The need to discuss the biological basis of drug addiction is not merely scientific, but also social. Even today, prevention and awareness campaigns concerning the “drug problem” proceed along two clearly divergent paths: on the one hand, they denounce the dangers drugs pose to the brain; on the other, they propose models for resolving the problem that rely on interpersonal relationships, their strength and stability, and the drug-dependent person’s decision to “turn their life around” after it has fallen into ruin. This second concept presupposes a substantially intact brain which, once current intoxication has been removed, regains its potential and sensitivity to the traditional moral and human stimuli that bring ordinary people “back onto the right path.”
The fact that drug addiction is a disease means precisely the opposite: the disease does not merely involve collateral brain damage; rather, it is based on a brain dysfunction common to all drug-dependent individuals, which constitutes the basis of their relapsing behavior, their ambivalence, their reluctance to undertake treatment, and their inability to conceive of well-being that is not “drug-induced.”
The neurobiology of drug addiction can be discussed on several levels. Hormonal, psychiatric, or neurological parameters can be described. The possibility of imaging the brain and selectively identifying the areas involved in drug addiction, with images that vary in brightness according to the level of activity in a given region, provides a rapid and striking illustration of the differences between a healthy brain and the brain of a drug-dependent individual.
Naturally, the fundamental knowledge concerning drug addiction is clinical. The first concept is that people are not born drug addicts; they become drug addicts. Even if we hypothesized that the brains of drug-dependent individuals all had something in common “before” addiction developed—which at present appears to be false—what we call drug addiction certainly occurs afterward.
So-called drugs of abuse—that is, substances that tend to be sought with an increasingly strong desire—share a cerebral effect: the release of the neurotransmitter dopamine in a pathway that connects the “lower” brain, particularly the midbrain, with certain frontal areas of the “higher” brain. Dopamine release functions as a signal whose consequence is the consolidation of a memory: the substance is worth using again. Cocaine, alcohol, amphetamines, opioids, and benzodiazepines are substances that differ in the type of cerebral receptor with which they initially interact and in their psychological effects, yet they share two characteristics: a sensation of pleasure/euphoria and a tendency to become increasingly desired.
This increase in desire, in the form of a memory, is then associated with drug-seeking behavior: the substance is pleasurable, therefore I want it again. The final mechanism through which a substance is capable of inducing drug-seeking behavior is called reinforcement. Memory and reinforcement are therefore effects shared by all drugs of abuse.
The same mechanism operates with indirectly pleasurable stimuli, such as food, sex, and, more generally, activities that an individual experiences as pleasurable.
For drugs of abuse to be “reinforcing,” they must essentially possess one characteristic: they must reach the brain rapidly. The speed with which their concentration increases in specific areas of the brain—or, for simplicity, throughout the brain—makes one substance pleasurable and another neutral. What matters is not the type of receptor to which the substances bind, nor how long the substances remain in the brain. The relevant variable is a “kinetic” one, namely the change over time in the concentration of the substance in bodily fluids.
Substances that “arrive quickly” are euphorigenic and potentially addictive. Others are not. Sometimes the same substance can be made euphorigenic and addictive by changing its route of administration if this alters its kinetics: a substance taken orally reaches the brain “slowly,” whereas when injected it reaches it “rapidly.” By using particular interfaces—for example, the pulmonary route through inhalation—it is possible to make a substance that is already euphorigenic when administered nasally even more rapidly acting and reinforcing.
By deliberately changing the chemical characteristics of a substance, variants can be created that “arrive faster,” as in the case of heroin compared with morphine. This is not a matter of potency, because, for example, heroin is less potent than morphine. Heroin, however, reaches the brain more rapidly and therefore, in practical terms, hits harder.
Who tends to appreciate drugs more?
Receptor imaging studies—particularly studies of dopamine D2 receptors—show that the more numerous the “antennae” for dopamine are, the more unpleasant the effect of intravenous methylphenidate tends to be. Brains that are highly sensitive to dopamine, perhaps because the system has become sensitized by low dopamine availability, may therefore respond unpleasantly to strongly dopaminergic drugs.
In individuals who have already learned to desire methylphenidate, the level of desire correlates with activation of the orbitofrontal cortex. Interestingly, placebo appears to deceive only the brains of individuals with low levels of desire, producing a sort of “illusory” euphoria. This does not occur in individuals with strong desire, who therefore presumably identify the inconsistency of the placebo almost immediately.
