The Phenomenon of Drug Craving

Jeffrey L. Fortuna, Dr.RH.* & David A. Smelson, Psy.D.**

Abstract—The phenomenology of drug craving has become the focus of much research within addictive
disorders because of the belief that desire plays a role in maintaining the addiction. Many of the studies
have focused on the activation of neural pathways, particularly within the dopamine system in response
to specific events or stimuli. While many of these studies have focused on a particular drug of choice,
little has been done across addictive disorders. This article will present and review phenomena that
induce drug craving, as well as delineate precise neural pathways which are activated during craving
and specific neurobiological markers which are associated with an increased risk for drug craving and
other forms of addictive behavior.

Keywords—amygdala, anterior cingulate, blue cone, cue-induced, dopamine-2, electroretinogram

A significant number of studies have investigated the
phenomenon of drug craving, specifically which events
trigger drug craving and what neural pathways are activated
when craving occurs. One deduction that can be made from
the many studies that have investigated drug craving is that
there is a range in the intensity of craving from individual
to individual. For example, craving has been described as
everything from an intense desire (Vblkow, Fowler & Wang
2003) to use a drug, to an undeniable compulsion to obtain
and use the drug. The range in intensity can be assessed us-
ing psychological scales, such as a Likert scale or a visual
analog scale. In addition to the psychological assessment of
craving, the physiologic and neural intensity can be evaluated
through a variety of brain imaging techniques (fMRI and
PET scans).
•Faculty, Department of Health Science, California State University,
FuUerton, CA.
••Department of Psychiatry, University of Massachusetts Medical
School, Worcester MA and the Edith Norse VE Medical Center, Bedford, MA.
Please address correspondence and reprint requests to Jeffrey L.
Fortuna, Dr.P.H., Department of Health Science, California State University,
Fullerton, 800 N. State College Blvd., Fullerton, CA 92634.
One element that clearly underlies drug craving regard-
less of the drug involved is memory—that is, the recollection
of pleasurable effects following the use ofthat drug. In actu-
ality it may not be the delivery of pleasure, but the ephemeral
decrease in psychological pain that is associated with the
intoxicated state. This would include a decrease in negative
feeling states (anger, anxiety, sadness), disengagement from
reality, and the production of mental dullness. It goes back
to the two primary themes that may underlie chronic drug
use: an increase in pleasure and/or a decrease in pain.
The memory and emotional elements of craving appear
to exist between the amygdala and the hippocampus as
well as the orbitofrontal cortex. In addition to intensity and
memory the other element of craving is compulsion and/or
motivation (Rolls 2000; Tucker, Luu & Pribram 1995; Insel
1992). That is, that the individual is planning to do some-
thing to obtain and use the drug. This mental state may be
more compulsive than contemplative in nature. Either the
compulsive or contemplative planning would involve the
frontal cortex and anterior cingulate.

Journal of Psychoactive Drugs 255 Volume 40 (3), September 2008

Fortuna & Smelson
THE PHENOMENA THAT ELICIT CRAVING
Odor/Olfactory Inspiration
It may seem obvious that the smell or odor of a particular
drug may elicit drug craving. Nonetheless, until recently the
effect of odor or smell on drug craving was not formally as-
sessed. Moreover, some drugs have a powerful aroma (beer,
marijuana, tobacco), whereas many other drugs have either
no odor or no perceptible odor.
The majority of odor-induced craving studies have fo-
cused on alcohol. One of thefirststudies used to examine this
effect used single photon emission computed tomography
(SPECT) technology, and found that the odor of alcohol
increased cerebral blood flow to the right caudate nucleus
in all subjects (Modell & Mountz 1995). More recently,
Schneider and colleagues (2001) found that just a two second
olfactory exposure to alcohol produced significant activa-
tion in the right amygdala and hippocampus as well as in
the cerebellum, as shown by fMRI. This activation was no
longer present following treatment with doxepin and group
therapy (Schneider et al. 2001).
The odor-induced activation in the right amygdala was
strikingly similar to the video-induced activation in recov-
ering cocaine-dependent patients seen in previous research
(Childress et al. 1999). Activation of the amygdala may be
a common neurophysiologic marker of craving, regardless
of the drug involved ( Goldstein & Volkow 2002; Brown
& Fibiger 1993). This may also hold true for other types of
addictive behavior. For example using fMRI technology.
Breiter and colleagues (2001) have reported subcortical
limbic activation in individuals who participated in a live
gambling game similar to roulette, involving monetary re-
wards or losses. Subjects could earn up to $10.00 for every
"good" spin of the wheel. Not surprisingly, those who won
the most money showed the greatest limbic activation.
With respect to odor elicited changes, Cooney and col-
leagues (2004) found that alcohol odor increased salivation
as well as heart rate in recovering alcoholics. Other research
has noted that this effect is more prominent from beer, which
is highly aromatic when compared to vodka (with a lower
potency odor; Stormark et al. 1995). Previous investigations
have noted a greater odor-induced craving among alcoholic
subjects, when compared with control subjects (Wrase et al.
2002; Wiesbeck, Weijers & Gross 2000).
