. Idealized dose response curves of an agonist, partial agonist, neutral antagonist, and inverse agonist. (

Full Agonist substitution.

Agonist substitution basically involves switching to a different, but equally efficacious, drug and/or to a different method of administration that is less harmful.  The systematic use of this strategy began with heroin addicts substituting a synthetic opiate called methadone, another full opiate agonist.  This strategy has since been applied to other drugs of abuse (e.g. nicotine gums for cigarettes, oral cannabis for smoked marijuana, amphetamines for cocaine).  This strategy, when employed,  attempts to achieve a number of goals.

One goal of this strategy is that the substitute drug should enter the brain more slowly so that it begins binding receptors more slowly while still satisfying the addict’s drug need.   Slower initial binding causes less of a “rush” and less euphoria, allowing the addict to function more normally.  This outcome can be accomplished in a variety of ways: by using a less lipophilic (fat-like) version of the drug which slows passage across the blood/brain barrier, by having the drug taken orally or by skin patch which causes slower entry into the blood and ultimately into the brain (versus intravenous, smoked, vaped, or snorted).

A second goal is that the substitute drug possesses a longer half-life to even out the addict’s drug response.  For example, heroin’s relatively short half-life results in the addict’s entry into unpleasant withdrawal several times a day as the heroin begins to wear off.  With the much longer half-life of methadone, these ups and downs are eliminated.  In addition, a longer half-life also reduces the intensity of withdrawal should the addict miss a dose.  Amphetamine (whose effects are virtually indistinguishable from cocaine) is sometimes substituted for cocaine, in part, for it’s longer half life.  A longer period of effectiveness can also be achieved through timed release formulations.

A third goal is shifting to a safer method of administration.  In the case of heroin users, that involves shifting from intravenous (I.V.) administration, which is fraught with disease hazard from dirty needles, to a much safer oral methadone administration.  Oral amphetamine is similarly viewed as safer than administering cocaine by either I.V. administration,  snorting or vaping.  Nicotine gum or skin patch is similarly viewed as less harmful than smoking.

And finally, from an economic/societal perspective, providing addicts access to legal drugs (such as methadone) is substantially cheaper than incarcerating them for using illicit ones.  While this approach can also be better for the addict’s wellbeing, it doesn’t necessarily turn the addict into well-functioning member of society.  However, it can reduce the addicts’ use of illegal drugs as well as criminal behavior to support their habit.

Partial Agonist substitution

This strategy involves using an alternative drug that binds to the same receptor as the addictive drug, but is only capable of producing a partial response.  The addict’s drug need is hopefully satisfied while producing a much milder high.  At the same time, should the subject relapse, the substitute also serves as a receptor blocker to keep the original drug from exerting its more powerful effect.  Some examples of this strategy are buprenorphine (e.g. Subutex ) for opiate addicts and varencline (Chantix and Champix) for nicotine addicts (used in smoking cessation).

Receptor Blockers (Neutral Agonists)

The idea here is that if the drug is no longer rewarding, the user will not use it and (hopefully) eventually lose interest in taking it.  One way of keeping a drug from being rewarding is to block its ability to bind to brain receptors.

A receptor blocker works by binding the same receptor site as the addictive drug but, unlike the addictive drug, produces no effect on its own.  However, by binding the receptor site, ideally with higher affinity than the drug, the blocker prevents the addictive drug from binding the receptor.  Probably the best-known examples are naloxone (e.g. Narcan ) and naltrexone (e.g. ReVia and Vivitrol) used to block the rewarding effects of heroin, fentanyl, and prescription opiates (and also can be lifesaving in treating opiate overdose).   One downside to the regular use of receptor blockers is that it causes the blocked receptors to upregulate (i.e. increase in numbers).  If the addict should discontinue taking the receptor blocker and perhaps a few days later begin taking the addictive drug again, the increased number of induced receptors greatly enhances the likelihood of overdose.

Inverse Agonists.

Inverse agonism can occur if a receptor system possesses some degree of spontaneous activity in the absence of agonist drug binding.  The inverse agonist can then suppress the spontaneous activity to produce its negative effect. Therapeutic drugs with this capability would probably be used more for their receptor blocking properties than for their inverse agonism (which ideally would be of small magnitude).

