Volume 12, Number 2
Rate and Duration of Drug Activity Play Major
Roles in Drug Abuse, Addiction, and Treatment
By Robert Mathias, NIDA NOTES Staff Writer
When smoked or taken intravenously, cocaine produces a fast, intense
high that dissipates quickly, creating a powerful need to take the drug
again. In this regard, cocaine provides a perfect illustration of the critical
role that a compound's rate and duration of action play in drug abuse and
Rate of Action
The rate at which a psycho-active drug occupies, or binds to, the brain
sites called receptors for that drug determines the intensity of its rewarding
effects and its abuse liability, according to a hypothesis discussed at
several scientific forums by Drs. George Uhl and David Gorelick of NIDA's
Division of Intramural Research (DIR) in Baltimore and Dr. Mary Jeanne Kreek
of the Rockefeller University in New York. The faster a drug such as heroin
or cocaine occupies enough brain receptors to produce a psychoactive effect,
the greater the euphoria users experience, the more they "like"
the drug, and the more liable they are to abuse it, according to this "rate
Why Does Rate of Action Affect
What makes a faster-acting psychoactive drug produce more euphoria
than a slower-acting one?
"The brain has many adaptive mechanisms, and if you disturb the
brain slowly, it often can catch up or compensate," explains Dr. George
Uhl, who directs the Molecular Neurobiology Branch of NIDA's Division of
Intramural Research in Baltimore. "But, if you do things rapidly, often
it can't." For example, going suddenly from a dark room into bright
sunlight will result in a temporary loss of vision because the light sensitivity
mechanisms of the eye and the brain cannot adapt that quickly, he says.
But, if you proceed from dark to light slowly by stages, the mechanism works
in a fairly automatic way, and you are able to see normally.
"If a drug acts slowly, the brain is able to compensate for the
changes that the drug produces," says Dr. Uhl. However, when a drug's
onset of action is very rapid, it may be able to overwhelm the brain's adaptive
mechanisms, thus producing a bigger boost in its pleasure circuits, he says.
Smoked and intravenous cocaine, for example, have fast rates of action.
They reach the brain within seconds and rapidly flood the brain's "pleasure
pathway" with excess dopamine, a brain chemical that helps transmit
pleasurable feelings. If the brain's adaptive mechanisms cannot respond
quickly enough to the sudden excess of dopamine, the euphoric rush ensues.
Conversely, the slower rate at which heroin treatment medications such
as methadone and LAAM (l-alpha-acetyl-methadol) occupy the same receptors
targeted by heroin may be a critical factor in their effectiveness in treating
heroin addiction and their low abuse liability, according to these scientists.
The fact that these slow-onset medications can be used to treat heroin,
which has a fast rate of action, suggests that a compound that slowly occupies
a sufficient number of the brain receptors targeted by cocaine might serve
similarly and be effective in the treatment of cocaine addiction, the researchers
The faster a drug such as heroin or cocaine
occupies enough brain receptors to produce
a psychoactive effect, the greater the euphoria
users experience, the more they "like" the drug,
and the more liable they are to abuse it.
"The rapid rate at which brain receptors are occupied may play an
underrecognized role in determining the euphoric effects of cocaine and
heroin. The slower rate of occupancy of heroin-treatment medications may
play an under-appreciated role in their effectiveness in treating heroin
addiction," says Dr. Uhl. Increasing evidence from various sources
indicates that this concept offers "a promising, theory-based approach
to developing a cocaine treatment medication," he says.
Method of Drug Administration Affect Rate of Action
The method of administering a drug can play a major
role in the drug's rate of action, which in turn affects its abuse liability
or potential as a treatment medication. Smoked drugs that are delivered
through a "crack" pipe or a cigarette and injected drugs that
are administered through a hyperdermic needle reach the brain very rapidly.
