Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): A commentary

ArticleinTheoretical Biology and Medical Modelling 5(1):24 · December 2008with55 Reads
Impact Factor: 0.95 · DOI: 10.1186/1742-4682-5-24 · Source: PubMed
Abstract

Background and hypothesis Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors. Proposal and conclusion The authors propose that D2 receptor stimulation can be accomplished via the use of Synapatmine™, a natural but therapeutic nutraceutical formulation that potentially induces DA release, causing the same induction of D2-directed mRNA and thus proliferation of D2 receptors in the human. This proliferation of D2 receptors in turn will induce the attenuation of craving behavior. In fact as mentioned earlier, this model has been proven in research showing DNA-directed compensatory overexpression (a form of gene therapy) of the DRD2 receptors, resulting in a significant reduction in alcohol craving behavior in alcohol preferring rodents. Utilizing natural dopaminergic repletion therapy to promote long term dopaminergic activation will ultimately lead to a common, safe and effective modality to treat Reward Deficiency Syndrome (RDS) behaviors including Substance Use Disorders (SUD), Attention Deficit Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. This concept is further supported by the more comprehensive understanding of the role of dopamine in the NAc as a "wanting" messenger in the meso-limbic DA system.

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Available from: Kenneth Blum
BioMed Central
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Theoretical Biology and Medical
Modelling
Open Access
Review
Activation instead of blocking mesolimbic dopaminergic reward
circuitry is a preferred modality in the long term treatment of
reward deficiency syndrome (RDS): a commentary
Kenneth Blum*
1,6,7,9
, Amanda Lih Chuan Chen
†2
, Thomas JH Chen
3
,
Eric R Braverman
4,9
, Jeffrey Reinking
3,5
, Seth H Blum
6
, Kimberly Cassel
6
,
Bernard W Downs
7
, Roger L Waite
7
, Lonna Williams
7
, Thomas J Prihoda
8
,
Mallory M Kerner
9
, Tomas Palomo
10
, David E Comings
11
, Howard Tung
12
,
Patrick Rhoades
13
and Marlene Oscar-Berman
14
Address:
1
Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA ,
2
Engineering &
Management of Advanced Technology, Chang Jung University, Taiwan, PR China,
3
Department of Occupational Health and Safety, Chang Jung
University, Taiwan, PR China,
4
Department of Neurosurgery, Weill Cornell College of Medicine, New York, NY, USA,
5
Department of
Occupational Health and Safety, Chang Jung University, Taiwan, PR China,
6
Department of Psychoneurogenetics, Synaptamine™, Inc., San
Antonio, TX, USA,
7
Deparment of Nutrigenomics, LifeGen, Inc, La Jolla, CA, USA,
8
Department of Pathology, University of Texas Health Science
Center, San Antonio, TX, USA,
9
Department of Neurological Research, Path Research Foundation, New York, NY, USA,
10
Hospital Universitario
12 de Octubre, Madrid, Spain,
11
Carlsbad Science Foundation, Emeritus, City Of Hope National Medical Center, Duarte, CA, USA,
12
University of
California, San Diego Medical Center, Neurological Surgery (Brain and spinal disorders), San Diego, CA, USA,
13
Central Valley Pain Management
& Wellness Modesto, CA, USA and
14
Boston University School of Medicine and Boston VAMC, Boston, MA, USA
Email: Kenneth Blum* - drd2gene@aol.com; Amanda Lih Chuan Chen - tjhchen@yahoo.com.tw; Thomas JH Chen - tjhchen@yahoo.com.tw;
Eric R Braverman - pathmedical@aol.com; Jeffrey Reinking - info@pain-mpmc.com; Seth H Blum - gosethgo@msn.com;
Kimberly Cassel - kimberlycassel@hotmail.com; Bernard W Downs - bdowns@alliednutraceutical.com; Roger L Waite - drw8@san.rr.com;
Lonna Williams - lwilliams@lifegen.com; Thomas J Prihoda - PRIHODAT@uthscsa.edu; Mallory M Kerner - Mallory_Kerner@brown.edu;
Tomas Palomo - tpalomo2004@yahoo.es; David E Comings - dcomings@earthlink.net; Howard Tung - hotung@ucsd.edu.com;
Patrick Rhoades - prhoadesmd@netscape.net; Marlene Oscar-Berman - oscar@bu.edu
* Corresponding author †Equal contributors
Abstract
Background and hypothesis: Based on neurochemical and genetic evidence, we suggest that
both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and
glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential
blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long
term activation of the mesolimbic dopaminergic system should involve activation and/or release of
Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and
potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic
receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the
COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA
release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive
internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling
of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well
being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors,
Published: 12 November 2008
Theoretical Biology and Medical Modelling 2008, 5:24 doi:10.1186/1742-4682-5-24
Received: 19 April 2008
Accepted: 12 November 2008
This article is available from: http://www.tbiomed.com/content/5/1/24
© 2008 Blum et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a
normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing
substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically
prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down
regulation, experiments in vitro have shown that constant stimulation of the DA receptor system
via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic
antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the
mesolimbic system to induce mRNA expression causing proliferation of D2 receptors.
