Blog Series Part 2: Effects of Substance Abuse

Effects of Substance Abuse

Imaging studies have revealed neurochemical and functional changes in the brains of drug-addicted subjects that provide new insights into the mechanisms underlying addiction (Volkow, 2003).  Most studies of drug addiction have concentrated on the brain dopamine system, since this is considered to be the neurotransmitter system through which most drugs exert their reinforcing effects (Koob, 1988). A reinforcer is defined as an event that increases the probability of a subsequent response, and drugs are considered to be much stronger reinforcers than natural reinforcers, like food or sex (Wightman, 2002). The brain’s dopamine system also regulates motivation and drive for everyday activities (Wise, 2002).

Neurochemical studies have shown that large and fast increases in dopamine are associated with the reinforcing effects of the drug and also has shown that after chronic drug abuse and during withdrawal, brain dopamine function is markedly decreased (Volkow, 2003). These decreases are associated with dysfunction of the prefrontal regions of the brain, including the orbitofrontal cortex (Volkow, 2003). The changes in brain dopamine function are likely to result in decreased sensitivity to natural reinforcers since dopamine also mediates the reinforcing effects of natural reinforcers and on the disruption of frontal cortical functions, such as inhibitory control (Hyman, 2001).

Functional imaging studies have also shown that during drug intoxication, or during craving, these frontal regions become activated as part of a complex pattern that includes the nucleus accumbens, the orbitofrontal cortex, the amygdala and hippocampus, and the prefrontal cortex and cingulated gyrus (Nestler, 2001). The nucleus accumbens is the brain circuitry involved in reward, the orbitofrontal cortex is the brain circuitry involved in motivation, the amygdala and hippocampus are involved with memory, and prefrontal cortex and cingulated gyrus are involved with cognitive control (Nestler, 2001).

Thus, in drug addiction, the value of the drug and drug-related stimuli is enhanced at the expense of other reinforcers (Volkow, 2003). During exposure to the drug or drug-related cues, the memory of the expected reward results in overactivation of the reward and motivation circuits while decreasing the activity in the cognitive control circuit (Hyman, 2001). When cues or stimuli occur that are associated with drug seeking, increased activation of projections from the prefrontal cortex occurs, which, in turn, increases the release of glutamate in the core of the nucleus accumbens (Thanos, 2001). This increase in glutamate causes an increase in drug seeking and intake (Thanos, 2001). Such cues or stimuli might include anything previously associated the drug use, a stressor, or even a single dose of the drug.

The release of dopamine in the prefrontal cortex and the amygdale is necessary for the amygdale to recognize cue-associations with drug use which are the motivationally relevant events, and for the prefrontal cortex to exert its effect on the nucleus accumbens which mediates behavior (Volkow, 2002). However, drug use does not allow the prefrontal cortex to restrict the compulsion to seek out stimuli that have cue associations with drug use (Volkow, 2002). This whole process may be the reason for the addiction or loss of control, with the addict continuing to use the drug even though there is no longer pleasure in using it (Volkow, 2002).

The changes that occur after chronic drug use are more permanent than changes that occur during acute drug use and may be a reason why relapse occurs in addicts (Simkin, 2006). Since adolescents may not be able to differentiate between motivationally relevant and irrelevant events, when addiction occurs, the prefrontal cortex may increase the tendency to seek out risky behaviors whether they are relevant or not (Simkin, 2006). Alternatively, addiction may turn the otherwise less sensitive amygdale found in adolescents into a more sensitive adult-like amygdala that seeks out only drug associated relevant events (Simkin, 2006).

Although patients may use substances to self-medicate their manic symptoms, it has been shown that the use of multiple substances may actually exacerbate the neurobiologic effects (Khantzian, 1997). In one study, patients (aged 18-65 years) presented with active marijuana and alcohol use in the manic phase, the marijuana did not decrease the level of the manic state (Salloum, 2005). It was determined that although the sensation of feeling calmer with marijuana may have been experienced by bipolar substance abusers who were manic and using alcohol, the mania symptoms were actually worse in those who presented with bipolar disorder and marijuana and alcohol use than in those  with bipolar disorder and alcohol use alone (Salloum, 2005).

