SUBSTANCE USE DISORDERS

GENETICS

For centuries, it has been common knowledge that “alcoholism runs in families”
leading clinicians and persons with Substance use disorders to believe that
addiction is genetically based. Indeed, family, twin, and adoption studies show that
Substance use disorders has high hereditability and that genes play a role in one’s
risk for developing addictions (Pihl & Stewart, 2013). Studies estimate that 40% to
60% of an individual’s vulnerability to addiction is due to genetic factors.

Family Studies

Family studies of individuals with alcohol use disorders have found that both their
male siblings and their female siblings had increased risk of also developing an
alcohol use disorder. Sometimes that risk is as high as 50% increase! First degree
relatives of individuals with a SUD (including cocaine, marijuana, opioids or
alcohol) can carry as high as an 8-fold risk of developing a SUD. Nicotine
addiction has also been shown to be more prevalent in family members than in the
general population.

Twin Studies

Some research with human twins has suggested that people may inherit a
predisposition to abuse substances. One classic study found an alcohol abuse
concordance rate of 54 percent in a group of identical twins; that is, if one identical
twin abused alcohol, the other twin also abused alcohol in 54 percent of the cases.
In contrast, a group of fraternal twins had a concordance rate of only 28 percent
(Kaij, 1960). Other studies have found similar twin patterns (Legrand et al., 2005;
Tsuang et al., 2001).

Adoption Studies

A clearer indication that genetics may play a role in substance abuse and
dependence comes from studies of alcoholism rates in people adopted shortly after
birth (Walters, 2002; Cadoret et al., 1995; Goldstein, 1994). These studies have
compared adoptees whose biological parents are dependent on alcohol with
adoptees whose biological parents are not. By adulthood, the individuals whose
biological parents are dependent on alcohol typically show higher rates of alcohol
abuse than those with nonalcoholic biological parents.

Linkage Studies

Genetic linkage strategies and molecular biology techniques provide more direct
evidence in support of a genetic explanation (Gelernter & Kranzler, 2008). One
line of investigation has found an abnormal form of dopamine-2 (D2) receptor
gene in a majority of research participants with alcohol, opioid, nicotine, or
cocaine dependence but in less than 20 percent of nondependent participants
(Cosgrove, 2010; Blum et al., 1996, 1990). Other studies have tied still other genes
to substance-related disorders (Gelernter & Kransler, 2008; Kreek, 2008).

NEUROANATOMY

Limbic System

The limbic system helps regulate basic drives, emotions, arousal and attentiveness.
As such, it helps coordinate the neurobiological experience of stress and the reward
system triggered by exposure to drugs. The amygdala along with
the hippocampus are two important components of the limbic system with regards
to substance misuse. The basal ganglia are a group of structures located deep
within the brain that play an important role in keeping body movements smooth
and coordinated, as well as learning routine behaviours and habit formation. Two
important sub-regions of the basal ganglia with regards to SUDs are the nucleus
accumbens, involved in motivation and the experience of reward, and the dorsal
striatum, involved in forming habits and other routine behaviors.
Amygdala

The amygdala plays a central role in emotional responses to internal and external
stimuli, including pleasure, fear, anxiety, and anger included. It is central to
survival as it manages the ‘fight or flight’ response to perceived threats in the
environment, implicated in the body’s stress response. The amygdala is also
responsible for the emotional content of our memories, determining experiences
related to pain and pleasure become encoded into memory, as well as the
emotional values attached to the formation of new memories. This area is
influenced by the action of a variety of classes of substances, and is also a target of
medications like anxiolytics(that mayata risk of misuse).
The withdrawal and negative affect stage of addiction involves a decrease in the
function of the brain reward systems and an activation of stress neurotransmitters,
such as corticotropin-releasing factor (CRF) and dynorphin, in the extended
amygdala. Together, these phenomena provide a powerful neurochemical basis for
the negative emotional state associated with withdrawal. The drive to alleviate
these negative feelings negatively reinforces alcohol or drug use and drives
compulsive substance taking.

Hippocampus

The hippocampus is involved in memory, as well, particularly memories related to

traumatic events and learned responses to environmental cues. This becomes an
important factor in the experience of cravings triggered by environmental cues, as
well as the relationship between trauma and substance misuse, including SUDs.