What happens to brains exposed to drugs of abuse?
The dopamine-based system becomes blunted. This probably occurs as an adaptive mechanism of the receptor system in response to the excessive dopamine release, because the receptors become less highly expressed.
During cocaine withdrawal, D2 receptors increase, but even after four months they remain markedly reduced compared with those of a normal individual.
As the years pass, this suppression of the D2 system becomes more pronounced: older cocaine users are those with the lowest number of receptors. With aging in general, receptors tend to decrease spontaneously even in healthy individuals, but in cocaine users this process is accelerated. A 35-year-old cocaine user may have a D2 receptor profile comparable to that of a normal 55-year-old individual.
Abuse of opioids, although these substances act primarily through a different and specific receptor, is likewise associated with alterations in dopamine D2 receptors.
Dopamine transporter (DAT) levels are reduced in methamphetamine abusers, and this correlates with the motor and memory problems observed in this population. After 14 months of abstinence from methamphetamine, dopamine transporter levels remain below normal, although they show a tendency to increase over time.
The comparison between these two findings is particularly interesting. The transporter is used as an indicator of structural injury, that is, loss of cellular material and/or reduction in neuronal branching. D2 receptor expression, by contrast, is relatively flexible on the surface of otherwise intact neurons.
The transporter therefore appears to indicate a more extensive form of damage, whereas alteration of the D2 receptor system may be more limited and potentially reversible: the neuron remains present and can produce D2 receptors again, whereas if the neuron has died it cannot recreate its DAT.
The time required for normalization, however, is slow even in receptor-level damage. Thus, the theoretical reversibility of the damage is in practice very slow, so that over time structural damage and functional damage may appear to recover at similar rates. If structural damage cannot theoretically recover completely, functional damage may nevertheless do so, albeit extremely slowly, over the course of years.
In DAT-type damage, recovery depends on the ability to reconstruct lost material. In receptor-level damage, by contrast, recovery is related to the ability to deconstruct a molecular memory that has fixed the functioning of the metabolic system according to the model “learned” through reinforcement.
Orbitofrontal cortex and cingulate gyrus
With regard to the orbitofrontal cortex and cingulate gyrus, metabolism in cocaine users appears to be reduced. In the absence of cocaine-related stimuli, the brain of a person heavily exposed to cocaine shows a reduced level of activity.
After 10 days of abstinence, the change is minimal, and even after 100 days of abstinence, cortical metabolism does not reach even half the level observed in a normal brain.
For amphetamines, restoration of normal function during abstinence does not occur completely even after several years.
Some substances affect not only the dopamine system but also other neurotransmitter systems. Ecstasy, for example, selectively affects the serotonin system. The reduction in the arborization of cortical serotonergic neurons remains clearly detectable, although with a slow tendency toward improvement, even after seven years of abstinence.
All of these findings, however, refer to the intoxicating effects of drugs of abuse and do not necessarily imply that these alterations encompass those specifically associated with drug addiction.
Drug-related cues and pathological reinforcement
If the brain of cocaine users is relatively “switched off” under baseline conditions, it becomes more active than normal when stimulated by images that evoke cocaine-related memories.
Dopamine release is greater than expected and powerfully activates the memory of pleasure and drug-seeking behavior. In other words, the reinforcement mechanism appears to become hypersensitive, almost automatic.
The brains of abstinent alcohol-dependent individuals behave in a similar manner: opioid receptors are expressed at higher-than-normal levels, as though the brain were “looking for” the alcohol that is no longer there. Because it does not find it, desire emerges and drug-seeking behavior begins.
The greater the number of these receptors, the greater the self-reported desire to drink. The brain of a person abstinent from alcohol is therefore not completely “calm”; it remains activated, and when exposed to specific stimuli it shows an abnormally intense response in recalling and initiating drug-seeking behavior.
Yet—and this is the crucial point—it is not necessarily the case that dopamine release is absolutely greater. In fact, the amount of dopamine released in response to methylphenidate in cocaine users is lower than in healthy individuals.
If the brains were otherwise identical, this should mean that cocaine users had less reason to desire cocaine after taking it than people who use it only occasionally. In reality, of course, the opposite is observed.