Videotapes/Visual Stimulation
In one study, recovering cocaine dependent subjects
were shown a 25-minute video of the purchase and use of
crack cocaine as well as a separate nature video. The inves-
tigators in this study found that the cocaine video induced
significant limbic activation in the amygdala as well as in
anterior cingulate among the recovering cocaine-dependent
subjects, and essentially no limbic activation among the
control (cocaine naive) subjects (Childress et al. 1999). It
could be hypothesized that the cocaine video kindled the
Journal of Psychoactive Drugs
Phenomenon of Drug Craving
memory of prior cocaine use. Moreover, activation of the
anterior cingulate seems to suggest that some subjects may
have been pondering (contemplating) the acquisition and
use of the drug.
Other research has found that adolescents with a current
alcohol use disorder show greater limbic activation upon
exposure to advertisements for alcoholic beverages, as con-
firmed by magnetic resonance imaging (Tapert et al. 2003).
Moreover, the activation extended into the left anterior and
visual system areas. In contrast, the alcohol advertisements
had little effect in comparably aged adolescents without
alcohol and/or other substance use disorders. The findings
from this investigation are important in that they suggest that
at least some adolescents are affected by advertisements for
alcoholic beverages.
Similar PET scan research with smokers has noted
significantly greater brain activation when they watch a
videotape simply showing the handling of a cigarette and
various cigarette-related cues when compared with tobacco
naive subjects (Brody et al. 2002). As with the cocaine (Chil-
dress et al. 1999) and alcohol (Tapert et al. 2003) videos,
the brain activation was greatest in those areas associated
with craving, arousal and compulsive behavior, including
the anterior cingulate and prefrontal cortex.
In addition, Grusser and colleagues (2000) have found
that the sight and smell of tobacco products can similarly
induce craving in smokers when compared to control sub-
jects. Using functional MRI testing. Due and colleagues
(2002) found that simply showing photographs and images
of "smoking" or tobacco products was sufficient to activate
reward circuits (right amygdala, hippocampus, ventral teg-
mental area) in nicotine-deprived smokers. These images
did not elicit any activation of reward circuits or "craving"
in nonsmoking comparison subjects.
Similar research conducted on pathological gamblers
(PG) has noted that when PG subjects are shown a pro-
vocative gambling video, the urge to engage in gambling
increases significantly when compared to control subjects
(Potenza et al. 2003). Moreover, the researchers noted a
relative decrease in brain activity in those areas associated
with impulse control (prefrontal cortex, anterior cingulate)
when compared with control subjects.
In addition, when PG subjects viewed the gambling
video, there was a notable increase in brain activity in
the right cuneus and the right middle occipital gyrus (an
indication of elevated attention to the visual cue) when
compared to control subjects. Pathological gamblers also
experienced a significant increase in subjective emotional
and motivational responses while watching the gambling
video, whereas there was little emotional activation and
virtually no "urge" to gamble among control subjects. This
increase in emotional and motivational activation
among PG subjects is quite similar to the effect of
recovering cocaine dependent patients watching the
drug video.
256 Volume 40 (3), September 2008
 Fortuna & Smelson
There was, however, one importatit difference between
PG subjects watching a gambling video and CD (cocaine de-
pendent) subjects watching a drug video. When CD subjects
were shown the cocaine video there was a notable activation
of the ventral anterior cingulate and prefrontal cortex (Kilts
et al. 2004; Childress et al. 1999), indicating that the CD
subjects were engaged in greater contemplation or ponder-
ing/dissonance. In contrast, there was a notable decrease
in activity within the frontal cortex and ventral anterior
cingulate among the PG subjects watching the gambhng
video (Potenza et al. 2003). These findings suggest that even
though cue-induced craving or "urges" can be provoked by
visual cues in both CD and PG subjects, there may be more
dysregulation in impulse control among the PG subjects. In
addition, the biologic dynamics of impulsivity in CD and
PG subjects may manifest differently.
The research on video-induced craving suggests that
very different forms of addictive behavior—pathological
gambling and cocaine dependence—share some of the same
subjective emotional and motivational responses. Moreover,
there appear to be several common neural pathways involved
in both disorders. Nonetheless, there are important neural
and behavioral differences between these forms of addictive
behavior, in terms of contemplation and the ability to issue
impulse control. A further clarification of these differences
is important in terms of prevention and treatment modalities
and research.
Three central points emerge regarding cue-induced
craving (visual and olfactory cues). First, there are similari-
ties in the neural pathways that are activated during drug
craving, regardless of the drug. Whether the craving is trig-
gered by the smell or the sight of the drug, the shared neural
pathways which are activated include the amygdala, the
anterior cingulate and orbitofrontal cortex, and the nucleus
accumbens.
The second point is that many different forms of ad-
dictive behavior (compulsive gambling, drug dependence,
and possibly others) appear to involve some of the same
subjective emotional and motivational responses. Indeed,
some of the neural pathways that are activated during cue-
elicited craving are the same. In other words, upon closer
examination, many of the addictive behaviors may be more
similar than they are different.
Third, there is new and definitive research to suggest
that there are important differences in some forms of ad-
dictive behavior, such as pathological gambling, which
apparently involve greater dysregulation of the frontal cortex
and anterior cingulate during an acute episode of craving.