Proposal and conclusion: The authors propose that D2 receptor stimulation can be
accomplished via the use of Synapatmine™, a natural but therapeutic nutraceutical formulation that
potentially induces DA release, causing the same induction of D2-directed mRNA and thus
proliferation of D2 receptors in the human. This proliferation of D2 receptors in turn will induce
the attenuation of craving behavior. In fact as mentioned earlier, this model has been proven in
research showing DNA-directed compensatory overexpression (a form of gene therapy) of the
DRD2 receptors, resulting in a significant reduction in alcohol craving behavior in alcohol preferring
rodents. Utilizing natural dopaminergic repletion therapy to promote long term dopaminergic
activation will ultimately lead to a common, safe and effective modality to treat Reward Deficiency
Syndrome (RDS) behaviors including Substance Use Disorders (SUD), Attention Deficit
Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. This
concept is further supported by the more comprehensive understanding of the role of dopamine
in the NAc as a "wanting" messenger in the meso-limbic DA system.
Background
It is well known that brain reward circuitry is regulated by
neurotransmitter interactions and net release of the sub-
stance Dopamine (DA) in the Nucleus accumbens (NAc)
[1]. The major loci for feelings of well-being and reward
occur in the meso-limbic system of the brain. The natural
sequence of events of the "brain reward cascade" leading
to reward involves the inter-relationship of at least four
important neurochemical pathways: serotonergic (5-HT);
enkephalinergic (Enk), GABAergic (GABA), and
dopaminergic (DA). The synthesis, vesicle storage, metab-
olism, release and function of these neurotransmitters are
regulated by genes and the expression thereof in terms of
messenger RNA (mRNA) directed proteins. It has been
postulated that genome orientated research will provide
genetic testing that will categorize individuals as to their
specific neurochemical makeup and thus provide useful
information to assist in appropriate development of the
most correct treatment options for the patient requiring
psychiatric care [2]. DA is a substance with many impor-
tant neurochemical functions and has been credited with
resultant behavioral effects such as "pleasure," "stress
reduction" and "wanting". Simply stated, without the nor-
mal functionality of DA, an individual will be lacking
hedonic response and an inability to cope with stress [3].
Thus genetic hypodopaminergic activity of the brain pre-
disposes an individual to seek substances and/or behav-
iors that will overcome this anhedonic state by activating
meso-limbic dopaminergic centers [4]. It turns out that
these substances and behaviors include: alcohol, opiates,
psychostimulants, nicotine, carbohydrates, cannabinoids,
gambling, sex, and indulgence in any excessive pleasure or
thrill seeking behaviors, like video gaming etc. [5-16]. Use
of these substances and engaging in these aforementioned
behaviors commonly induces the release of neuronal DA
into the synapse at the NAc, the reward center of the brain
[3]. Acute indulgence in these behaviors can be classified
as self-medicating and leads to a preferential release of
DA, which overcomes the hypodopaminergic state for
that individual. The resultant self-medication provides a
temporary relief of discomfort and a "pseudo feeling" of
well-being [17]. Unfortunately, chronic abuse of these
psychoactive substances and excessive indulgence in the
aberrant behaviors leads to inactivation of the brain
reward cascade (i.e. neurotransmitter synthesis inhibition,
neurotransmitter storage depletion, toxic formation of
pseudo neurotransmitters and receptor dysfunction
(structural and or density)). The abusive behaviors also
lead to neurotransmitter dysfunction via depletion. There-
fore both substance seeking and pathological behaviors as
ways of providing a feel good response (FGR) "fix" result
in ever escalating and uncontrollable craving behavior. It
has been well established that individuals possessing cer-
tain genetic polymorphisms (variations) are particularly
prone to amplified polymorphic expressions with envi-
ronmental or lifestyle insult and will be at increased risk
for impulsive, compulsive and addictive behaviors [18].
