The Brain Under Siege

According to the World Health Organization, addiction is “a disorder of altered brain function brought on by the use of psychoactive substances.”  Recent advances in neuroscience confirm the conclusion of the World Health Organization that addiction is as much a brain disease “as any other neurological or psychiatric illness.”  These findings have fundamentally changed the way that addiction is viewed in the scientific and medical communities and will have a great impact on how treatment will be approached.

The Human Brain on Methamphetamine

The Yin and Yang of Science, however, demand that dysfunction cannot truly be comprehended without an understanding of normal function.  To this end, Part I of this essay reviews the normal structure and function of the human brain.  Then in Part II, the neurological dysfunction of addiction is explained and supported by compelling scientific evidence.  In the end, there should be no doubt that addiction is indeed a disease like any other and that it must be treated as such.


The Human Brain – Structure and Function
There are three major divisions of the brain:  the forebrain, the midbrain, and the hindbrain.  The forebrain is responsible for a variety of functions including receiving and processing sensory information, thinking, perceiving, producing and understanding language, and controlling motor function.  Within the forebrain lies the cerebrum which is divided into two hemispheres each consisting of four lobes (frontal, parietal, occipital, and temporal).  The outer layer of the cerebrum forms the cerebral cortex, also known as gray matter, which covers the nuclei deep within the cerebral hemisphere known as white matter.

  • The gray matter includes regions of the brain involved in muscle control, sensory perceptions (such as seeing and hearing), memory, emotions, and speech.
  • The white matter is found between the brainstem and cerebellum and consists of structures at the core of the brain such as the thalamus and hypothalamus.  The nuclei of white matter are involved in the relay of sensory information from the rest of the body to the cerebral cortex and in the regulation of autonomic functions such as heart rate and body temperature.  Certain nuclei within the white matter are involved in the expression of emotions, the release of hormones from the pituitary gland, and the regulation of food and water intake.  These nuclei are generally considered part of the limbic system.

The midbrain connects the hindbrain to the forebrain.  It is involved in auditory and visual responses and in motor function.  The hindbrain extends from the spinal cord and is comprised of several structures including the walnut-shaped cerebellum which is situated at the base of the brain.  The cerebellum coordinates sensory input from the inner ear and muscles to provide accurate control of position and movement.  Other important hindbrain structures include the pons, which relays sensory information between the cerebrum and cerebellum; and the medulla oblongata, which helps control autonomic functions.

The stalk-like brainstem forms the link between the spinal cord and the forebrain.  It consists of the midbrain, the medulla oblongata, and the pons.  Every nerve impulse that passes between the brain and spinal cord is transmitted through the brainstem.  The brainstem contributes to the control of breathing, sleep, and circulation.

The Primitive Brain
The limbic system is a set of primitive brain structures located at the top of the brainstem.  It is buried beneath the cerebral cortex.  The limbic system is involved in generating feelings of pleasure related to our survival such as those experienced from eating and having sex.  Major structures of the limbic system include:

  • The Amygdala — This almond-shaped structure helps in storing and classifying emotionally charged memories.  It plays a central role in producing emotions — especially fear.  It is also involved in triggering physical responses to strong emotions such as sweaty palms, increased heart-beat/respiration, and the release of stress hormones.
  • The Hippocampus — This structure plays a crucial role in the indexing of memories.  It sends short-term memories out to the appropriate part of the cerebral hemisphere for long-term storage and retrieves those memories when needed.
  • The Hypothalamus — About the size of a pearl, this structure performs a multitude of functions including monitoring and controlling cicadian rhythms (the daily wake/sleep cycle); maintenance of homeostasis; initiation of appetite, thirst, and emotional response; and it is involved in various autonomic and motor functions.  The hypothalamus also plays an important role in the regulation of hormones.
  • The Thalamus — The thalmus is essentially the relay station of the brain.  This structure processes sensory input signals between the spinal cord and cerebrum.
  • The Nucleus Accumbens — This structure is a collection of brain cells thought to play an important role in determining the motivational value of stimuli, reward, and learning.  In the scientific study of addiction, the nucleus accumbens has been identified as especially important because it is targeted by drugs of abuse.

