Anecdotes such as these are common in the drug abuse treatment
community. These anecdotes plus animal studies on this subject point
toward an important role for stress in drug abuse relapse. In addition,
the fact that addicts often relapse apparently in response to what most
people would consider mild stressors suggests that addicts may be more
sensitive than nonaddicts to stress.
This hypersensitivity may exist before drug abusers start taking
drugs and may contribute to their initial drug use, or it could result
from the effects of chronic drug abuse on the brain, or its existence
could be due to a combination of both, Dr. Kreek has proposed. She has
demonstrated that the nervous system of an addict is hypersensitive to
chemically induced stress, which suggests that the nervous system also
may be hypersensitive to emotional stress.
the Body Copes With Stress
The body reacts to stress by secreting two types of chemical
messengers - hormones in the blood and neurotransmitters in the brain.
Scientists think that some of the neurotransmitters may be the same or
similar chemicals as the hormones but acting in a different capacity.
Some of the hormones travel throughout the body, altering the
metabolism of food so that the brain and muscles have sufficient stores
of metabolic fuel for activities, such as fighting or fleeing, that help
the person cope with the source of the stress. In the brain, the
neurotransmitters trigger emotions, such as aggression or anxiety, that
prompt the person to undertake those activities.
Normally, stress hormones are released in small amounts throughout
the day, but when the body is under stress the level of these hormones
increases dramatically. The release of stress hormones begins in the
brain. First, a hormone called corticotropin-releasing factor (CRF) is
released from the brain into the blood, which carries the CRF to the
pituitary gland, located directly underneath the brain. There, CRF
stimulates the release of another hormone, adrenocorticotropin (ACTH),
which, in turn, triggers the release of other hormones - principally
cortisol - from the adrenal glands. Cortisol travels throughout the
body, helping it to cope with stress. If the stressor is mild, when the
cortisol reaches the brain and pituitary gland it inhibits the further
release of CRF and ACTH, which return to their normal levels. But if the
stressor is intense, signals in the brain for more CRF release outweigh
the inhibitory signal from cortisol, and the stress hormone cycle
Researchers speculate that CRF and ACTH may be among the chemicals
that serve dual purposes as hormones and neurotransmitters. The
researchers posit that if, indeed, these chemicals also act as
neurotransmitters, they may be involved in producing the emotional
responses to stress.
The stress hormone cycle is controlled by a number of stimulatory
chemicals in addition to CRF and ACTH and inhibitory chemicals in
addition to cortisol both in the brain and in the blood. Among the
chemicals that inhibit the cycle are neurotransmitters called opioid
peptides, which are chemically similar to opiate drugs such as heroin
and morphine. Dr. Kreek has found evidence that opioid peptides also may
inhibit the release of CRF and other stress-related neurotransmitters in
the brain, thereby inhibiting stressful emotions.
Addiction Changes the Body's Response to Stress
Heroin and morphine inhibit the stress hormone cycle and presumably
the release of stress-related neurotransmitters just as the natural
opioid peptides do. Thus, when people take heroin or morphine, the drugs
add to the inhibition already being provided by the opioid peptides.
This may be a major reason that some people start taking heroin or
morphine in the first place, suggests Dr. Kreek. "Every one of us
has things in life that really bother us," she says. "Most
people are able to cope with these hassles, but some people find it very
difficult to do so. In trying opiate drugs for the first time, some
people who have difficulty coping with stressful emotions might find
that these drugs blunt those emotions, an effect that they might find
rewarding. This could be a major factor in their continued use of these
When the effects of opiate drugs wear off, the addict goes into
withdrawal. Research has shown that, during withdrawal, the level of
stress hormones rises in the blood and stress-related neurotransmitters
are released in the brain. These chemicals trigger emotions that the
addict perceives as highly unpleasant, which drive the addict to take
more opiate drugs. Because the effects of heroin or morphine last only 4
to 6 hours, opiate addicts often experience withdrawal three or four
times a day. This constant switching on and off of the stress systems of
the body heightens whatever hypersensitivity these systems may have had
before the person started taking drugs, Dr. Kreek says. "The result
is that these stress chemicals are on a sort of hair-trigger release.
They surge at the slightest provocation," she says.
Studies have suggested that cocaine similarly heightens the body's
sensitivity to stress, although in a different way. When a cocaine
addict takes cocaine, the stress systems are activated, much like when
an opiate addict goes into withdrawal, but the person perceives this as
part of the cocaine rush because cocaine is also stimulating the parts
of the brain that are involved in feeling pleasure. When cocaine's
effects wear off and the addict goes into withdrawal, the stress systems
are again activated - again, much like when an opiate addict goes into
withdrawal. This time, the cocaine addict perceives the activation as
unpleasant because the cocaine is no longer stimulating the pleasure
circuits in the brain. Because cocaine switches on the stress systems
both when it is active and during withdrawal, these systems rapidly
become hypersensitive, Dr. Kreek theorizes.
for the Link Between Stress and Addiction
This theory about stress and drug addiction is derived in part from
studies conducted by Dr. Kreek's group in which addicts were given a
test agent called metyrapone. This chemical blocks the production of
cortisol in the adrenal glands, which lowers the level of cortisol in
the blood. As a result, cortisol is no longer inhibiting the release of
CRF from the brain and ACTH from the pituitary. The brain and pituitary
then start producing more of these chemicals.
Physicians use metyrapone to test whether a person's stress system is
operating normally. When metyrapone is given to nonaddicted people, the
ACTH level in the blood increases. However, when Dr. Kreek and her
colleagues administered metyrapone to active heroin addicts, the ACTH
level hardly rose at all. When the scientists gave metyrapone to heroin
addicts who were abstaining from heroin use and who were not taking
methadone, the synthetic opioid medication that suppresses cravings for
opiate drugs, the ACTH level in the majority of the addicts increased
about twice as high as in nonaddicts. Finally, when the scientists gave
metyrapone to heroin addicts maintained for at least 3 months on
methadone, the ACTH level rose the same as in nonaddicts.
Addicts on heroin underreact because all the excess opioid molecules
in the brain greatly inhibit the brain's stress system, Dr. Kreek
explains. Addicts who are heroin-free and methadone-free overreact
because the constant on-off of daily heroin use has made the stress
system hypersensitive, she says, and heroin addicts who are on methadone
react normally because methadone stabilizes this stress system.
Methadone acts at the same sites in the brain as heroin, but methadone
stays active for about 24 hours while the effects of heroin are felt for
only 4 to 6 hours. Because methadone is long-acting, the heroin addict
is no longer going into withdrawal three or four times a day. Without
the constant activation involved in these withdrawals, the brain's
stress system normalizes.
Recently, Dr. Kreek's group reported that a majority of cocaine
addicts who are abstaining from cocaine use overreact in the metyrapone
test, just like the heroin addicts who are abstaining from heroin and
not taking methadone. As with heroin addicts, this overreaction in
cocaine addicts reflects hypersensitivity of the stress system caused by
chronic cocaine abuse.
"We think that addicts may react to emotional stress in the same
way that their stress hormone system reacts to the metyrapone
test," says Dr. Kreek. At the slightest provocation, CRF and other
stress-related neurotransmitters pour out into the brain, producing
unpleasant emotions that make the addict want to take drugs again, she
suggests. Since life is filled with little provocations, addicts in
withdrawal are constantly having their stress system activated, she
Kreek, M.J., and Koob,
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