Such common genetic antecedents influencing the natural
brain reward cascade provide the understanding that
impulsive, compulsive and addictive behaviors are com-
monly linked and support the emerging concept of
Reward Deficiency Syndrome (RDS) as an umbrella term
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to characterize and classify these commonly linked genet-
ically induced behaviors [19-21]. In this scenario any and
all of these abusable psychoactive drugs or pathological
behaviors are candidates for addiction (tolerance/depend-
ence) and are chosen by the individual as a function of
both genes and environmental factors (e.g. availability,
peer pressure, etc.) [18].
Brain reward cascade explanation
While dopamine (DA) is critical to maintain normaliza-
tion of natural rewards, the neuronal release of DA into
NAc synaptic sites is somewhat complex. In 1989 our lab-
oratory proposed an interactive cascade of events of mes-
olimbic function that lead to net DA release [1]. It was
termed the "brain reward cascade' (see Figure 1)
The interactions of activities in the separate subsystems
mentioned above merge together into the much larger
global system. These activities take place simultaneously
and in a specific sequence, merging like a cascade. The end
result is a sense of peace, pleasure, and well-being when
these systems work normally. If there is a deficiency or
imbalance, the system works abnormally, causing the
sense of well-being to be displaced by feelings of anxiety,
anger, low self-esteem, and/or other "bad feelings"[15].
This can lead to cravings for substances and/or behaviors
that mask or relieve those bad feelings such as carbohy-
drate bingeing, alcohol, or cocaine; or to other addictive
behaviors such as compulsive gambling, compulsive sex,
workaholism, or engaging in high risk activities; all exces-
sive desires spurred by the need for a dopamine fix [19-
21].
Other research has confirmed that the reward sensation is
related to complex cascade reactions involving several
neurotransmitters and structures in the limbic system
[22]. The ultimate result of the process is the activation of
the meso-limbic dopamine pathway, which starts in the
tegmental ventral area and ends at the dopamine D2
receptors on the cell membranes of neurons located in the
NAc and the hippocampus [22].
The process, as described by Blum and Kozlowski [1],
starts in the hypothalamus with the excitatory activity of
serotonin-releasing neurons. This causes the release of the
opioid peptide met-enkephalin in the ventral tegmental
area, which inhibits the activity of neurons that release the
inhibitory neurotransmitter gamma-aminobutyric acid
(GABA). The disinhibition of dopamine-containing neu-
rons in the ventral tegmental area (VTA) allows them to
release dopamine in the NAc and (via amygdala) in cer-
tain parts of the hippocampus, permitting the completion
of the cascade and the development of the reward sensa-
tion [23]. Usually, if the cascade is working properly, the
reward or feeling of "well-being", or FGR, is obtained pro-
vided certain basic conditions are fulfilled [1].
RDS and genetic antecedents
Understanding the brain reward cascade provides insight
into the development of a blue-print for unlocking certain
candidate genes and polymorphisms that could impact
the brain in a negative manor. Impairment of the brain
reward cascade ultimately leads to a reduction of net DA
release, a reduction in dopamine receptors and as such an
enhancement of substance craving activity. While there
are many genes involved, it has been adequately estab-
lished that polymorphisms of the serotonergic- 2 A recep-
tor (5-HTT2a); dopamine D2 receptor (DRD2) and the
Catechol-o-methyl-transferase (COMT) genes predispose
individuals to aberrant RDS behaviors especially cravings
[19,71]. In the case of both serotonin and dopamine gene
polymorphisms, their respective receptors are signifi-
cantly lower than normal [24,25]. A certain type of poly-
morphism in the COMT gene results in an increase in the
catabolism of synaptic DA and subsequent reduced func-
tion [26]. Polymorphic identification of at least these
three genes provides insight into a genetic window of an
impaired brain reward cascade that places that individual
at high risk for excessive craving behaviors. Based on a
published [27] mathematical "Bayesian" approach, it was
found that individuals carrying these known polymor-
phisms (in particular the DRD2) have a 74% chance that
given the trigger of environmental insult will develop RDS
(for reviews see [1,18-21]).