Neurons and Neurotransmitters
A.  Anatomy of a Neuron
Neurons, or nerve cells, are specialized cells that form the basic building blocks of the nervous system.  Neurons generally process and transmit information by electro-chemical signaling.  The human brain is comprised of 100 billion neurons.

There are three basic parts of the neuron:  the soma, the dendrite, and the axon.

  • The soma, also called the cell body, is the central part of the neuron.  It contains the nucleus of the cell.
  • The dendrites extend away from the soma into multiple branches, the overall shape and structure of which is referred to as a dendritic tree.  Dendrites are specialized to receive impulses from the axons of other neurons.
  • The axon is a fine, cable-like projection that carries nerve signals away from the soma.  Axons generally undergo extensive terminal branching thereby enabling communication with many target cells.

B.  Interneuronal Communication
Neurons communicate with each other via synapses where the axon terminal of one cell impinges the dendrite, soma, or less commonly the axon, of another neuron.   For every neuron, there are between 1000 and 10,000 synaptic clefts.

Interneuronal communication begins when chemicals contact the surface of a neuron thereby changing the balance of ions inside and outside of the cell membrane.  When this change reaches a threshold level, this effect runs across the cell membrane to the axon.  Upon reaching the axon, an action potential is generated.  An action potential is a rapidly moving exchange of ions down the length of the axon.  At the axon terminal, the action potential opens voltage-gated calcium channels allowing calcium ions to enter the terminal.  Calcium causes synaptic vesicles filled with neurotransmitter molecules to fuse with the cell membrane resulting in the release of neurotransmitter into the synaptic cleft.

The neurotransmitter molecules diffuse across the synaptic cleft and activate receptors on the post-synaptic neuron.  Because of their chemical properties, receptors will only bind to a specific neurotransmitter.  In this respect, the neurotransmitter acts like a key and the receptor a lock.  The binding of the neurotransmitter and receptor causes the transmission of a post-synaptic signal which may be excitatory (propagates a post-synaptic action potential) or inhibitory (inhibits the propagation of a post-synaptic action potential) depending on the chemical properties of the receptor.

Specialized protein transporters allow the neurotransmitter molecules released into the synaptic cleft to be reabsorbed into the pre-synaptic neuron in a process known as reuptake.  Reuptake is a biological necessity as it allows for the recycling of neurotransmitters, regulates the level of neurotransmitter present in the synapse, and controls how long the signal generated by the release of the neurotransmitter will last.

C.  Neurotransmitters
Neurotransmitters are essentially chemical messengers that facilitate communication between neurons.  Neurons differ in the type of neurotransmitter they principally manufacture.  Some examples include:

  • Dopaminergic neurons which produce dopamine — Dopamine has many functions in the brain including important roles in behavior and cognition, voluntary movement, motivation, punishment and reward, sleep, mood, attention, working memory and learning;
  • Serotonergic neurons which produce serotonin — Serotonin functions to regulate appetite, sleep, memory and learning, temperature, mood, behavior, and muscle contraction.  Deficits in serotonin are believed to contribute to depression.
  • GABAergic neurons which produce gamma aminobutyric acid (GABA) — GABA is the major inhibitory neurotransmitter of the central nervous system.  It works to reduce anxiety and stress and significantly impacts mood; and
  • Glutamatergic neurons which produce glutamate — Glutamate is the major excitatory neurotransmitter of the brain and is required for learning and memory.  Abnormal glutamate levels are present in neurodegenerative conditions such as Alzheimer disease.

D.  Neural Pathways
Neurons do not function in isolation.  They are organized into specific circuits (or pathways) for processing specific types of information and facilitating communication between different areas of the brain.  The arrangement of any given neural pathway varies depending on its intended function.  Additionally, the neuroplasticity of the brain allows it to create and reorganize neural pathways based upon new experiences and conditioned learning.

The mesolimbic pathway is a dopaminergic circuit in the brain that plays a central role in the neurological process of addiction.  This reinforcement pathway, which is composed of both central nervous system structures and endogenous neurotransmitters communicating between these structures, is often referred to as “the reward pathway“.

The mesolimbic pathway begins in the ventral tegmental area (VTA) of the midbrain; connects to the limbic system via the nucleus accumbens, the amygdala, and the hippocampus; and ends at the medial prefrontal cortex.  The release of dopamine by the nucleus accumbens drives the electro-chemical communication within the mesolimbic system.  Damage to the nucleus accumbens and drugs that block the release of dopamine in this region of the brain make everything seem less rewarding.