Rimonabant (Acomplia, Zimulti), a cannabis CB-1-receptor inverse agonist, provides a cautionary tale.  This drug could, of course, be used to block the rewarding effects of marijuana.  However, rimonabant was introduced in Europe in 2006 as a diet pill (by blocking food reward) and had off label use as an aid in smoking cessation (by blocking nicotine reward).   Shortly thereafter, in 2008, rimonabant had to be withdrawn from the European market (and also was not approved for use in the U.S.)  because its use was associated with an increased incidence of psychiatric problems including depression and suicide.

Some now think endogenous cannabinoids working through CB-1 receptors may help many forms of reward turn on the dopamine reward circuitry accounting for rimonabant’s therapeutic uses described above.  However, rimonabant’s side effects not only disqualify it as a therapeutic drug,  they also provide serious concerns for other therapeutic strategies designed to suppress the general capacity to experience reward.

Aversion Therapy Drugs. 

The idea here is that if the use of a particular drug is made aversive, the addict will be disinclined to use it.  Disulfram (Antabuse), a drug developed to treat alcoholics, makes alcohol consumption aversive by blocking aldehyde dehydrogenase, the enzyme that eliminates aldehyde buildup following alcohol consumption.  This drug normally has little effect on its own.  However when the alcoholic takes a drink, the resulting toxicity causes flushing, nausea, vomiting and anxiety.  Needless to say, disulfram compliance can be a problem.

Drug Vaccines. 

Another strategy that might be available in the near future is using vaccines against specific drugs.  The antibodies stimulated by the vaccine would attach to the drug preventing it from crossing the blood/brain barrier.  Without access to the brain, the drug would not be able produce its rewarding effects. However, you have to “trick” the immune system to get it to produce the required antibodies.

The problem is that most neuroactive drugs (e.g. cocaine, heroin, nicotine, etc.) have to be very small lipid molecules in order to slip through the blood/brain barrier.  However, their small size normally prevents detection by the immune system.  To make these small drugs recognizable, the drug must first be modified and then attached to a much larger carrier protein.  If done correctly, such a drug/protein complex can then be used to make a vaccine that will stimulate antibodies against the drug.  Should a vaccinated addict take the drug, the drug antibodies can then attach to the drug and prevent it from exerting its effects. ( A video by the NIH describes the process in more detail.)

While the technique works in principle, the problem so far has been in getting the human immune system to produce sufficient antibodies, or sufficiently active antibodies, to provide meaningful protection.  However, vaccine developers haven’t given up, and vaccines for many drugs of abuse are currently in development (e.g. cocaine, nicotine, methamphetamine, fentanyl, fentanyl analogs, heroin, and oxycodone).  A downside is that vaccination works only for the drug you have been vaccinated against.   Other drugs could still be abused for their rewarding value.

Detoxification and Rehabilitation.

The drug strategies mentioned are used both in easing the addict’s ongoing problems and in trying to quit.  All treatment strategies are more likely to work if the addict is strongly committed to the treatment.  However, as noted earlier, I am not a clinician, so for a broader overview of drug rehabilitation, I refer you to an excellent on-line document by the Substance Abuse and Mental Health Administration (SAMHSA) entitled “What is Substance Abuse: A Treatment Book for Families?”

People seeking treatment should certainly research the possibilities first.   If you’re concerned about alcoholism treatment, I also recommend a relevant article published in the New York Times.

Addiction III: Is Addiction Caused by Your Genes?


In two previous posts, I addressed issues in defining addiction, how the brain’s reward circuitry is involved, and suggested that addiction is caused by a highly maladaptive form of learning in unconscious parts of the brain that are highly resistant to conscious influences.  In this post, I briefly address the role of genes and environment in addiction.

How do genes affect addiction? 

While genes clearly contribute to addiction, they do not cause addiction!  The way genes contribute is by providing a predisposition that may or may not be expressed depending upon environmental circumstances.

Addiction does sometimes run in families and many human behavioral genetic studies have used family data to estimate the heritability of addiction to various drugs.  While estimates vary, all find a heritability greater than zero with the average of all the studies being around 0.5.  A heritability of 0.5 would mean that, on average, 50% of the differences seen among individuals are caused by underlying genetic differences and 50%, by underlying environmental differences.  However, heritability is a population statistic that tells you nothing about specific individuals.  In addition, single genes with large contributions to addiction liability have not been discovered.  The genetics likely involve many genes interacting in complex ways that may be somewhat different from one person to the next.