Decreased activity in the frontal cortex and ventral anterior
cingulate may underlie impaired judgement and impulse
control. The differences in impulse control that may
underlie pathological gambling and various other forms
of addictive behavior, as well as other possible behav-
ioral and biologic differences, clearly warrant future
investigations.
Journal of Psychoactive Drugs
Phenomenon of Drug Craving
Discussion of Drug Use
Wang and colleagues (1999) reported that just having
a recovering drug addicted individual discuss the "high"
can trigger craving. Again, this is manifested on functional
MRI by increased activity in the right amygdala and the
orbito-frontal cortex. The recollection of the drug experience
or high, sometimes called "euphoric recall," is enough to
activate the amygdala and kindle craving. Even the antici-
pation of drug use or other rewards can activate the central
pleasure pathways. For example, using fMRI, Knutson
and colleagues (2001) found that the anticipation of even
a nominal monetary reward ($5.00 at the highest level)
significantly increased activity in the nucleus accumbens.
Breiter and colleagues (2001) found a similar link between
the amount of the anticipated monetary gain and activation
within the nucleus accumbens, extended amygdala, and the
orbitofrontal cortex.
In summary, there are probably multiple sensory trig-
gers that underlie drug craving. Further research is needed
to determine whether other sensory stimuli may trigger or
activate drug craving in specific areas of the brain.
BIOLOGIC SUBSTRATES OF CRAVING
AND ADDICTIVE BEHAVIOR
A number of invasive and peripheral markers have been
used to identify the brain regions involved in craving. This
section will focus on the research involving a deficiency in
dopamine-2 receptors within the striatum since this appears
to play a major role in cue-elicited craving. We will also
review the line of research focusing on the visual system,
particularly involving the eiectroretinogram since it ap-
pears to be a cost-effective peripheral marker of dopamine
dysfunction among cocaine-dependent patients.
PET scans have shown a notable deficiency of dopa-
mine-2 receptors within the striatum of drug-dependent
subjects when compared with control subjects. Low do-
pamine-2 receptor levels have been implicated in alcohol
dependence (Volkow et al. 1996), cocaine dependence
(Volkow et al. 1993), and methamphetamine dependence
(Volkow et al. 2001).
More recently, low levels of dopamine-2 receptors
have also been identified in the striatum of pathologically
obese individuals (Wang et al. 2001). One characteristic
of pathologically obese individuals is frequent bingeing
on high carbohydrate/high fat foods, including sugars and
starchs, such as ice cream, cookies, chocolate, cakes, pies,
Danish, pasta, rice, bread, and bagels. Research by Wang
and colleagues (2004) has postulated that decreased levels
of dopamine D2 receptors predisposes subjects to search
for reinforcers, which might be a drug in the case of drug-
addicted subjects or food in the case of obese subjects, as
a means of compensating for decreased sensitivity of do-
pamine D2 regulated reward circuits. Moreover, the scans
of obese subjects look nearly identical to the scans
257 Volume 40 (3), September 2008
Fortuna & Smelson
of methamphetamine-dependent subjects (Wang et al.
2001). This may represent another example where many
of the addictive behaviors may be more similar than they
are different. That is, there may be some biologic common
denominators.
In many obese individuals food binges may cause a
spontaneous increase in dopamine activity and theoreti-
cally an up-regulation in dopamine-2 receptors (Wang et al.
2001). More recently the so-called "hot spot" for the sweet
tooth was identified in the nucleus accumbens (Pecina &
Berridge 2005). These findings suggest that pathological
obesity, or at the least food binges, are a form of addictive
behavior since these binges precipitate changes in the brain's
production and utilization of dopamine (Blum et al. 2007).
The deficiency of dopamine-2 receptors in obese subjects (as
seen in CD subjects), coupled with the ephemeral increase in
dopamine activity following the ingestion of a high carbo-
hydrate meal or snack (as seen in CD subjects who binge on
cocaine, methamphetamine, alcohol), may represent a similar
biologic substrate of an addictive disorder (Blum et al. 2006).
The neurotransmitter dopamine regulates motivation
and self-restraint in the frontal cortex and anterior cingulate
(Tucker, Luu & Pribram 1995). A deficiency of dopamine-2
receptors within the frontal cortex may underlie the compul-
sive behavior seen in many drug dependent subjects (Vblkow
et al. 2001). The deficiency in dopamine-2 receptors sug-
gests low endogenous dopamine levels. Low endogenous
dopamine levels may predispose some individuals to drug
abuse or other addictive behaviors that activate dopamine
turnover (Wang et al. 2001). Moreover, low dopamine levels
may have created a down-regulation of dopamine-2 receptors.
This phenomenon would only be exacerbated by drug abuse.
While much of the research has focused on neuroimag-
ing procedures for identifying dopamine disturbances among
individuals with cocaine dependence, there is an interest-
ing line of work focusing on the blue-cone system in the
retina. Dopamine, a critical modulator in retinal processing,
has long been recognized as a method for detecting corti-
cal dopamine abnormalities (Bodis-Wollner & Piccolino
1988; Kramer 1971). Various dopamine receptors have
been identified in several levels of the mammalian retina
(Bodis-Wollner & Tzelepi 1998; Djamgoz & Wagner 1992).