This rapid action is an important factor in the strong effect and high abuse
liability of such drugs. Drug abuse treatment medications, shown here in
purple, are often administered orally or through a patch affixed to the
skin and take longer to reach the brain. This slower rate of action is an
important factor in the milder effect and low abuse liability of treatment
Alhough there is clinical evidence that fast-acting drugs can have more
of a euphoric effect than slow-acting drugs have, "careful pharmacological
studies demonstrating that different rates of cocaine and heroin administration
produce different effects have been sparse," Dr. Uhl says. However,
recent research is now providing additional support for the rate hypothesis,
Smoked and intravenous cocaine act faster
and produce greater euphoria than snorted
cocaine, which in turn, acts faster and
generates more euphoria than oral cocaine.
This research includes DIR animal studies that indicate that rapid infusion
of cocaine and heroin produces greater reward than slower infusion does.
In addition, DIR studies examining the effects of different methods of administering
cocaine indicate that smoked and intravenous cocaine act faster and produce
greater euphoria than snorted cocaine, which, in turn, acts faster and generates
more euphoria than oral cocaine.
The link between the effect of a drug and its rate of receptor occupancy
also has been buttressed in recent years by the cloning of the gene for
the mu opiate receptor, the principal site in the brain where heroin works
to produce its rewarding effects. Using the cloned mu opiate receptor, NIDA
researchers have determined that opiate treatment medications such as methadone
and LAAM work through the same receptor that heroin works through to produce
euphoria. Previously, some researchers had suggested that because these
medications produce effects that are so different from heroin's effects,
they might work through different receptors than heroin does, says Dr. Uhl.
Now, it appears that the dramatic difference in effects produced by the
abused substance and its treatment medication stems from the fact that heroin
occupies the receptors within seconds and produces a brief, intense "rush,"
whereas methadone occupies the same receptors much more slowly, producing
only a very modest rewarding effect, he says.
While the fast rate at which cocaine acts on
the brain plays a major role in its rewarding
effects, it is cocaine's extremely rapid removal
from the brain that both promotes and enables
its frequent reuse and abuse.
Duration of Action
Duration of action, or how long the drug occupies a receptor once it
gets there, also plays an important role in drug abuse and treatment. For
example, cocaine has both a fast rate of action that produces euphoria and
a rapid offset, or short duration of action, that allows frequent abuse.
Compounds with these traits may foster craving for more drug and stronger
conditioning of the drug-taking habit, according to a hypothesis proposed
by Dr. Nora Volkow of Brookhaven National Laboratory in Upton, New York.
Brain imaging studies conducted by Dr. Volkow indicate that while the fast
rate at which cocaine acts on the brain plays a major role in its rewarding
effects, it is cocaine's extremely rapid removal from the brain that both
promotes and enables its frequent reuse and abuse.
Conversely, a long, sustained duration of action is important in determining
the potential usefulness of a treatment compound, says Dr. Kreek. First,
longer-lasting medications such as methadone are more practical because
they can be given every 24 hours, whereas shorter-lasting medications require
more frequent doses. Second, because their effects dissipate slowly, long-duration
medications appear to be particularly useful in normalizing physiological
functions such as regulation of hormonal activity and behaviors that have
been disrupted by the rapid "on-off" effects produced by abused
drugs, she says.
Clinical experience with both methadone and LAAM indicates that these
medications have a much lower abuse potential than heroin has, Dr. Kreek
says. They prevent withdrawal symptoms and reduce craving, thereby decreasing
or eliminating heroin abuse. And they stabilize patients physiologically
and psychologically, she points out. Once patients taking methadone have
been stabilized at a therapeutically appropriate dose, "their behavior
is essentially no different from that of any other healthy human being,
and they are able to get an education or a job and improve their family
relationships," she says.
Developing a Cocaine Treatment Medication
Several rate-based approaches to developing a potential cocaine treatment
medication are possible, says Dr. Frank Vocci, acting director of NIDA's
Medications Development Division. One approach is to search for compounds
with a slower onset of action than cocaine that produce less euphoria and
have a longer duration of action. Another is to design very slow onset compounds
that would probably produce only subtle effects. To determine their treatment
potential, compounds "that meet these parameters would need to be tested
to see if they could block cocaine's effects and/or reduce chronic craving
while they were active, Dr. Vocci says.