Clearly some individuals appear more predisposed than others and require less drug exposure, although we have little understanding of the genes that might be involved.  There is some evidence that the sensitivity of the brain reward circuitry and functioning of the frontal lobe may be different in some predisposed individuals.  In other cases, it may be as simple as differences in the ability to be affected the drug.  For example, when I was approaching adulthood in Texas, we thought it “manly” to be able to “hold your liquor” and admired peers who could drink a lot with minimal outward effects (not sure what this says about me). However, we now know that such individuals are significantly more likely to become alcoholics.  Again, this trait doesn’t dictate that you will become an alcoholic, but it does increase the likelihood. This principle likely applies to other addictive drugs as well.  People less responsive to an addictive drug’s incapacitating effects will likely consume more of it, and more regularly, thereby increasing the risk of addiction.

At the same time, some genetic predispositions may be from genes promoting behaviors that, for whatever reason, simply increase the likelihood of using an addictive drug.  Although using a drug doesn’t necessarily result in addiction, it does statistically increase the likelihood.  In the following, I provide some examples.

A genetic predisposition to alcoholism might be whether you like the taste.  For example, one genetic strain of mice (C57BL/6J) prefers water adulterated with alcohol while another (DBA/2J) avoids it altogether.  Similar preferences in humans could promote alcohol use and, in some of those who abuse it, result in addiction.  Addiction to other drugs might be affected by similar ‘likes”

In addition, many psychiatric conditions are associated with increased addiction risk.  The increased likelihood seen among untreated individuals with ADHD is thought to be related to their higher impulsiveness and lower self-control.  In the case of individuals suffering from schizophrenia, bipolar disorder, anxiety, or depression, the effects of the addictive drug sometimes overlap those of the therapeutic drugs used to treat these disorders (there is no clear boundary between addictive and therapeutic drugs!).  While the initial motivation may be self-medication for symptomatic relief, with abuse, addiction is a potential outcome.

Conversely, if you avoid a drug, addiction to it is impossible.  In the earlier example, an innate dislike for the taste of alcohol should provide protection against alcoholism.  Additionally, there are individuals possessing a defective enzyme that allows the toxic buildup of aldehyde after drinking alcohol.  These individuals experience extremely unpleasant symptoms, almost never drink alcohol after their first experience, and are at virtually no risk for developing alcoholism.  A defective enzyme for nicotine degradation similarly reduces the risk for becoming an addicted smoker.  At the same time these protections would not affect risk for other drugs.

So, genes are clearly involved in addiction, but the paths by which they exert their effects are often indirect and variable from person to person.

How do environmental factors contribute?

Although the focus here has been on genetic factors, the environment is approximately equally important.  As with genes, the environment’s contribution is complicated and may vary from addict to addict. Like genes, environmental factors that promote drug use, or even drug access, are associated with a higher risk.  Peer pressure, low educational opportunities, scarce job opportunities, low recreational opportunities, and environments in which drug dealers are role models, are all associated with a higher risk.  Additionally, stress is definitely a factor in precipitating drug use.  While I have focused on biological factors in my blogs on addiction, any comprehensive understanding of addiction must take environmental factors into consideration as well.

To learn more.

Advocat, Comaty & Julien (2019).  Chapter 4: Epidemiology and neurobiology of addiction.  In Julien’s Primer of Drug Action. Thirteenth Edition. Worth Publishers. 267-295.  (A good textbook that I last used in my teaching.  Many references to primary literature at the end of this chapter)

Charles P. O’Brian.  Drug use disorders and addiction.  Chapter 24 in Goodman and Gilman’s The pharmacological basis of therapeutics.  McGraw-Hill Publishers.  (written for medical professionals so fairly technical)








Addiction II: Is Addiction a Highly Maladaptive Form of Learning?


In the previous post, I covered some issues in defining addiction and also presented current thinking about the role of the brain’s reward circuitry in addiction development.  While the reward circuitry, prefrontal cortex, and amygdala are clearly involved , I suggest here that isn’t the whole story.  In this post, I present the hypothesis that the unreasoning and lasting need of an addict may be strongly influenced by neural circuitry located in the more primitive parts of our brain.