However, the Dl or D2 receptor subtypes are most common
(Stanzione et al. 1992). It is interesting to note that these
are the same subtypes involved in the rewarding effects of
cocaine (Mattingly et al. 1994).
The electroretinogram (ERG) is a noninvasive physi-
ologic technique for recording electrical potentials from
the retina in response to flashes of light. Previous research
suggests that dopamine in the retina is involved with ERG
responses, particularly blue cone b wave amplitude (Holopigeon
etal. 1994,1988;Maruiwaetal. 1994;Takatsunaetal. 1992;
Bodis-Wollner 1990; Gottlob et al. 1987). The ERG is also
sensitive in identifying patients with cortical dopamine
system abnormalities and in detecting acute changes in the
Journal of Psychoactive Drugs
Phenomenon of Drug Craving
dopamine system. For example, patients with Parkinson's
Disease display reduced dopamine in the basal ganglia and
also showed a 50% decrease of dopamine in the retina and
reduced ERG blue cone system amplitude (Ellis et al. 1987).
Researchers have also found that an acute dose of dopamine
antagonist haloperidol reduced the amplitude of the ERG in
humans (Holopigian et al. 1994).
Because of the existence of dopamine in the retina, re-
searchers were interested in examining whether withdrawn
cocaine-dependent patients would show abnormal ERG am-
plitudes. In the first study using the ERG in this population,
withdrawn cocaine-dependent patients with mean cocaine
abstinence of approximately 30 days were matched for age,
sex, and race with normal controls. The results suggested that
the cocaine dependent patients had a significantly reduced
ERG blue cone b wave amplitude response. In fact, the mean
blue cone ERG b wave amplitude of the cocaine-dependent
patients was > 0.5 microvolts, about half the amplitude of the
normal controls (Roy et al. 1997). Because of the research
suggesting that dopamine is a critical modulator in cocaine
craving (Markou et al. 1993), these authors examined
whether there was a relationship between patients with a
reduced blue-cone b wave amplitude and self-reported co-
caine craving. Withdrawn cocaine-dependent patients were
dichotomized into a "blunted" (or a reduced ERG blue cone
b wave amplitude, i.e. > 0.5 microvolts) and "non-blunted"
(or a normal ERG blue-cone b wave amplitude, i.e. < 0.5)
microvolts group. The results suggested that about half of
the cocaine-dependent patients had a blunted ERG blue-
cone response and this subgroup reported significantly
more cocaine craving than the patients without the ERG
blunted blue-cone response (Roy, Smelson & Roy 1996).
These investigators also did a study longitudinally and found
that the individuals with a blunted ERG blue-cone b wave
amplitude remained blunted for eight weeks and correlated
with cocaine craving (Roy, Smelson & Roy 1997).
These preliminary studies with the ERG and cocaine
craving utilized a self-report methodology. A laboratory-
based cue-exposure paradigm is a much more sophisticated
way to induce craving and study the state (Childress et al.
1998; Smelson et al. 1998; Robbins et al. 1997; Margolin,
Avants & Kosten 1994; Ehrman et al. 1992). Previous
research with cue-exposure suggests that approximately
half of the patients respond to laboratory cocaine cues with
increased craving and physiological changes (Avants et al.
1995). It is interesting to note that in previous studies about
half of the cocaine-dependent patients had a blunted blue
cone system response. In an effort to examine whether this
cue reactive subgroup would also have a blunted blue cone
b wave ERG amplitude, Smelson and colleagues (1998)
challenged recently withdrawn cocaine-dependent patients
with laboratory cues and examined their responses after sub-
grouping them by their ERG performance. Preliminary data
suggested that the subgroup of cocaine-dependent patients
with a decreased ERG blue-cone b wave amplitude display
258 Volume 40 (3), September 2008
 Fortuna & Smelson
more cue-elicited cocaine craving. These researchers did a
replication study and again found that the cocaine-dependent
patients with a reduced blue-cone ERG amplitude showed
significantly more cue-elicited cocaine craving (Smelson
et al. 2001). Additional support for the utility of the ERG
for subgrouping cocaine addicts with increased dopamine
disturbances come from a recent study by Roy and col-
leagues (2003), in which concentrations of the dopamine
metabolite homovanillic correlated with ERG blue cone b
wave amplitude. Furthermore, the authors previously studied
color vision abnormalities among individuals with cocaine
dependence. The results suggested that the cocaine-dependent
patients showed significantly more blue-yellow color vision
deficits compared to matched controls (Desai et al. 1997).
The ERG and other measures of the visual system
appear to be a good noninvasive marker for subgrouping
cocaine addicts with increased dopamine abnormalities and
heightened craving who may need specialized treatments
to manage that state. It should be noted that these authors
examined the dopamine antagonist risperidol for managing
the acute eiïects of cocaine and found that risperidol had
reduced ERG amplitude as well as cue-elicited craving (Roy,
Roy & Smelson 1998; Smelson, Roy & Roy 1997). Further
pharmacological studies are underway to place cocaine-de-
pendent individuals with dopamine abnormalities detected
in the visual system on a medication to regulate that system
and reduce craving.