Nucleus Accumbens

The nucleus accumbens is part of what is called the mesolimbic dopamine system
—it is highly involved in positive reinforcement, leading to a person anticipating
reward with repetition of the previously positively reinforced behavior. Thus, if a
substance increases the release of dopamine in this area, the person comes to
anticipate positive reinforcement again with future use. The amount of dopamine
increase can far exceed what natural behaviors trigger (eating or sex, for example)
and the amount of dopamine directly relates to the degree of pleasure experienced
(Volkow et al., 2010). Thus, a person may come to preferentially engage in
substance use over naturally rewarding behaviors (like eating or sex).All addictive
substances produce feelings of pleasure. These “rewarding effects” positively
reinforce their use and increase the likelihood of repeated use. The rewarding
effects of substances involve activity in the nucleus accumbens, including
activation of the brain's dopamine and opioid signaling system. Many studies have
shown that neurons that release dopamine are activated, either directly or
indirectly, by all addictive substances, but particularly by stimulants such as
cocaine, amphetamines, and nicotine. Activation of the opioid system by these
substances stimulates the nucleus accumbens directly or indirectly through the
dopamine system. Brain imaging studies in humans show activation of dopamine
and opioid neurotransmitters during alcohol and other substance use (including
nicotine).Cannabinoids such as delta-9-tetrahydrocannabinol (THC), the primary
psychoactive component of marijuana, target the brain's internal or endogenous
cannabinoid system. This system also contributes to reward by affecting the
function of dopamine neurons and the release of dopamine in the nucleus
accumbens.

A person learns to associate the stimuli present while using a substance—including

people, places, drug paraphernalia, and even internal states, such as mood—with
the substance's rewarding effects. Over time, these stimuli can activate the
dopamine system on their own and trigger powerful urges to take the substance.
These “wanting” urges are called incentive salience and they can persist even after
the rewarding effects of the substance have diminished. As a result, exposure to
people, places, or things previously associated with substance use can serve as
“triggers” or cues that promote substance seeking and taking, even in people who
are in recovery.

Dorsal Striatum

As alcohol or substance use progresses, repeated activation of the “habit circuitry”

of the basal ganglia (i.e., the dorsal striatum) contributes to the compulsive
substance seeking and taking that are associated with addiction. Density of
dopamine receptors in striatum is significantly reduced with substance use, and the
following image represents this based on fMRI studies (where areas in red
represent the density of dopamine receptors). Low dopamine receptor density in
this region was associated with loss of control.
Prefrontal Cortex

The prefrontal cortex is linked to the amygdala, though it directly leads the higher
order brain functions, like cognition, comprehension, concentration, reasoning,
planning, and initiating goal-directed behavior takes place. The area is responsible
for a person’s intentional responses to the experiences the amygdala sends forward.
For example, the conscious decision to initially engage in substance use. This part
of the brain is also highly susceptible to alteration, even damage, from exposure to
many substances, reducing its capacity to mediate responses triggered by the
amygdala (Begun & Brown, 2014). As a result, a person might be less able to
dampen the amygdala’s push to action, acting more impulsively than
thoughtfully/intentionally, especially in terms of relapse responses. The paradox is
that the very area responsible for helping someone control substance misuse is an
area impaired by the behaviour in question.

NEUROCHEMICAL THEORY

Receptor and Receptor Systems

With the exception of alcohol, researchers have identified particular

neurotransmitters or neurotransmitter receptors involved with most substances of
abuse. The opioids, for example, act on opioid receptors. A person with too little
endogenous opioid activity (e.g., low concentrations of endorphins) or with too
much activity of an endogenous opioid antagonist may be at risk for developing
opioid dependence. Even in a person with completely normal endogenous receptor
function and neurotransmitter concentration, the long-term use of a particular
substance of abuse may eventually modulate receptor systems in the brain so that
the presence of the exogenous substance is needed to maintain homeostasis. Such a
receptor-level process may be the mechanism for developing tolerance within the
CNS.

Pathways and Neurotransmitters

The major neurotransmitters possibly involved in developing substance abuse and
substance dependence are the opioid, catecholamine (particularly dopamine), and
gamma-aminobutyric acid (GABA) systems. The dopaminergic neurons in the
ventral tegmental area are particularly important. These neurons project to the
cortical and limbic regions, especially the nucleus accumbens. This pathway is
probably involved in the sensation of reward and may be the major mediator of the
effects of such substances as amphetamine and cocaine. The locus ceruleus, the
largest group of adrenergic neurons, probably mediates the effects of the opiates
and the opioids. These pathways have collectively been called the brain-reward
circuitry.