Role of dopamine agonists in proliferation of D2
receptors
Studies in vitro have shown that constant stimulation of
DA receptors by agonists result in proliferation of
Dopamine D2 receptors coupled to G proteins. Specifi-
cally it was shown [28,29] in transfected kidney cells and
expressed in Spodoptera frugiperda insect cells that stimula-
tion of DA receptors by the pure D2 receptor agonist Bro-
mocriptine resulted in proliferation of D2 receptors over
a 14 day period. In the same study it was shown that
administration of a DA antagonist caused the prolifera-
tion of D2 antagonist receptors as well. These two inde-
pendent effects suggest that environmental manipulation
in spite of genetic antecedents will result in receptor pro-
liferation. This can best be explained by the understand-
ing that agonist activity involves the stimulation of the
mRNA that is involved in transcription. Activation of the
DRD2/mRNA results in a negative feedback that promotes
an enhancement of mRNA directed D2 receptor prolifera-
tion. This fact becomes very important when coupled with
the findings that an increase in substance seeking is due to
a paucity of DA D2 receptors [24,25]. Therefore, if low D2
receptors equate to increased craving behavior then an
increase in D2 receptors should result in attenuation of
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brain reward cascade [1] -modified with permission from Gene Therapy PressFigure 1
Brain reward cascade [1]-modified with permission from Gene Therapy Press. In this cascade, stimulation of the ser-
otonergic system in the hypothalamus leads to the stimulation of delta/mu receptors by serotonin to cause a release of
enkephalins. Activation of the enkephalinergic system induces an inhibition of GABA transmission at the substantia nigra by
enkephalin stimulation of mu receptors at GABA neurons. This inhibitory effect allows for the fine tuning of GABA activity.
This provides the normal release of dopamine at the projected area of the n. accumbens (reward site of the brain). It is note-
worthy that other important neurotransmitters and receptors are involved such as endocannibinoids and glutamate.
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craving behavior. Our solution is to stimulate DA release
at the NAc naturally, not via powerful DA agonists that
could ultimately lead to DA down-regulation. Whereas
DA activation could occur with targeted pharmaceuticals
such as Bromocriptine or other DA agonists [30], we pre-
fer a more natural approach developed to mimic the brain
reward cascade; in essence, through the utilization of pre-
cursor amino-acids and simultaneous enkephalinase/
COMT inhibition, which we suggest will systematically
induce natural release of DA without side effects.
Traditional anti-craving treatments block
dopamine activity at the brain reward centers
Most recent examples of pharmaceuticals that block DA
release and or receptor activation include Acomplia
(Rimonabant), the cannabinoid (CB1) receptor blocker
and possibly Gabapentin. While there are numerous stud-
ies supporting the therapeutic benefits of Acomplia as an
anti-craving drug the long term adverse effects resulted in
a recent rejection by the United States Federal Drug
Administration (FDA). A recent PUBMED search revealed
1007 papers on Acomplia. Since the prevalence of obesity
continues to increase, there is a demand for effective and
safe anti-obesity agents that can produce and maintain
weight loss and improve comorbidity. Christensen et al
[31] did a meta-analysis of all published randomized con-
trolled trials to assess the efficacy and safety of the newly
approved anti-obesity agent Rimonabant. They searched
the Cochrane database and Controlled Trials Register,
Medline via Pubmed, Embase via WebSpirs, Web of Sci-
ence, Scopus, and reference lists up to July, 2007. They
collected data from four double-blind, randomized con-
trolled trials (including 4105 participants) that compared
20 mg per day Rimonabant with placebo. Patients given
Rimonabant had a 4.7 kg (95% CI 4.1–5.3 kg; p < 0.0001)
greater weight reduction after 1 year than did those given
placebo. Rimonabant caused significantly more adverse
events than did placebo (Odds Ratio (OR) = 1.4; p =
0.0007; number needed to harm = 25 individuals [95% CI
17–58]), and 1.4 times more serious adverse events (OR =
1.4; p = 0.03; number needed to harm = 59 [27–830]).
Patients given Rimonabant were 2.5 times more likely to
discontinue the treatment because of depressive mood
disorders than were those given placebo (OR = 2.5; p =
0.01; number needed to harm = 49). Furthermore, anxiety
caused more patients to discontinue treatment in
Rimonabant groups than in placebo groups (OR = 3.0; p
= 0.03; number needed to harm = 166). Their findings
suggest that 20 mg per day of Rimonabant increases the
risk of adverse psychiatric events – i.e. depressed mood
disorders and anxiety; despite depressed mood being an
exclusion criterion in these trials. Taken together with the
recent US Food and Drug Administration finding of
increased risk of suicide during treatment with Rimona-
bant, these researchers recommend increased alertness by
physicians to these potentially severe psychiatric adverse
reactions. Concerning this report, we propose that the
negative effects on mood are due to the continued block-
ade of naturally required DA release at the NAc.