The reward pathway evolved to promote activities that are essential to human survival — such as eating and sexual reproduction.  Thus, when a human performs an action that satisfies a need or fulfills a desire, dopamine is released into this pathway resulting in feelings of pleasure.  The release of dopamine serves as a signal that the action promotes survival.  When we do something that stimulates the reward pathway, the experience is remembered in concert with the attendant pleasure and we are therefore likely to repeat the action.

And just as the brain is dependent upon the intercommunication of neurons for its normal function, so too is it dependent upon communication between neural pathways.  For example, GABAergic, serotonergic, and opioid circuits have all been shown to interact at various points along the mesolimbic “reward” pathway to modulate its activity.


The Neurochemistry of Acute Intoxication
Acute intoxication occurs in the immediate aftermath of the ingestion of drugs of abuse.  It is the state of mind and body which is induced by the presence of these foreign substances in the tissues.

Experiments have shown that drugs of abuse affect various neurochemical processes by attacking different areas of the brain.  The nucleus accumbens is the primary place of action of cocaine, amphetamines, opiates, THC, phencyclidine, ketamine, and nicotine.  Opiates, alcohol, barbiturates, and benzodiazapines stimulate neurons in the VTA.  The final common action of most drugs of abuse is to increase dopamine levels in the mesolimbic pathway.  This flood of dopamine is what causes the drug-induced euphoria or “high” and it is by this means that drugs of abuse exert a reinforcing effect.  A reinforcer is an event that increases the likelihood of a subsequent response to the same stimulus.  So, for example, the pleasure of orgasm reinforces the likelihood that sexual activity will be repeatedly engaged.  Unfortunately, drugs of abuse are much more effective reinforcers than their natural counterparts.  In fact, addicts often describe the intense feelings of pleasure derived from drug use as being “an orgasm of the entire body.”

The difference between the reinforcing effects of the natural stimulation of the reward pathway versus the artificial and amplified stimulation induced by the ingestion of drugs of abuse has been vividly demonstrated in animal experimentation.  In self-stimulation experiments, electrodes are attached to structures in the animal brain which are similar to the human mesolimbic “reward” pathway.  When the animal presses a lever, the electrode stimulates the reward pathway which gives rise to intense feelings of pleasure.  In models of addiction, hungry animals will compulsively self-stimulate the reward pathway and ignore food and water — to the point of death by starvation.  These experiments provide overwhelming proof that drugs of abuse highjack the reward system of the brain and become exponentially more rewarding than natural stimuli it evolved to subserve.

A.  Alcohol
Due to its legal regulation, alcohol is the most commonly abused psychoactive substance in society.  Acute alcohol intoxication produces many pharmacological effects in the brain as a result of the stimulation of multiple neural pathways including dopaminergic pathways.  Blocking the effects of dopamine decreases the self-administration of alcohol in animal studies.  However, animals will continue to self-administer alcohol even if the mesolimbic pathway is destroyed by a selective neurotoxin.  Therefore, additional biochemical mechanisms are obviously involved in modulating the rewarding effects of alcohol.

B. Stimulants
Stimulants, such as cocaine and amphetamines, are substances that induce euphoria, arousal, and racing thoughts.  Both cocaine and amphetamines increase dopamine levels in the mesolimbic pathway by binding to transporters thereby blocking the reuptake of dopamine from the synapse.  In addition to acting as a reuptake inhibitor, amphetamine has been shown to also stimulate the release of dopamine into the synaptic cleft.

The importance of these pharmacodynamic effects on drug-taking behavior has been clearly demonstrated in animal studies.  For example, psychostimulants are self-administered to a lesser extent in animals in which lesions of the mesolimbic pathway have been produced by application of a selective neurotoxin or when pretreated with dopamine receptor blockers.

Additionally, in human test subjects where positron emission tomography (PET) is used to observe brain activity, the intensity of the “high” induced by methylphenidate (a synthetic psychostimulant drug) administration correlates significantly with the levels of dopamine activity in the brain.  Test subjects for whom methylphenidate does not increase dopamine levels do not become “high”.