Wanting vs Liking a Drug.

Intuitively, you might think that wanting a drug and liking a drug are flip sides of the same coin.  However, their paradoxical dissociation in drug addicts might provide a clue as to where the critical addiction circuitry is located.  For example, compulsively wanting a drug is lowest when you first use the drug and increases as addiction sets in.  When wanting a drug reaches some intensity, we would say the person is addicted.  At the same time, drug addicts will tell you that a drug is most pleasurable in the early days of use, while pleasure tends to dull with continued use.  This inverse relationship (very roughly schematized below) suggests that the cause of wanting a drug is not the same as that of liking a drug.

Figure 1: Changes in liking and wanting a drug over time

We know a great deal about the neuroanatomy of “liking.”  Liking is related to activation of the reward circuitry which allows the amygdala to assign hedonic value to stimuli and behaviors. This information can then can be made available to the the prefrontal cortex for use in conscious thought processes and behavior.

Addiction as maladaptive learning?

However, to understand the neuroanatomy of addiction, the neural circuitry underlying “wanting” is most critical.  Wanting should be guided by brain areas that encode “reward expectancy”.  According to this explanation, you should want to encounter stimuli or perform behaviors associated with an expectation of reward and avoid those associated with an expectation of adverse outcomes.  Reward expectancy is normally acquired by associative learning through repeated experiences with a particular situation.  For example, learning to want a stimulus is typically acquired through Classical (or Pavlonian) Conditioning while learning a desired appetitive behavior (that provides access to a reward) is learned through Operant (or Skinnerian) Conditioning.

Addiction is a relatively permanent change in behavior brought about by experience (which also happens to be the classical definition of learning).  In fact, some experts now think that addiction is a form of maladaptive learning in parts of the brain that encode “reward expectancy.”  However, the learning is so powerful that once acquired, it overrides all other expectancies. The addict can’t seem to help herself even though she often knows better.

So, what areas of the brain encode reward expectancy?  There is some evidence that the cingulate gyrus (a part of the cerebral cortex) in its interactions with the prefrontal cortex plays such a role in humans.  By occurring in a part of the brain that can be consciously accessed, such expectancies provide us with a conscious knowledge of what we like and dislike.  However there is a problem for conscious reward expectancies being solely responsible for encoding the compulsive desires of addicts.  As the drug becomes less rewarding and the increase in adverse consequences enter the addict’s consciousness, drug use should begin to extinguish.  (This doesn’t mean that the original expectancy is being forgotten, but rather that new competing knowledge should keep the original expectation from being acted upon).  In contrast, despite liking the drug less and suffering increasingly negative consequences, many addicts intensify their drug use.

This outcome suggests that the circuitry underlying reward expectancies may not be entirely in conscious areas of the brain.  I don’t consider myself a Freudian, but I do think Freud got at least one thing right: there are a lot of important things that occur below the level of conscious awareness over which we humans have relatively little control.

Evolution of the unconscious and conscious parts of our brains.

In what follows I give you my simplified “big picture” of human brain evolution to provide some background as to where the “addiction circuitry” might be found.

The brain began as an enlargement of the upper part of the spinal cord to provide executive control over the rest of the nervous system and ultimately the body.  Natural selection favored this change because it led to better adapted and more reproductively fit organisms.  The primitive brain not only detected sensory inputs and directed motor outputs, it also optimized homeostatic processes critical to life such as breathing, heart rate, swallowing, blood pressure etc.  And since associative learning is a fundamental property of ALL nervous tissue, the primitive brain was capable of using simple stimulus/response learning to connect sensory inputs to motor outputs.  Consciousness had not yet evolved, so all these processes were below the level of conscious awareness.  Thus, the capabilities of the primitive vertebrate brain (as seen in a fish) would, for the most part, appear innate, reflexive, and hard-wired.