Opioids

Opioids attach to opioid receptors in the brain, which leads to a release of

dopamine in the nucleus accumbens, causing euphoria (the high), drowsiness, and
slowed breathing, as well as reduced pain signalling (which is why they are
frequently prescribed as pain relievers). Opioid addiction typically involves a
pattern of:

 intense intoxication,
 the development of tolerance,
 escalation in use, and
 withdrawal signs that include profound negative emotions and physical
symptoms, such as bodily discomfort, pain, sweating, and intestinal distress
and, in the most severe cases, seizures.

As use progresses, the opioid must be taken to avoid the severe negative effects
that occur during withdrawal. With repeated exposure to opioids, stimuli
associated with the pleasant effects of the substances (e.g., places, persons, moods,
and paraphernalia) and with the negative mental and physical effects of withdrawal
can trigger intense craving or preoccupation with use.

Alcohol

When alcohol is consumed it interacts with several neurotransmitter systems in the

brain, including the inhibitory neurotransmitter GABA, glutamate, and others that
produce euphoria as well as the sedating, motor impairing, and anxiety-reducing
effects of alcohol intoxication. Alcohol addiction often involves a similar pattern
as opioid addiction, often characterized by periods of binge or heavy drinking
followed by withdrawal. As with opioids, addiction to alcohol is characterized by
intense craving that is often driven by negative emotional states, positive emotional
states, and stimuli that have been associated with drinking, as well as a severe
emotional and physical withdrawal syndrome. Many people with severe alcohol
use disorder engage in patterns of binge drinking followed by withdrawal for
extended periods of time. Extreme patterns of use may evolve into an opioid-like
use pattern in which alcohol must be available at all times to avoid the negative
consequences of withdrawal.

Stimulants

Stimulants increase the amount of dopamine in the reward circuit (causing the
euphoric high) either by directly stimulating the release of dopamine or by
temporarily inhibiting the removal of dopamine from synapses. These drugs also
boost dopamine levels in brain regions responsible for attention and focus on tasks
(which is why stimulants like methylphenidate [Ritalin] or dextroamphetamine
[Adderall] are often prescribed for people with attention deficit hyperactivity
disorder). Stimulants also cause the release of norepinephrine, a neurotransmitter
that affects autonomic functions like heart rate, causing a user to feel energized.
Addiction to stimulants, such as cocaine and amphetamines (including
methamphetamine), typically follows a pattern that emphasizes the
binge/intoxication stage. A person will take the stimulant repeatedly during a
concentrated period of time lasting for hours or days (these episodes are called
binges). The binge is often followed by a crash, characterized by negative
emotions, fatigue, and inactivity. Intense craving then follows, which is driven by
environmental cues associated with the availability of the substance, as well as by
a person's internal state, such as their emotions or mood.

Marijuana (Cannabis)
Like other drugs, marijuana (also called cannabis) leads to increased dopamine in
the basal ganglia, producing the pleasurable high. It also interacts with a wide
variety of other systems and circuits in the brain that contain receptors for the
body's natural cannabinoid neurotransmitters. Effects can be different from user to
user, but often include distortions in motor coordination and time perception.
Cannabis addiction follows a pattern similar to opioids. This pattern involves a
significant binge/intoxication stage characterized by episodes of using the
substance to the point of intoxication. Over time, individuals begin to use the
substance throughout the day and show chronic intoxication during waking hours.
Withdrawal is characterized by negative emotions, irritability, and sleep
disturbances. Although the craving associated with cannabis has been less studied
than for other substances, it is most likely linked to both environmental and
internal states, similar to those of other addictive substances.

Synthetic Drugs
Different classes of chemically synthesized (hence the term synthetic) drugs have
been developed, each used in different ways and having different effects in the
brain. Synthetic cathinones, more commonly known as “bath salts,” target the
release of dopamine in a similar manner as the stimulant drugs described above. To
a lesser extent, they also activate the serotonin neurotransmitter system, which can
affect perception. Synthetic cannabinoids, somewhat mimic the effects of
marijuana but are often much more powerful. Drugs such as MDMA (ecstasy) and
lysergic acid diethylamide (LSD) also act on the serotonin neurotransmitter system
to produce changes in perception. Fentanyl is a synthetic opioid medication that is
used for severe pain management and is considerably more potent than heroin.
Prescription fentanyl, as well as illicitly manufactured fentanyl and related
synthetic opioids, are often mixed with heroin but are also increasingly used alone
or sold on the street as counterfeit pills made to look like prescription opioids or
sedatives.