C.  Opiates
Opiates, such as morphine and codeine, are commonly used in the clinical setting for pain relief.  However, these drugs can also induce euphoria and are therefore frequently abused.  Opiates act as reinforcers through indirect modulation of the mesolimbic pathway by binding to the mu-opiod receptors of GABAergic neurons.  Absent interference by opiates, GABA neurons inhibit the dopaminergic neurons in the VTA.  However, when opiates block the inhibitory influence of GABA, the dopaminergic neurons are free to become more active.  Additionally, opiates bind directly to receptors in the nucleus accumbens.

Evidence supporting these mechanisms of action includes the observation that morphine and heroin self-administration can be modified in animals by blocking the action of GABA in the VTA; and by blocking opioid receptors in the nucleus accumbens.

D.  Marijuana
is the common name of the drug obtained from the hemp plant, Cannabis sativa.  Hemp contains more than 400 chemicals.  The main psychoactive chemical is tetrahydrocannabinol (THC).  THC affects brain function by binding to specific cannabinoid receptors.  Recent research demonstrates that cannabinoids also share with other drugs of abuse the ability to increase dopamine levels by stimulation of the mesolimbic neurons.

The Neuroscience of Relapse
For the purpose of this discussion, a relapse is the subsequent ingestion of drugs of abuse after a state of acute intoxication has cleared.  The period of time between episodes of relapse is dependent upon a multitude of factors and varies widely for the individual ranging from as little as a few hours to many years.  While the discussion to this point has primarily focused on the immediate effects of acute drug intoxication upon the mesolimbic pathway, the neuroscience of relapse goes beyond mere reward.

Using functional magnetic resonance imaging (fMRI), scientists have found that acute drug intoxication not only activates the neuronal circuits associated with reward, but that other pathways — including those which are associated with motivation and drive (orbitofrontal cortex); memory and learning (amygdala and hippocampus); and control (prefrontal cortex and cingulate gyrus) — are affected.  Relapse is directly attributable to enduring changes in brain structure and function caused by the interaction of the mesolimbic “reward” pathway with these other pathways during acute intoxication.

Any given reaction to a stimulus is dependent upon its saliency — that is, the expected reward.  The motivational value of the expected reward is affected by memory.  The brain records the memory associated with a particular stimulus as being pleasurable or aversive.  These memories activate the motivational circuit which increases the desire to procure that which will provide the pleasurable reward.  Ultimately, the choice of whether or not to procure the stimulus is a cognitive decision of higher brain function.

In the addicted person, the saliency value of the drug of abuse is enhanced in the reward and motivation/drive circuits to the detriment of other reinforcers.  Drugs of abuse are more salient due to the their much higher intrinsic reward properties.  The increase in dopamine levels induced by acute intoxication is three (3) to five (5) times higher than those of natural reinforcers.  This hyper-activation of the mesolimbic pathway resets typical reward thresholds.  The individual then becomes less susceptible to the reinforcing effects of natural stimuli because these stimuli cannot induce reward comparable to that achieved by the ingestion of drugs of abuse.  Through the experience of acute intoxication, memories are formed in relation to the intense pleasure derived from drug use to the detriment of the motivational value of natural stimuli.  Therefore, when these memories are triggered, the acquisition of the drug becomes the main motivational drive for the individual overriding the control typically exerted by the frontal cortex.

This disinhibition, or lack of control, may be due in part to structural changes in the neurons which comprise the affected neural circuits.  For example, chronic administration of cocaine or amphetamine result in a significant increase in dendritic branching and density in the prefrontal cortex.  These changes in synaptic connectivity are likely involved in the impaired decision-making, judgment, and cognitive control that occur in the addicted individual and which are hallmarks of chronic relapse.

Additionally, the overstimulation of neurons brought about by the flooding of dopamine (and other neurotransmitters) leads to a decrease in dopamine production; a decrease in post-synaptic dopamine receptors; and the desensitization of the dopamine receptors which remain.  Desensitization reflects the actions of the nervous system to maintain homeostasis — a constant degree of cell activity notwithstanding major changes in receptor stimulation.  Thus, the natural reaction of the brain to repeated hyper-stimulation of the reward pathway is to reduce the effect of dopamine which then interferes with the ability to experience pleasure.  PET images of the brains of individuals addicted to cocaine, methamphetamine, and heroin show fewer dopamine receptors.  This decrease in brain activity compels the addicted person to obtain more drugs in an attempt to bring dopamine function back to normal.  However, due to structural and functional changes in the brain, larger amounts of the drug become necessary in order to achieve the same dopamine high — an effect known as tolerance.