SECONDARY MANIFESTATIONS OE
DOPAMINE LEVEL AND ADDICTION
Dopamine is also the pleasure neurochemical in the
nucleus accumbens. Low endogenous levels of dopamine
and dopamine-2 receptors within the nucleus accumbens
suggest that the individual may have difficulty feeling good
(e.g., getting high) from normal life events such as a good
book, a good movie, being with friends, natural highs, mu-
sic, and the like. This phenomenon has been referred to as
reward deficiency syndrome ( Blum et al. 1996).
The interesting phenomenon is that acute drug use ex-
cites the release of dopamine within the nucleus accumbens.
It could be hypothesized that the drug-dependent individual
may be "self-medicating" to compensate for an underactive
dopaminergic system. Cocaine, methamphetamine and al-
cohol all excite the release of dopamine within the nucleus
accumbens. Additionally, cocaine blocks the re-uptake of
synaptic dopamine, thereby prolonging the high.
The interesting fact is that bingeing on specific drugs
(i.e., cocaine, methamphetamine) acutely, and often greatly
increases dopamine turnover (Koob et al. 1988). PET scans
of the striatum, taken during and shortly after an acute
binge, show significantly increased dopamine activity. However,
following prolonged periods of bingeing, which greatly elevate
dopamine tumover but also lead to significant dopamine depletion,
dopamine-2receptorsdown-regulate (Volkow et al. 2002).
Journal of Psychoactive Drugs
Phenomenon of Drug Craving
The same dynamic appears to be true in obese subjects.
They have low dopamine-2 receptor levels in the striatum
and low dopamine tumover within the nucleus accumbens
(Wang et al. 2001). Recent research (Bassareo & Di Chiara
1999) has confirmed that bingeing on snack foods can greatly
stimulate dopamine tumover within the nucleus accumbens.
It has been suggested that bingeing on high-carbohydrate,
high-fat foods (ice cream, pizza, cookies, chocolate) has a
dmg-like effect in the nucleus accumbens, limbic cortex, and
frontal cortex (Fortuna 1998; Wurtman & Wurtman 1989).
High carbohydrate foods also have an antidepressant and
calming effect, by increasing central production of serotonin
(Fortuna 1998).
Unfortunately, recent research (Wang et al. 2001) has
also suggested that following the binge on drugs or food,
dopamine-2 receptors down-regulate or re-adjust to their
abnormal., lower than normal level. This becomes a vicious
cycle, whereby craving and compulsion to use the dmg or
food again to "feel normal" recommences.
Even some medications that mimic the effect of do-
pamine may be problematic. For example, several studies
evaluating the treatment of patients with Parkinsons disease
(PD) with specific dopaminergic medications (such as
bromocriptine, mirapec), have noted a peculiar side ef-
fect—compulsive gambling (Driver-Dunckley, Samanta &
Stacy 2003; Gschwandtner et al. 2001). Driver-Dunckley
and colleagues (2003) studied more than 1,800 Parkinson's
patients for a year. Of the 529 who received mirapex, a po-
tent dopaminergic agent, nine developed serious gambling
addictions. In all nine of the subjects there was no prior
history of compulsive gambling; it appears that the excited
dopamine tumover created an addictive disorder. Indeed,
the gambling behavior was so severe that it caused serious
financial hardship: two patients reported losses of over
$60,000.00. In contrast, none of the patients who received
levodopa therapy experienced an urge to gamble or engaged
in gambling behavior.
Other research has noted a link between levodopa
therapy among Parkinsons patients and acute episodes of
hypersexuality (van Deelen et al. 2003; Uitti et al. 1989).
This side effect appears to related to two things: (1) the
agonist action of levodopa on dopamine receptors, and;
(2) patients independently taking higher doses of levodopa
than were prescribed. This unusual side effect is transitory
and disappears when the patient takes the prescribed dos-
age.
Low endogenous dopamine levels as well as a defi-
ciency in dopamine-2 receptors appear to underlie a wide
variety of addictive behaviors including dmg dependence,
obesity, compulsive gambling and sex addiction. This
important area of study requires further investigation using
MRI and PET scan technologies. Enhanced understanding
of the biologic and behavioral bases of these disorders has
important treatment and prevention implications.
259 Volume 40 (3), September 2008
Fortuna & Smelson
REFERENCES
Avants, K.S.; Margolin, A.; Kosten, T. & Cooney, N.L. 1995. Differences
between responders and non-responders to cocaine cues in a
laboratory. Addictive Behaviors 20 (2): 215-24.
Bassareo, V. & Di Chiara,G. 1999. Differential responsiveness of dopamine
transmission to food stimuli in nucleus accumbens shell/core
compartments. Neuroscience 89 (3): 637-41.
Blum, K.; Chen, T.J.; Meshkin, B.; Downs, B.W.; Gordon, C.A.; Blum,
S.; Mengucci, J.F.; Braverman, E.R.; Arcuri, V.; Deutsch, R. & Pons,
M.M. 2007. Genotrim, a DNA-customized nutrigenomic product
targets genetic factors of obesity: Hypothesizing a dopamine-glucose
correlation demonstrating reward deficiency syndrome (RDS).
Medical Hypotheses 68 (4): 844-52.