Gabapentin is a gamma-aminobutyric acid (GABA) ana-
logue, with GABAmimetic pharmacological properties.
Gabapentin is used for the treatment of seizures, anxiety
and neuropathic pain. It has been proposed that Gabap-
entin may be useful in the treatment of cocaine depend-
ence. However, clinical trials with Gabapentin have
shown conflicting results, while preclinical studies are
sparse. In one study, Peng et al [32] investigated the effects
of Gabapentin on intravenous cocaine self-administration
and cocaine-triggered reinstatement of drug-seeking
behavior, as well as on cocaine-enhanced DA in the NAc.
They found that Gabapentin (25–200 mg/kg, i.p., 30 min
or 2 h prior to cocaine) failed to inhibit intravenous
cocaine (0.5 mg/kg/infusion) self-administration under a
fixed-ratio reinforcement schedule or cocaine-triggered
reinstatement of cocaine-seeking behavior. In vivo micro-
dialysis showed that the same doses of Gabapentin pro-
duced a modest increase (approximately 50%, p < 0.05)
in extracellular NAc GABA levels, but failed to alter either
basal or cocaine-enhanced NAc DA. These data suggest
that Gabapentin is a weak GABA-mimic drug. At the doses
tested, it has no effect in the addiction-related animal
behavioral models. This is in striking contrast to positive
findings in the same animal models shown by another
GABAmimetic – gamma-vinyl GABA – by Garner's group
(see [18] for review). Based on our current theoretical
model we are opposed to the use of Gabapentin to treat
substance seeking behavior especially in long term care.
Other than a few scientific groups that suggest serotoner-
gic/dopaminergic agonist therapy [33], most strategies
embrace dopaminergic receptor blockade/attenuation of
dopamine release [2,3,18-21]. We propose that, in most
circumstances, utilization of amino acid precursors affect-
ing positive dopaminergic activation is a better alternative
[34-48] (see tables 1 &2).
Amino acid therapy as an anti-craving agent
Although DA release (and/or DA receptor binding) could
in theory be potentiated by the above proposed ingredi-
ents (summarized in table 1) for dopaminergic activation,
no one to date has actually shown this important poten-
tial and is the subject of future intensive investigation.
However indirect support is derived from the effects
obtained with these ingredients in a number of clinical tri-
als over two decades (see table 1).
Table 1 illustrates the anti-craving and other effects
observed with the Synaptamine™ complex. Other more
recent published clinical trials include:
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Table 1: Summary of completed clinical studies with nutraceutical supplementation: a literature review
Drug Abused or
Dysfunction
Supplement Used No. of Patients No. of Days Study Type Significant Results Publication
Alcohol SAAVE 22 28 TO
IP
100% decrease in BUD
scores. Detoxification
measures: reduction in
benzodiazepine
requirement, reduction in
withdrawal tremors after
72 hours, reduction in
depression
Blum K, Trachtenberg MC,
Ramsey J. Improvement of
inpatient treatment of the
alcoholic as a function of
neuronutrient restoration:
a pilot study. Int J Addiction.
1988; 23:991–98.
Blum K, Trachtenberg MC.
Neurogenic deficits caused
by alcoholism: restoration
by SAAVE. Journal of
Psychoactive Drugs. 1988;
20:297.
Alcohol plus
Polydrugs
SAAVE 62 21 DBPC
IP
Reduction in psychosocial
stress reduction as
measured by SCL, reduced
BESS score, improved
physical score, six-fold
decrease in likelihood of
leaving AMA after five days.
Blum et al. Enkephalinase
inhibition and precursor
amino acid loading
improves inpatient
treatment of alcoholics and
poly-drug abusers: a
double-blind placebo-
controlled study of the
neuronutrient intervention
adjunct SAAVE. Alcohol.
1989; 5:481.
Cocaine Tropamine 54 30 TO
IP
Drug hunger significantly
reduced in patients taking
SAAVE as compared to
controls; 4.2 percent AMA
rate for patients on
Tropamine versus 28
percent for patients on
SAAVE and 37 percent for
controls. </SPAN>
Blum et al. Reduction of
both drug hunger and
withdrawal against advice
rate of cocaine abusers in a
30 day inpatient treatment
program with the
neuronutrient tropamine.
Curr Ther Res. 1988;
43:1204.
Alcohol and
Cocaine
SAAVE and
Tropamine
60 379 TO
CP
At end of one year over 50
percent of the alcoholic
DUI offenders not using
SAAVE dropped out of the
program while less than 15
percent of those using
SAAVE dropped out. For
the cocaine abusers over
90 percent of the Non-
Tropamaine group
dropped out, but less than
25 percent of the patients
in the control group.