A general evolutionary principle is that any genotype or trait that makes a big contribution to adaptation and reproductive success tends to be conserved (i.e. doesn’t change much) over evolutionary time.  While the human brain has diverged significantly from that of fish, the organization of their brainstems (hindbrain, midbrain, and posterior part of the forebrain) has remained remarkably similar.  All the same areas are represented, and for the most part, are doing the same sorts of things.  If you understand the anatomy of the fish brainstem, you also know a great deal about the anatomy of the human brainstem.  Clearly mother nature did an excellent job in designing this structure and has not made dramatic changes from fish to human.    However, the anterior part of the mammalian forebrain was selected by natural selection to go in a new and very different direction.  This part of the brain not only became much larger, more complicated, and added new functionality, it also provided the basis for the evolution of mammalian consciousness.

Mammalian consciousness reaches its zenith in the human cerebral cortex due, in some unknown way, to its large size, greatly increased storage capacity, highly interconnected circuitry, and much more complicated executive functioning by the prefrontal cortex.  The prefrontal cortex is the part of the brain that you “think” with.  It makes conscious decisions about what you should be doing and when you should be doing it.  The prefrontal cortex uses sensory input as well as information that it has stored elsewhere in the cortex to aid in making decisions.  At the same time, for the prefrontal cortex to be consciously aware of something, that something must be represented by neural activity within the cortex itself.  While the cortex may be vaguely aware of the brain’s unconscious activities, it doesn’t know details.  For example, while your cortex knows you can ride a bike, it doesn’t know which muscles need to be contracted or relaxed, and in what sequence.  Those “motor melodies” are encoded in an unconscious part of the brain (the cerebellum).

At the same time, new cortical tissue was added over time in what appears to be a modular fashion.  The new conscious processing did not replace the older unconscious processing, it was in addition to the older processing.  As a result, there is some redundancy in the conscious processing of the cortex and unconscious processing of the lower brain.  However, neural connections between them normally allows for adaptive coordination.

While the highly modified mammalian forebrain (i.e. cortex, limbic system, basal ganglia, and the fiber tracts that interconnect them) expanded behavioral flexibility and promoted broader adaptation, the more primitive brainstem remained tightly linked to unconscious homeostatic processes such as breathing, blood flow, body temperature regulation, etc.  In the unusual situation where higher and lower brain areas would be in conflict regarding these critical processes, the lower brain areas should normally win out.  For example, it’s virtually impossible to commit suicide by consciously holding your breath.  No matter how hard you try, the unconscious breathing centers in the medulla (lowest part of the brain) will make you start breathing again.  (Hopefully nobody reading this proves me wrong!)  It is also instructive to look at the effects of brain damage.  Because the medulla is in charge of homeostatic processes critical to life, damage to the primitive medulla is much more likely to be lethal than damage to the much more complicated cortex.

Conflicts arising from independent processing in different parts of the brain.

While independent processing in different parts of the brain usually works together, it is possible to have conflicts.  Some of the best examples are found in split-brain preparations where the corpus callosum (the fiber tract that connects the two cortical hemispheres) has been cut (typically to treat epilepsy), causing the 2 hemispheres to be disconnected in their functioning.  When this happens, the two hemispheres are less able to coordinate their processing and occasionally bizarre outcomes can occur where one hemisphere will try to produce one set of motor responses while the other hemisphere will try to produce another.  More important to the addiction argument would be conflicts between higher and lower brain areas.  While higher and lower brain areas also usually work together, conflicting processing should be possible here as well.

A good example of independent processing by higher and lower brain areas is the brain’s processing of visual information.  As seen in the figure below, our conscious visual experience is begun by processing occurring in the primary visual cortex of the occipital lobe.  However, a lower part of the human brain (the superior colliculus in the midbrain) is also independently processing visual input, but below the level of conscious awareness.  In fact, for vertebrates that lack a neocortex (such as reptiles and birds), the optic tectum (equivalent to the human superior colliculus) is the primary visual processing center.

Figure 2: A cross section schematic of the human brain showing the visual pathways and 2 visual processing areas in red. The lateral geniculate nucleus (LGN) is a relay station where optic nerve fibers must first synapse before sending the information up to the primary visual cortex in the occipital lobe via a fiber tract called the optic radiation.  In contrast, optic nerve fibers go directly to the superior colliculus

Visual processing by the superior colliculus is thought by some to to explain another bizarre phenomenon in humans known as “blindsight”.  Blindsight occurs following brain damage to the primary visual cortex in the occipital lobe of the cortex (necessary for conscious visual processing).  Such a person would be diagnosed as blind by an ophthalmologist. However, if the eyes, the optic nerve, and visual pathways into the lower parts of the brain including the superior colliculus are undamaged,  such a “blind” person can still behaviorally respond to certain types of visual input.  However, when asked what caused the response and why they responded, the person cannot give a good explanation.  A commonly accepted explanation is that the visual input is being processed by the superior colliculus operating below the level of conscious awareness.