Blum, K.; Chen, T.J.; Meshkin, B.; Downs, B.W.; Gordon, C.A.; Blum,
S.; Mengucci, J.F.; Braverman, E.R.; Arcuri, V.; Varshavskiy, M.;
Deutsch, R. & Martinez-Pons, M. 2006. Reward deficiency syndrome
in obesity: Apreliminary cross-sectional trial with a genotrim variant.
Advances in Therapeutics 23 (6): 1040-51.
Blum, K.; Cull, J.G.; Braverman, E.R. & Comings, D.E. 1996. Reward
deficiency syndrome. American Scientist 84: 132-45.
Bodis-Wollner, I. 1990. Visual deficits related to dopamine deficiency in
experimental animals and Parkinson's disease patients. Trends in
Neuroscience 13: 296-302.
Bodis-Wollner, I. & Tzelepi, A. 1998. The push-pull action of dopamine
on spatial tunning of the monkey retina: The effects of dopaminergic
deficiency and selective Dl and D2 receptor ligands on the pattern
electroretinogram. Vision Research 38 (10): 1479-87.
Bodis-Wollner, I. & Piccolino, M. (Eds.) 1988. Dopaminergic Mechanisms
in Vision. New York: Alan R. Liss, Inc.
Breiter, H.C.; Aharon, I.; Kahneman, D.; Dale, A. & Shizgal, P. 2001.
Functional imaging of neural responses to expectancy and experience
of monetary gains. Neuron 30 (2): 619-39.
Brody, A.L.; Mandelkern, M.A.; London, E.D.; Childress, A.R.; Lee,
G.S.; Bota, R.G.; Ho, M.L.; Saxena, S.; Baxter, L.R.; Madsen, D. &
Jarvik, M.E. 2002. Brain metabolic changes during cigarette craving.
Archives of General Psychiatry 59 (12): 1162-72.
Brown,E.E.&Fibiger,H.C. 1993. Differential effects of excitotoxic lesions
of the amygdala on cocaine-induced conditioned locomotion and
conditioned place preference./'.s>'c/iop/iarmaco/og>' 113: 123-30.
Childress, A.R.; Mozley, P.D.; McElgin, W.; Fitzgerald, J.; Reivich, M. &
O'Brien, C.P. 1999. Limbic activation during cue-induced cocaine
craving. American Journal of Psychiatry 156: 11-18.
Childress, A.R.; McLellan, A.T.; Ehrman, R. & O'Brien, C.P. 1988.
Classically conditioned responses in opioid and cocaine dependence:
A role in relapse? In: B. Ray (Ed.) Learning Factors in Substance
Abuse. NIDA Research Monograph # 84. Rockville, MD: NIDA.
Cooney,N.L.; Baker, L.H.; Pomerleau, O.F. & Josephy, B. 1984. Salivation
to drinking cues in alcohol abusers: Toward the validation of a
physiological measure of craving. Addictive Behavior 9: 91-94.
Desai, P.; Roy, M.; Roy, A.; Brown, S. & Smelson, D.A. 1997. Impaired
color vision in cocaine patients. Archives of General Psychiatry 54:
696-99.
Djamgoz, M. & Wagner, H. 1992. Localization and function of dopamine
in the adult vertebrate retina. Neurochemistry International 20:
139-91.
Driver-Dunckley, E.; Samanta, J. & Stacy, M. 2003. Pathological gambling
associated with dopamine agonist therapy in Parkinson's disease.
Neurology 61 (3): 422-23.
Due, D.L.; Huettel, S.A.; Hall, W.G. & Rubin, D.C. 2002. Activation in
mesolimbic and visuospatial neural circuits elicited by smoking cues:
Evidence from magnetic resonance imaging. American Journal of
Psychiatry 159 (6): 954-60.
Ehrman, R.N.; Robbins, S.J.; Childress, A.R. & O'Brien, C.P. 1992.
Conditioned responses to cocaine-related stimuli in cocaine abuse
patients. Psychopharmocology 107: 523-29.
Ellis, C ; Allen, T.; Marsden, C. & Ikeda H. 1987. Electroretinographic
abnormalities in idiopathic Parkinson's disease and the effect of
levodopa administration. Clinical Visual Sciences 1: 347-55.
Fortuna, J.L. 1998. Food, Brain Chemistry and Behavior. Second Edition.
Boston: Pearson Publishing.
Journal of Psychoactive Drugs
Phenomenon of Drug Craving
Goldstein, R.Z. & Volkow, N.D. 2002. Drug addiction and its underlying
neurobiological basis: Neuroimaging evidence for the involvement of
the frontal cortex. American Journal of Psychiatry 159: 1642-52.
Gottlob, I.; Schneider, E.; Heider, W. & Skrandies, W.A. 1987. Alterations
of visual evoked potentials and electroretinograms in Parkinson's
disease. Electroencephalograms and Clinical Neurophysiology 66:
349-57.
Grusser, S.M.; Heinz, A. & Flor, H. 2000. Standardized stimuli to assess
drug craving and drug memory in addicts. Journal of Neural
Transmission 107 (6): 715-20.
Gschwandtner, U.; Aston, J.; Renaud, S. & Fuhr, P. 2001. Pathological
gambling in patients with Parkinson's disease. Clinical
Neuropharmacology y. 170-72.