"We're starting to see some compounds now in our cocaine medication
discovery program that have very slow onsets, days as opposed to minutes
or hours, to reach peak levels," Dr. Vocci says.
Some of these compounds may enter the brain very slowly, but once they
are there, they may hang onto the receptors for a long time. Others may
be compounds that are slowly activated and gradually accumulate on brain
receptors, he says. It is also possible to modulate a compound's onset of
action pharmaceutically by manipulating its rate of absorption by the body
with transdermal patches or controlled-release forms of administration,
Dr. Vocci points out.
How Does Method of Administration Influence
Rate of Action?
Many complex factors affect a compound's rate of action in the
human body. These factors include the compound's structure and properties,
how quickly the body absorbs it and transports it to the brain, and how
rapidly it crosses the blood-brain barrier and binds to a sufficient number
of targeted brain sites called receptors to produce its effects. Because
the method of administering a drug affects a number of these factors, it
can play a major role in the drug's rate of action and abuse liability.
By using different methods of administering a compound, scientists can
slow its rate of action and produce milder effects that may substitute for
the stronger effects of an abused substance. Such a compound may be an effective
medication for patients in treatment.
The effect that method of administration has on rate of action may be
best illustrated by the transdermal nicotine patch, which uses the abused
substance itself-nicotine-to ease withdrawal symptoms and aid smoking cessation.
However, unlike smoking a cigarette, which delivers an almost instantaneous
burst of nicotine-laden blood to the brain, administering nicotine through
a patch affixed to the skin slows its rate of action and produces more sustained,
lower peak levels of nicotine in the blood. This lower, slower dose of nicotine
has proven to be effective in short-term treatment of nicotine dependence
and aiding smoking cessation.
To increase the potential usefulness of rate-based approaches in the
development of a cocaine treatment medication, DIR and extramural researchers
are attempting to answer basic questions about the rate at which cocaine
brain receptor sites need to be occupied and the degree of occupancy that
is required to either produce or block cocaine's rewarding effects, Dr.
Gorelick says. "At this point, we don't really know the minimum level
of receptor occupancy we need to block cocaine's euphoria, but that information
should come from ongoing studies," he says.
"We're starting to see some compounds
now in our cocaine medication discovery
program that have very slow onsets, days
as opposed to minutes or hours, to reach
Once scientists have that information in hand, they can attempt to develop
a compound that achieves the precise rate of action and degree of receptor
occupancy that is needed to produce a milder effect and longer duration
of action than cocaine. Such a compound, the rate hypothesis suggests, should
be effective in reducing cocaine-seeking behavior and normalizing physiological
functions that are disrupted by long-term cocaine abuse.
Gorelick, D.A. The rate hypothesis and agonist substitution approaches
to cocaine abuse treatment. In: Goldstein, D., ed. Catecholamines: Bridging
Basic Science with Clinical Medicine (Advances in Pharmacology: 42).
San Diego, CA: Academic Press,in press.
Kreek, M.J. Opiates, opioids and addiction. Molecular Psychiatry
Uhl, G.R.; Kreek, M.J.; and Gorelick, D.A. Rates of Dopamine Transporter
and Mu Opiate Receptor Occupancies, Cocaine and Heroin Reward, and Therapeutic
Opportunities. Presented at Grand Rounds at the National Institutes of Health
Clinical Center, Bethesda, MD, 1995.
Volkow, N.D.; Ding, Y.-S.; Fowler, J.S.; and Wang, G.-J. Cocaine addiction:
Hypothesis derived from imaging studies with PET. Journal of Addictive
Diseases 15:55-71, 1996.
From NIDA NOTES, March/April 1997
Home Page][NIDA NOTES Index][1997 Archive Index Index]