While both the human visual cortex and superior colliculus normally work together, their independent visual processing  is thought to serve different purposes.  While the much more sophisticated cortical processing influences conscious thought and behavior, the simpler superior colliculus processing may be important for quick reflexive responses to visual input.   We do know that the human superior colliculus does process visual input to influence several different reflexive eye and head movements known to facilitate vision.  However, whether the superior colliculus underlies blindsight is based more upon indirect evidence.  Like the primary visual cortex, a retinotopic map exists in the superior colliculus where specific locations in the superior colliculus correspond to particular locations in the retina.   The relationship suggests that the human superior colliculus might have the neural machinery to reconstruct some representation of what the person is seeing. The superior colliculus also is connected to the spinal cord by a fiber tract (the tectospinal pathway) that could mediate quick output to human body muscles as it does in birds and reptiles.  This role also makes anatomical sense because the superior colliculus both receives visual information sooner and, can reflect it back out to muscles faster than the cortex, allowing for quick (but unconscious) visual reflexes.

The point of this digression is that while different parts of the brain normally work together, independent processing of similar information does occur at different brain levels.  And should conflicts arise concerning issues important to survival and reproductive fitness, the lower brain areas should sometimes have priority.  And few things are more important to survival than quickly identifying and responding to rewarding (and aversive) stimuli.

So where is the addiction circuitry? 

I offer the hypothesis (not original with me) that addiction may be influenced by memory circuitry somewhere in the unconscious parts of the brain relatively immune to the influence of conscious learning.  Exactly where is a question I won’t try to answer.   However, I would suggest that the lower this circuitry is in the brain, the more resistant it would be.  I will now weasel out of the situation by hoping that future research will be able to address this very important question.  I will also leave it to persons smarter than me to figure out what, if any, implications this could have for addiction treatment.

As I pointed out in the first post on addiction, the prevailing school of thought is that addiction can be accounted for by dysfunctions in the reward circuitry as well as in the prefrontal cortex and amygdala.  I am not discounting the important role these forebrain structures play, particularly in encoding the initial conscious reward expectancies.  However, I am suggesting as addiction proceeds, the forebrain dysfunctions (particularly in the prefrontal cortex) may contribute even more by impairing the organized conscious thought processes necessary to override powerful primeval reward expectancies unconsciously encoded the brainstem.

Figure 3. A cartoon showing the proposed conflict between conscious and unconscious parts of the brain in a drug addict

The reality is that we don’t really completely understand what encodes and maintains the need to engage in this highly compulsive, long-term, out-of-control behavior and all explanations (including the one presented here) should be taken with a grain of salt.

Sorry to take so long to reach such an unsatisfying conclusion.  🤷‍♂️But…….that’s the way science sometimes goes!  Still a lot to learn!

To learn more.

Advocat, Comaty & Julien (2019).  Chapter 4: Epidemiology and neurobiology of addiction.  In Julien’s Primer of Drug Action. Thirteenth Edition. Worth Publishers. 267-295.  (A good textbook that I last used in my teaching.  many references to primary literature at the end of this chapter)

Charles P. O’Brian.  Drug use disorders and addiction.  Chapter 24 in Goodman and Gilman’s The pharmacological basis of therapeutics.  McGraw-Hill Publishers.  (written for medical professionals so fairly technical)

I also refer you to Wikipedia for information on addiction, split-brain preparations, blindsight, and consciousness.  The Wikipedia entries also provide citations to the primary literature.



Addiction I: The Role of Reward in Addiction


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.

Figure 1: A schematic cross section of the human brain showing the reward circuitry in red.  The neurons of this circuitry have their cell bodies in the ventral tegmental area and their axons project up to the nucleus accumbens where they secrete dopamine under conditions of reward.  These axons are part of a larger ascending fiber tract called the mesolimbic/mesocortical pathway.

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.