Use of multiple substances may be a sign of a more progressive addiction, which would likely decrease the ability to inhibit compulsive behavior and the level of mania (Salloum, 2005). Furthermore, the type of treatment used may have greater effect on those who are actively using marijuana during their presentation with mania and alcohol (Salloum, 2005). Those who were treated with lithium and psychosocial therapy in this study, as opposed to those treated with one of those therapies alone, had the highest percentage of heavy drinking days (Salloum, 2005). The individuals who used alcohol and marijuana were younger than the other study participants; because alcohol and marijuana are the most frequent substances of abuse in adolescents with bipolar disorder, early onset of bipolar disorder and multiple substance abuse disorders may have a greater neurobiologic effect on the immature brain if the disorders go undetected and untreated (Geller, 1999).

If substance abuse occurs before the development of bipolar disorder, there may be a more rapid onset of mania because there is less ability to control or inhibit symptoms of mania or mood associated with sub-cortical structures because of the effect of addiction on the orbitofrontal cortex (Chang, 2004; Goldstein & Volkow, 2002). If the bipolar disorder occurs before the substance abuse , the effect on the orbitofrontal cortex may strengthen the compulsion to use drugs (Larson, 2005). In addition, the addiction process changes the way the orbitofrontal cortex normally performs by forming different connections; thus, the orbitofrontal cortex may not function as it normally would have before the addiction (Larson, 2005).

The reorganization of these connections may prevent the orbitofrontal cortex from ever fully developing (Simkin, 2006). If normal functioning or maturation of the orbitofrontal cortex does not occur in adolescence, this may lead to less control of symptoms of mania in adulthood (Simkin, 2006). This could explain why early onset of mania has a higher risk for a worse prognosis. Alternatively, if all adolescents must rely more on the less efficient dorsolateral prefrontal cortex for inhibitory control during adolescence, the adolescent with bipolar disorder, who has a less mature dorsolateral prefrontal cortex, may have more difficulty throughout this period of time (Simkin, 2006). Decreases in N-acetylaspartate levels in the dorsolateral prefrontal cortex which is used primarily during adolescence for inhibition, were found in euthymic bipolar patients and manic bipolar patients as compared to healthy adolescent subjects (Simkin, 2006). It is believed that earlier detection and treatment of bipolar disorder and substance abuse disorder, whether presented separately or together, would increase the likelihood that the orbitofrontal cortex would be able to fully mature (Simkin, 2006).


Early detection and treatment of bipolar disorder and substance abuse disorder seems extremely important to normal brain development in adolescents. If the developmental processes  discussed in this paper are accurate, not treating adolescents with bipolar disorder and substance abuse disorder may prevent normal development of the brain and decrease the ability of the adolescent to function at his or her fullest potential upon reaching adulthood as well as avoid permanent neurological damage (Winters, 2008). Similarly, not treating these disorders early may decrease the responsiveness of mature brain to medication interventions (Simkin, 2006). Since neurobiology is still in the early stages, more research is necessary to pinpoint and understand the underlying causes of bipolar disorder and substance abuse disorder in the developing brain (Volkow, 2002). More research is also needed in the area of finding treatments that would allow normal development of the brain to occur despite the onset of psychiatric disorders.

Blog Series Part 1: The Effects of Bipolar Disorder and Substance Abuse Disorder on the Developing Brain

Human Growth and Development


There is a strong association between bipolar disorder and substance abuse disorder.  This phenomenon has been explained in several ways. First, bipolar disorder may be causing substance abuse disorders. Next, substance abuse disorders may be causing bipolar disorder. Finally, both disorders may share common origins. However, the most recent literature states that none of these explanations is completely accurate (Brown, 2005).


Since both of these disorders predominantly have their onset in adolescence, it is important to look at the effects that bipolar disorder and substance abuse disorder have on brain development (Simkin, 2006). It is thought that either or both of these disorders disrupt the normal development of the brain to the extent that the brain never reaches full maturity (Simkin, 2006). As such, the question becomes whether or not the immature brain is more vulnerable to a much worse course of these disorders then if the brain had fully matured (Dahl, 2004). This paper will look at the development of the brain and whether neurobiology of the brain can play a role in predicting risk for future bipolar and substance abuse disorders.