Brown et al.
Neurodynamics of relapse
prevention: a neuronutrient
approach to outpatient DUI
offenders. J. Psychiatric
Drugs. 1990; 22:173.
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Over-Eating PCAL 103 27 90 TO
OP
The PCAL 103 group lost
an average of 27 pounds in
90 days compared with an
average loss of 10 pounds
for the control group. Only
18.2 percent of the PCAL
103 patient group relapsed
compared to 82 percent of
the patients in the control
group.
Blum et al.20
Neuronutrient effects on
weight loss on
carbohydrate bingeing in a
bariatric setting. Curr Ther
Res. 1990; 48:2a17.
Over-Eating PCAL 103 247 730 PCOT
OP
After two years, craving
and binge eating were
reduced one-third in group
of patients on PCAL 103,
as compared to the control
patients. PCAL 103 group
regained 14.7 pounds of
their lost weight compared
with 41.7 percent weight
regained in control
patients.
Blum K, Cull JG, Chen JHT,
Garcia-Swan S, Holder JM,
Wood R, et al. Clinical
relevance of PhenCal in
maintaining weight loss in
an open-label, controlled 2-
year study. Curr Ther Res.
1997; 58:745–63.
Over-Eating Chromium
Picolinate (CP) and
L-Camitine
40 112 RDBPC
CP
21 percent increase (p <
0.001) in resting metabolic
rate (RMR), no change in
lean body mass (LBM),
RMR:LBM increased 25
percent (p < 0.001). Body
fat decreased
approximately 1.5 lbs./
week, and reduction in
serum cholesterol while
incre asing RMR with no
loss of LBM
Kaats FE et al. The short-
term therapeutic effect of
treating obesity with a plan
of improved nutrition and
moderate caloric
restriction. Curr Ther Res.
1992; 51:261.
Over-Eating Chromium
Picolinate
32 180 DBPC
OP
After six months the CrP
group had an increase in
lean body mass and
avoided non-fat related
weight loss. Difference
between groups was
significant at p < 0.001.
Bahadori B, Habersack S,
Schneider H, Wascher TC,
Topiak H. Treatment with
chromium picolinate
improves lean body mass in
patients following weight
reduction. Federation Am
Soc Exp Bio 1995.
Over-Eating Chromium
Picolinate
154 72 RDBPC OP 200 and 400 mcg of CrP
brought about significant
changes in Body Mass
composition indicies when
compared with placebo
Kaats FE, Blum K, Fisher JA,
Aldeman JA. Effects of
chromium picolinate
supplementation on body
mass composition: a
randomized, double-blind,
placebo-controlled study.
Curr Ther Res. 1996;
57:747–56
Table 1: Summary of completed clinical studies with nutraceutical supplementation: a literature review (Continued)
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Over-Eating Chromium
Picolinate
122 90 RDBPC
OP
After controlling for
differences in caloric
expenditure and caloric
intake as compared with
the placebo group, 400
mcg CrP group lost
significantly more weight (p
< 0.001) and body fat (p <
0.004), had a greater
reduction in body fat (p <
0.001), significantly
improve body composition
(p < 0.004).
Kaats FE, Blum K, Pullin D,
Keith SC, Wood R. A
randomized double-masked
placebo-controlled study of
the effects of chromium
picolinate supplementation
on body composition: a
replication of previous
study. Curr Ther Res. 1998;
59:379–88.
Over-Eating Chromium
Picolinate
122 90 RDBPC
OP
Measures of changes in fat
weight, change in body
weight, percent change in
weight, and body weight
changes in kgms were all
significant in A2/A2 group,
and non-significant in A1/
A2 and A1/A1 carriers.
Blum K, Kaats G, Eisenbery
A, Sherman M, Davis K,
Comings DE, Cull JG, Ch
en THJ, Wood R, Bucci L,
Wise JA, Braverman ER,
and Pullin D. Chromium
Picolinate Induces Changes
in Body Composition as a
Function of the Taq1
Dopamine D2 Receptor A1
Alleles. Submitted to
International J. Eat. Dis.