Holopigian, C ; Clewner, L.; Seiple, W. & Kupersmith, M.J. 1994. The
effects of dopamine blockade on the human flash electroretinogram.
Documenta Ophthalmologica 86: 1.
Insel, T.R. 1992. Towards a neuroanatomy of obsessive-compulsive
disorder. Archives of General Psychiatry 49: 739-44.
Kilts, CD.; Gross, R.E.; Ely, T.D. & Drexler, K.P. 2004. The neural
correlates of cue-induced craving in cocaine dependent women.
American Journal of Psychiatry 161 (2): 233-41.
Knutson, B.; Adams, CM.; Fong, G.W. & Hommer, D. 2001. Anticipation
of increasing monetary awards selectively recruits nucleus accumbens.
Journal of Neuroscience 2\ (16): 159.
Koob, G.F. & Bloom, F.E. 1988. Cellular and molecular mechanism of
drug dependence. Science 242: 715-23.
Kramer, S.G. 1971. Dopamine: A retinal neurotransmitter. Retinal uptake,
storage and light-stimulated release of H3-dopamine in vivo.
Investigative Opthalmology and Visual Science 10: 438-53.
Margolin, A.; Avants, S.K. & Kosten T.R. 1994. Cue elicited cocaine
craving and autogenic relaxation. Association with treatment
outcome. Journal of Substance Abuse Treatment. 11(6):549-52.
Markou, A.; Weiss, F.; Gold, L.; Caine, B.; Shulteis,G. & Koob, G. 1993.
Animal models of craving. Psychopharmocotogy 112: 163-82.
Maruiwa, F.; Kim, S.; Nao, N. & Sawada, F. 1994. Effects of
metoclopramide, dopamine receptor blockade, on the ERG light peak.
Nippon Ganka Gasshei Japónica 98 (5): 375-80.
Mattingly,B.A.;Hart,T.C;Lim,K.&Perkins,C.1994.Selective antagonism
of Dopamine Dl and D2 receptors does not block the development
of behavioral sensatization to cocaine. Psychopharmacology 114
(2): 239-42.
Modell, J.G. & Mountz, J.M. 1995. Focal cerebral blood now change for
alcohol measured by SPECT. Journal ofNeuropsychiatry and Clinical
Neuroscience 1 (I): 15-22.
Pecina, S. & Berridge, K.C 2005. Hedonic hot spot in nucleus accumbens
shell: Where do mu-opiods cause increased hedonic impact of
sweetness? Journal of Neuroscience 25 (50): 11777-786.
Potenza, M.N.; Steinberg, M.A.; Skudlarski, P.; Fulbright, R.K.; Lacadie,
CM.; Wilbur, M.K.; Rounsaville, B.J.; Gore, J.C & Wexler, BE.
2003. Gambling urges in pathological gambling. ArcAiVeî of General
Psychiatry 60 (8): 828-36.
Robbins, S.J.; Ehrman, R.N.; Childress, A.R. & O'Brien, C.P. 1997.
Relationship among physiological and self-report responses produced
by cocaine-related cues. Addictive Behaviors 22: 157-67.
Rolls, E.T. 2000. The orbitofrontal cortex and reward. Cerebral Cortex
10: 284-94.
Roy, A.; Roy, M. & Smelson, D.A. 1998. Risperidone, ERG and cocaine
craving. American Journal of Addictions 7 (1): 90.
Roy, M.; Smelson, D.A. & Roy, A. 1997. Longitudinal study of blue cone
retinal function in cocaine-withdrawn patients. Biological Psychiatry
41:252-53.
Roy, M.; Smelson, D. & Roy, A. 1996. Abnormal electroretinogram in
cocaine dependent patients: Relationship to craving. British Journal
of Psychiatry 168:507-11.
Roy, M.; Roy, A.; Williams, J.; Weinberger, L. & Smelson, D.A. 1997.
Reduced blue cone electroretinogram in cocaine dependent patients.
Archives of General Psychiatry 54: 153-56.
260 Volume 40 (3), September 2008
 Fortuna & Smelson
Roy, A.; Roy, M.; Berman, J. &. Gonzalez, B. 2003. Blue cone
electroretinogram amplitudes are related to dopamine function in
cocaine-dependent patients. Psychiatric Research 117(2): 191-95
Schneider,F.S.;Habel,U.;Wagner,M.;Franke,P.;Salloun,J.B.;Shah,N.J.;
Toni, I,; Sulzbach,C.; Honig, K.; Maier, W.; Gaebel, W. & Zilles.K.
2001. Subcortical correlates of craving in recently abstinent alcoholic
çatienis. American Journal of Psychiatry 158: 1075-83.
Smelson, D.A.; Roy, A. & Roy, M. 1997. Risperidone diminished cue-
elicited craving in withdrawn cocaine dependent patients. Canadian
Journal of Psychiatry 42 (9): 984.
Smelson, DA.; Roy, M.; Roy, A. & Torshikovic, D. 2001. Electroretinogram
blue cone amplitude and cue-eliciting cocaine craving: Areplication.
American Journal of Drug and Alcohol Abuse 27 (2): 391-97.