Substance abuse disorders are exceptionally common in bipolar patients (Strakowski & DelBello, 2000). In the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area (ECA) study, substance abuse occurred in over 60% of type I bipolar patients (Regier, 1990). Correspondingly, rates of bipolar disorder are elevated five to eight times in patients with substance abuse disorders (Kessler, 1997; Regier, 1990). Substance abuse in bipolar disorder is clinically important because it is typically associated with poor treatment response and poor clinical outcome (Goodwin & Jamison, 1990; Strakowski, 1998; Tohen, Waternaux, & Tsuang, 1990).


Bipolar disorder is a debilitating psychiatric illness that is uniquely characterized by switching between psychopathologically contrasting phases of mania and depression (Olley, 2005). These phases often have intervening periods of euthymia which are periods of remission (Olley, 2005). However, these periods of apparent clinical recovery (euthymia) are marked by subtle social, occupational, and cognitive impairments (Olley, 2005).


It has been shown that patients with either manic or euthymic bipolar disorder (aged 17 to 45 years), and healthy control subjects, performed virtually the same on tests which measure the spatial working memory involving the dorsolateral prefrontal cortex (Larson, 2005). However, patients with only euthymic bipolar disorder performed poorly on tests which measure inhibitory control involving the orbitofrontal cortex, which is the part of the brain that influences inhibition (Larson, 2005). This finding suggests that patients with bipolar disorder may have a deficit in the orbitofrontal cortex (Larson, 2005).


Inhibitory control may be involved in inhibiting manic symptoms, such as hypersexuality (Simkin, 2008). Inhibitory control also plays a part in substance abuse disorder (Simkin, 2006). Since bipolar disorder and substance abuse disorder may have their onset during adolescence, it is important to explore whether the orbitofrontal cortex deficit occurs as a result of these disorders preventing the brain from normal maturation or whether these disorders cause damage to the orbitofrontal cortex regardless of when they occur (Larson, 2005).


Adolescent Brain Development

In order to understand how brain development may be disrupted by the emergence of bipolar disorder or substance abuse disorder during adolescence, it is necessary to understand the normal development of the brain during this period. While a significant amount of research has emerged on the development of the adolescent brain, some of the findings can be summarized in terms of three important events: (1) pruning neurons; (2) the role of hormones; and (3) maturation of the prefrontal cortex (Chambers, 2003).


Advanced technology in brain imaging has provided windows to the developing brain. Evidence is accumulating that the brain is not fully formed at the end of childhood as earlier thought (Giedd, 2004). The juvenile brain is still maturing in the teenage years and reasoning and judgment are developing well into the early to mid-20s (Giedd, 2004).



During childhood, the brain grows an excessive number of connections between brain cells (Winters, 2008). At about 11 or 12, an adolescent begins to lose or “prune back” a substantial fraction of these connections (Winters, 2008). During pruning, adolescents lose 20% to 40% of their total connections, or neurons (Simkin, 2008). This loss is actually healthy in the long run and is a vital part of growing up because the pruning clears out unneeded wiring to make way for more efficient and faster information-processing as we become adults (Winters, 2008).  It also promotes building the long chains of nerve cells that are required for the more demanding problem-solving in adulthood (Winters, 2008).


However, one of the neurons involved during this pruning period is associated with serotonin (Simkins, 2006). When serotonin neurons are lost, impulsivity increases and may very well be the reason that adolescents are less able to carry on cognitive processes (Simkin, 2006). In a study of adolescent decision-making, it was shown that adolescents, as compared to adults, took significantly longer to decide whether or not a presented scenario was a “good idea” (Baird, 2005). Adults are usually able to quickly elicit mental images of possible outcomes that impact their decision-making processes (Baird, 2005). Adolescents may act impulsively without carefully considering their decision and are far less likely to use mental images when making that choice (Baird, 2005).


This does not mean that adolescents cannot make a rational decision or appreciate the difference between right and wrong (Winters, 2008). The adolescent brain is quite capable of demonstrating mental ability, but the adolescent with less than optimal brain-based mechanisms has the propensity to act impulsively when confronted with stressful or emotional decisions and to ignore the negative consequences of such behavior (Winters, 2008).