Over-Eating Chromium
Picolinate and
Chromium
Picolinate
comparison
43 63 ROTPC
OP
CrP supplementation
resulted in significant
weight gain, while exercise
training combined with
CrP supplementation
resulted in significant
weight loss and lowered
insulin response to an oral
glucose load. Concluded
high levels of CrP
supplementation are
contraindicated for weight
loss, in young obese
women. Moreover, results
suggested that exercise
combined with CrP
supplementation may be
more beneficial than
exercise training alone for
modification of certain
CAD or NIDDM risk
factors
Grant KE, Chandler RM,
Castle AL, Ivy JL.
Chromium and exercise
training: effect on obese
women.20J Am Sports Med
1997; 29(8):992–8.
Healthy
Volunteers
Tropagen 15 30 DBPC
OP
Non-drug subjects with
Tropagen performed
better on computer
memory and performance
tasks as measured with
P300 wave evoked
potential. Changes in P300
wave evoked potential
result in better focusing
ADHD patients
Defrance JJ, Hymel C,
Trachtenberg MC et al.
Enhancement of attention
processing by Kantrol in
healthy humans: A pilot
study. Clin Electroencephalgr.
1997; 28:68–75.
Abbreviations used: BUD – building up to drink; AMA – withdrawal against medical advice; OP – outpatient; MMPI – Minnesota Multiphasic
personality inventory; DB – double-blind; IP – inpatient; SCL – skin conductance level; BESS – behavioral, emotional, social, spiritual; DBPC –
double-blind placebo-controlled; DUI – driving under the influence; R – randomized; TO – open trial
Source : Chen et al 2004 [39]with permission Elsevier.
Table 1: Summary of completed clinical studies with nutraceutical supplementation: a literature review (Continued)
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1. In a one year open trial consisting of 600 patients mod-
erate to severe alcoholics utilization of both Oral and IV
forms of Synaptamine resulted in significant reduction in
cravings; reduced depression, reduced anxiety; reduced
anger; reduced fatigue; reduced lack of energy, and
reduced crisis [36].
2. In a one year open trial consisting of 76 patients severe
poly drug addicts utilization of oral forms of Synaptamine
resulted in significant attenuation of drug cravings;
reduced relapse; reduced stress; reduced depression;
reduced anger; and increased energy. The drop- out rate
for alcoholics was only 7% [40].
3. In a one year cross sectional open trial study of 24
unscreened individuals utilization of oral Synaptamine
variant resulted in the following benefits: stress reduction;
sleep enhancement; increase in energy level; generalized
well-being; reduction in cravings (sweets/carbs); improve-
ment in mental focus/memory; improvement in blood
sugar levels; reduction in food consumption; loss of
inches around waist; loss of weight; reduction in blood
pressure; improvement in workout performance; reduc-
Table 2: Amino acid nutrition therapy
Supplemental
Ingredient
Restored Brain
Chemical
Addictive Substance
Abuse
Amino Acid Deficiency
Symptoms
Expected Behavior
Change
D-Phenylalanine or DL-
Phenylalanine
Enkephalins, Endorphins Heroin, Alcohol, Marijuana,
Sweets, Starches,
Chocolate, Tobacco
Most Reward Deficiency
Syndrome (RDS)
conditions sensitive to
physical or emotional pain.
Crave comfort and
pleasure. Desire certain
food or drugs. D-
Phenylalaine is a known
enkephalinease inhibitor.
Reward stimulation. Anti-
craving. Mild anti-
depression. Mild improved
energy and focus. D-
Phenylalaine promontes
pain relief, increases
pleasure.
L-Phenylalanine or L-
Tyrosine
Norepinephrine,
Dopamine
Caffeine, Speed, Cocaine,
Marijuana, Aspartame,
Chocolate, Alcohol,
Tobacco, Sweets, Starches
Most RDS conditions.
Depression, low energy.
Lack of focus and
concentration. Attention-
deficit disorder.
Reward stimulation. Anti-
craving. Anti-depression.
Increased energy.
Improved mental focus.
L-Tryptophan or 5
hydroxytryptophan (5HTP)
Serotonin Sweets, Alcohol, Starch,
Ecstasy, Marijuana,
Chocolate, Tobacco
Low self esteem.
Obsessive/compulsive
behaviors. Irritability or
rage. Sleep problems.
Afternoon or evening
cravings. Negativity. Heat
intolerance. Fibromyalgia.
Seasonal affective disorder.
Anti-craving. Anti-
depression. Anti-insomnia.
Improved appetite control.
Improvement in all mood
and other serotonin
deficiency syndromes.
Gamma-amino butyric acid
(GABA)
GABA Valium, Alcohol, Marijuana,
Tobacco, Sweetes,
Starches
Feeling of being stressed
out. Nervous. Tense
muscles. Trouble relaxing.