This reduced intensity of reinforcement in individuals who use cocaine continuously is highly suggestive of addiction: they should want less, yet they want more.
Unlike the occasional user, who tends to use the substance more when they experience its effects more strongly, the cocaine-dependent individual continues to use it even when they experience it less strongly than normal. Their drug-seeking mechanism is so sensitive that only a small amount of dopamine is sufficient to activate it.
In addiction, pleasure is reduced compared with the past, and it is precisely this anomaly that distinguishes use from addiction. Further evidence comes from what cocaine users report when receiving intravenous methylphenidate: compared with healthy individuals, they experience it less intensely, yet desire it more.
In very simple terms, this discrepancy is drug addiction, provided, of course, that we are referring to a stable or recurrent pattern over time and not to a transient phase that will subsequently resolve with cessation of drug use.
Many people who reach a stage in which their brain responds paradoxically—desiring the substance even though they experience it less—will eventually realize that it is no longer worth it, although they may continue for a while because of the memory of past pleasure.
Others, however, will not stop. Instead, they will retain the strong belief that pleasure comes from the substance, or rather that future pleasure will come from the substance.
Inhibitory control and the reinforcement circuit
Some authors have proposed that the reduction in frontal cortical activity in drug-dependent individuals reflects a lack of inhibitory control over behavior, as though the substance damaged the inhibitory centers governing appetitive behavior.
This mechanism may indeed be involved, but it could operate indirectly. The hypertrophy of the circuit linking the memory of pleasure to drug-seeking behavior—the reinforcement circuit—could grow disproportionately and exert an inhibitory influence on other brain areas, which would become functionally overshadowed because they are “antagonistic” to the reinforcement circuit.
The ultimate effect would be to facilitate the task learned by the reinforcement circuit.
Clinically speaking, drug-dependent individuals do not appear to lose their inhibitory mechanisms. Rather, they retain them as “orphaned” and useless functions: “good intentions” without neurofunctional power.
The degree of growth of the reinforcement circuit corresponds to what we call salience, namely the relative importance and priority assigned to different actions.
For the drug-dependent individual, the salience of drug-seeking has increased to such an extent that it is no longer significantly influenced by other considerations; it becomes self-sustaining “with little or nothing.”
The same may occur with positive and negative memories, the latter being referred to as negative reinforcement. These memories are probably mostly “slow,” whereas the memory underlying reinforcement is “fast.” It is also possible, however, that the reinforcement memory, because it comes into play first and becomes dominant, overshadows negative memories, which are experienced with reduced “salience.”
Conclusion
In conclusion, clinical diagnosis remains the simplest and most direct way of identifying drug addiction, with the reassurance that neurofunctional imaging provides suggestive evidence of differences between drug use and drug addiction.
The brain regions involved in addiction are less extensive than those “damaged” by drugs and are less visible because they are fundamentally expressed not at the level of motor or performance functions.
By the time these alterations become clinically apparent, the individual is already seeking the substance.
References
Volkow, N. D., Wang, G.-J., Fowler, J. S., Logan, J., Gatley, S. J., Gifford, A., Hitzemann, R., Ding, Y.-S., & Pappas, N. Brain dopamine D2 receptor levels predict reinforcing responses to psychostimulants in humans. American Journal of Psychiatry, September 1999.
Volkow, N. D., & Fowler, J. S. Addiction, a Disease of Compulsion and Drive: Involvement of the Orbitofrontal Cortex. Cerebral Cortex, 2000; 10:318–325.
Volkow et al. Synapse, 14(2):169–177, 1993.
Volkow et al. Neuropsychopharmacology, 14(3):159–168, 1996.
Wang, G.-J. et al. Neuropsychopharmacology, 16(2):174–182, 1997.
Volkow et al. American Journal of Psychiatry, 2001.
Volkow, N. D. et al. Journal of Neuroscience, in press.
Volkow et al. American Journal of Psychiatry, 156:19–26, 1999.
Volkow et al. Journal of Neuroscience, 2006.
Heinz, A. et al. Archives of General Psychiatry, 2005; 62:57–64.
Volkow et al. Nature, 386:830–833, 1997.
Volkow et al. Journal of Clinical Investigation, 111(10):1444–1451, 2003.