The concept of addiction as a disease of altered brain function is not without controversy.  Until recently, many viewed addiction not as a disease, but as a matter of personal, moral failure.  But focusing on the role of “personal choice” in addiction ignores concrete science and is a social injustice.  Society generally does not cast aspersion upon those who suffer from lung cancer for having smoked cigarettes nor upon those who are diabetic for having too often consumed foods high in sugar content.  And as is the case with many diseases, research has shown that a variety of factors, both biological and environmental, increase the risk that an individual will become addicted — a point which further undermines any focus on personal failure and moral turpitude.  Regardless of why an individual becomes addicted, there can be no doubt that once addicted the structure and function of the brain are altered in a way that ensures the addictive behavior will likely continue even though the addict knows that it is harmful.

As any addict can attest, the difficulty in fighting addiction is not so much the stopping any given episode of use as it is staying stopped for any length of time.  Advances in neuroscience help explain not only why individuals become addicted, but also why the addict cannot simply leave drugs alone by unaided force of the will.  Those who are afflicted can take comfort in knowing that their addiction is no more a personal, moral failure than would be carcinoma for those who bathe in the sun.

While convincing proof that addiction is a brain disease is compelling science, the information serves little purpose absent effective treatment.  Addiction is ultimately a terminal condition.  Traditional pharmacological approaches to addiction treatment are sparse at best due to a lack of understanding of neurochemical processes.  However, scientists are actively researching treatment alternatives such as vaccines which can block the gratifying effects of drug use.  These treatment concepts are not without multiple pontential pitfalls but they do nevertheless provide hope.  Given the robust nature of medical research, it is not difficult to envision a time when when the function of the brain will be understood to a degree which will allow addiction to be aggressively treated as a purely neurological disorder.

Presently these scientific findings are nonetheless useful in the application of cognitive behavioral therapy to addiction treatment — including those approaches advocated by recovery programs such as Alcoholics Anonymous and Narcotics Anonymous.  One of the most significant barriers to treatment is personal acceptance that addiction is a disease.  For those so inclined to investigate, even the current state of the medical evidence — which remains rudimentary though no less convincing —  compels the conclusion that addiction is at the very least a disorder of brain function.  Once this is understood and accepted, the barriers of denial become surmountable and the addicted person becomes willing to follow the necessary regimen of treatment.  However, both science and experience demonstrate that for the addicted person the process of learning and application of new principles is not achieved in isolation, but requires that the addict receive significant therapeutic support.

Finally, the question arises that if addiction is a physical disorder of the brain, how is it that recovery can be had through a purely psychological approach?  No one believes, for example, that an individual who suffers from blindness can undergo cognitive behavioral therapy to regain vision.  While the question ultimately requires the consideration of that which transcends the physical plane, the answer is partly found in the fact that modern neuroscience continues to blur the distinction between that which is purely physical and that which is psychological  — particularly where the function of the human brain is concerned.  In this respect, the ability to recover from addiction by emotional and mental upheaval may only be limited, if at all, by the mechanics of neuroplasticity.


Tomkins, Denise M. and Sellers, Edward M., Addiction and the Brain:  The Role of Neurotransmitters in the Cause and Treatment of Drug Dependence, Canadian Medical Association Journal, March, 2001.

University of Colorado, Center on Antisocial Drug Dependence, Neuroanatomy and Physiology of the Brain Reward System in Substance Abuse, September, 2007.

Bettinardi-Angres, Kathy and Angres, Daniel H., Understanding the Disease of Addiction, Journal of Nursing Regulation, July, 2010.

Volkow, Nora D., Fowler, Joanna S., and Wang, Gene-Jack, The Addicted Human Brain:  Insights from Imaging Studies, The Journal of Clinical Investigation, May, 2003.

World Health Organization, Neuroscience of Psychoactive Substance Use and Dependence, Geneva, Switzerland, 2004.

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