Smelson, D.A.; Roy, A.; Roy, M. & Santana, S. 1998. Electroretinogram in
withdrawn cocaine dependent patients: Relationship to cue-elicited
craving. British Journal of Psychiatry 172: 537-39.
Stanzione, P.; Traversa, R.; Pierantozzi, M.; Semprini, R.; Marciani,
M.G. & Bemardi, G. 1992. An electrophysiological study of D2
dopamanergic actions in normal human retina: A tool in Parkinson's
dXit&st. Neuroscience Letters 136: 125-28.
Stormark, K.M.; Laberg, J.C; Bjerland, T.; Nordby, H. & Hugdahl, K.
1995. Autonomie cue reactivity in alcoholics: The effect of olfactory
stimuli. Addictive Behavior 20: 571-84.
Takatsuna,Y.;Adachi-Usami,E.;Ino,H.&Chiba,T.1992,EffectsofMPTP
on the mouse retina. Nippon Ganka Gakkai Zasshi 96: 767-75.
Tapert. S.F.; Cheung, E.H.; Brown, G.G.; Frank, L.R.; Paulus, M.P.;
Schweinsburg, A.D.; Meloy, M.J. & Brown, S.A. 2003. Neural
response to alcohol stimuli in adolescents with alcohol use disorder.
Archives of General Psychiatry 60 (7): 727-35.
Tucker, D.M.; Luu, P. & Pribram, K.H. 1995. Social and emotional self
regulation. Annals of the New York Academy of Science 769: 213-
39.
Uitti, R.J.; Tanner, CM.; Rajput, A.H.; Goetz, CG.; Klawans, H.L. &
Thiessen, B. 1989. Hypersexuality with antiparkinsonian therapy.
Clinical Neuropharmacology 12: 375-83.
Van Deelen,R.A.;Rommers,M.K.;Eerenberg,J.G.&Egberts,A.C. 2003.
Hypersexuality during use of levodopa. Ned Tijdschr Geneeskd 146
(44): 2095-298.
Volkow, N .D. ; Fo wler, J .S. & Wang, G .J. 2003. The addicted human brain :
Insights from imaging studies. Journal of Clinical Investigation
111: 1444-51.
Journal of Psychoactive Drugs
Phenomenon of Drug Craving
Volkow, N.D.; Fowler, J.S.; Wang, G-J. & Goldstein, R.Z. 2002. Role of
dopamine, the frontal cortex and memory circuits in drug addiction:
Insight from imaging studies. Neurobiology ofLearning and Memory
78 (3): 610-24.
Volkow, N.D.; Chang, L.; Wang, G.J.; Fowler, J.S.; Ding, Y.S.; Sedler,
M.; Logan, J.; Franceschi, D.; Gatley, J.; Hitzemann, R.; Gifford,
A.; Wong, C & Pappas, N. 2001. Low level of brain dopamine D-2
receptors in methamphetamine abusers: Association with metabolism
in the orbitofrontal cortex. American Journal of Psychiatry 158:
2015-21.
Volkow, N.D.; Wang, G.J.; Fowler, J.S.; Logan, J.; Hitzemann, R.; Ding,
Y.S.; Pappas,N.; Shea,C. & Piscani,K. 1996. Decreases in dopamine
receptors but not in dopamine transporters in alcoholics. Alcohol
Clinical and Experimental Research 20: 1594-98.
Volkow.N.D.; Fowler, J.S.; Wang, G.J.; Hitzemann, R.; Logan, J.;Schlyer,
D.; Dewey, S. & Wolf.A.P. 1993. Decreased dopamine D-2 receptor
availability is associated with reduced frontal metabolism in cocaine
abusers. Synap.?« 14: 169-77.
Wang, G.J.; Volkow, N.D.; Thanos, P.K. & Fowler, J.S. 2004. Similarity
between obesity and drug addiction as assessed by neurofunctional
imaging: A concept review. Journal of Addictive Disease 23 (3):
39-53.
Wang, G.J.;Volkow, N.D.; Logan, J.; Pappas, N.R.; Wong, CT.; Zhu,
W.; Netusil, N. & Fowler, J.S. 2001. Brain dopamine and obesity.
Lancet 3: 354-57.
Wang, G.J.; Volkow, N.D.; Fowler, J.S.; Cervany, P.; Hitzemann, R.J.;
Pappas, N.R.; Wong, C T . & Felder, C 1999. Regional brain
metabolic activation during craving elicited by recall of previous
drug experiences. Life Sciences 64 (9): 775-84.
Wiesbeck,G.A.; Weijers, H.G. & Gross, J.P. 2000. Craving for alcohol and
dopamine receptor sensitivity in alcohol dependent men and control
subjects. Journal of Neural Transmission 107 (6): 691-99.
Wrase, J.; Grusser, S.M.; Klein, S.; Diener, C ; Hermann, D.; Flor, H.;
Mann, K.; Braus, D.F. & Heinz, H. 2002. Development of alcohol
associated cues and cue-induced activation in alcoholics. European
Psychiatry \1 (5): m-9\.
Wurtman, R. & Wurtman, J. 1989. Carbohydrates and depression. Scientific
American 260 {iy.6&-l5.
261 Volume 40 (3), September 2008