Second, when hormones are added to the equation, it is thought that they influence the primary motivational circuitry, which increases sensitivity to pleasurable experiences (Bjork, 2004). The seeking out of pleasurable experiences, many of which may be risky, may be caused not only by an increased sensitivity to these experiences but also by the inability to distinguish which events are motivationally relevant or irrelevant (Bjork, 2004).


The amygdala is the part of the brain that effects memory and establishes learned associations between motivationally relevant events (Kalivas & Volkow, 2005). This inability to anticipate what events are motivationally relevant or irrelevant may be why adolescents seek out risky behaviors more than adults (Kalivas & Volkow, 2005). In a study comparing adolescents to young adults, it was shown that there were no differences in brain activity while performing a task for monetary gain (Bjork, 2004). However, the adolescents had less recruitment of the right amygdala than adults while anticipating response for such gain (Bjork, 2004).


Hormones encourage novelty seeking and promote social competitiveness (Winters, 2008). The massive hormonal production of adolescence may promote drug use to the extent that it represents a novel experience to the adolescent who is also seeking social approval from peers during the experience (Winters, 2008).


Maturation of the prefrontal cortex

Third, brain maturation tends to occur from the back of the brain to the front (Winters, 2008). So the front region of the brain, known as the prefrontal cortex does not become fully mature until around the early to mid-20s (Casey, 1997; Tamm, 2002). This means, of course, that the prefrontal cortex is immature in adolescents. The prefrontal cortex is the part of the brain that enables a person to think clearly, to make good decisions and to control impulses (Winters, 2008). As a result, adolescents will not have proper connections to other parts of the brain that would allow inhibition to occur quickly, especially in emotionally charged situations (Casey, 1997; Tamm, 2002). There is a growing sentiment among experts that when adolescents are feeling intense emotion or intense peer pressure, conditions are optimal for the still-maturing circuitry in the front part of the brain to be overwhelmed, resulting in inexplicable behavior and poor judgment (Winters, 2008).


Another separate process that occurs during adolescence is myelination (Simkin, 2006). This is the change or maturation of certain nerve cells whereby a layer of myelin forms around the axons which allows the nerve impulses to travel faster (Luna & Sweeney, 2004). This can influence the speed with which one processes and the speed with which one inhibits responses (Luna & Sweeney, 2004). The changes in the brain during adolescence occur in order to move from a brain that requires much more energy to process information to a more efficient adult brain (Luna & Sweeney, 2004). These processes can explain why experimentation is more likely to occur in adolescence (Luna & Sweeney, 2004). If adolescents do not have significant interests such as athletics or academics, they may be more likely to engage in risky behaviors if they are having to seek out other pleasurable experiences (Hops, 1999). In fact, academic and social failure by age 7 through 9 can predict substance abuse by age 14 through 15 (Hops, 1999). This suggests that prevention efforts for alcohol and other drugs may be more effective if directed at earlier antecedent behaviors rather than those that are concurrent with substance use (Hops, 1999).


If the adolescent does not succumb to substance abuse, or other psychiatric disorders that may influence normal development, the brain will continue to undergo these changes (Simkin, 2006). In particular, the prefrontal cortex and the corresponding inhibitory response will mature (Simkin, 2006). Therefore, one can assume that if the brain is allowed to develop normally, the mature prefrontal cortex can help to control or inhibit the disease state more effectively if bipolar emerges after adolescence than it could if the disorder emerges earlier (Simkin, 2006).


In a study of adolescents treated for bipolar disorder, scientists found that they had significantly lower levels of a chemical called N-acetylaspartate, which measures the density of neurons in the brain, in the dorsolateral prefrontal cortex (Chang, 2003). N-acetylaspartate acts as a “brake control” during adolescence and reduced levels of this chemical may mean reduced effectiveness of bipolar disorder patients to inhibit mania (Chang, 2003). This and other studies also found that there was no significant difference in N-acetylaspartate levels in patients with early onset bipolar disorder and in healthy control subjects (Chang, 2003; Gallelli, 2005). Therefore, these studies indicate that the longer the bipolar disorder progresses, the greater the effect on the dorsolateral prefrontal cortex (Chang, 2003; Gallelli, 2005).


Stay tuned for the conclusion – Part 2: Effects of Substance Abuse.