Promotes calmness.
Promotes relaxation.
L-Glutamine GABA (mild enhancement).
Fuel source for entire brain
Sweets, Starches, Alcohol Stress. Mood swings.
Hypoglycemia.
Anti-craving, anti-stress.
Levels blood sugar and
mood. GABA (mild
enhancement). Fuel source
for entire brain.
Table 2 Comments: Rhodiola rosea has been added to the formula and is a known Catechol-O-methyl transferase (COMT) inhibitor. This
provides more synaptic dopamine in the VTA/NAc.
Source: Perfumi M, Mattioli L.
Adaptogenic and central system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in
mice. Phytother Res. 21 2007 37–43
Chromium salts – This has been added to the formula to enhance insulin sensitivity and resultant brain concentration of serotonin.
Note: To assist in amino acid nutritional therapy, the use of a multivitamin/mineral formula is recommended. Many vitamins and minerals serve as
co-factors in neurotransmitter synthesis. They also serve to restore general balance, vitality and well-being to the RDS patient who typically is in a
state of poor nutritional health. The utilization of GABA is limited due to its polar nature and ability to cross the blood brain barrier. Glutamate is
used in a low level only to prevent over-inhibition of enkephalin breakdown and subsequent inhibition of GABAergic spiny neurons of the substantia
nigra.
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tion in drug seeking behavior ; reduction in hyperactivity;
reduction in cholesterol levels [37].
4. In a subset of 27 individuals out of 1000 self-identified
obese subjects geneotyped for polymorphisms of the
DRD2 gene and of those carrying the Taq A1 allele had a
significant Pearson correlation with days on treatment
compared to the A2 carriers. For the DRD2A1 carriers the
number of days on Synaptamine Complex (variant
changed according to geneotyping a total of five candidate
genes) was 110 compared to only 52 days in A2 probands
suggesting that DRD2 genotype can predict treatment
compliance [76].
5. In a subset of 27 individuals out of 1000 self-identified
obese subjects geneotyped for polymorphisms of the
DRD2, PPAR gamma 2, MTHDFR, 5-HT2a genes and sub-
sequently provided a customized Synaptamine variant
based on polymorphisms the following significant results
were obtained: weight loss; sugar craving reduction; appe-
tite suppression; snack reduction; reduction in late night
bingeing; increased perception of over-eating; increased
energy; enhanced quality of sleep; and increased happi-
ness [77].
Table 2 provides a list of proposed ingredients for
dopaminergic activation.
The result of utilizing this natural dopaminergic activating
approach over time should lead to neuronal DA release at
the NAc, potentiating a proliferation of D2 receptors
[28,29]. Moreover, support in humans is derived from
anti-craving effects observed in numerous peer reviewed
published clinical trials including randomized double-
blind placebo controlled studies [34-48] (see also Table
2). It is noteworthy that animal gene therapy utilizing
cDNA vectors of the DRD2gene implanted into the NAc
results in decrease alcohol craving behavior [49]. We are
cognizant that the dopaminergic activation approach
should be utilized to treat not only alcohol, cocaine and
nicotine cravings, but glucose craving as well. Thus the
coupling of genetic antecedents and nutrition may be a
very viable alternative approach for the treatment of obes-
ity.
Nutrigenomics of obesity: a case study
Obesity-related medical conditions are the second leading
cause of death in the U.S. Classified as a chronic disease in
1985, the understanding of obesity and its causes and
effects has been further elucidated through additional
research into the genetic and biologic factors influencing
this deadly disease. What used to be understood as prima-
rily a behavioral problem of overeating and under-exercis-
ing has only contributed to continued increases in the
rates of obesity despite increases in dieting, exercise and
the understanding of genes [50]. Successful strategies to
induce sustainable fat loss and manage obesity effectively
have been elusive. For the most part, the tactics employed
have not been multi-faceted, multi-system approaches,
but have been characterized by one-dimensional meta-
bolic approaches (e.g. cannabinoid (CB1) receptor block-
ade; serotonin receptor stimulation) targeted at achieving
weight loss as measured by linear criteria (i.e. scale weight,
Body Mass Index (BMI), percent body fat, etc).
Recent evidence indicates a much more complex and mul-
tidimensional syndrome, characterized by the simultane-
ous breakdown of many facets of metabolism exacerbated
or limited by the predispositions of inherited genetic traits
[51,52]. There is significant evidence to substantiate the
existence of RDS as a new paradigm shift in the under-
standing of Obesity [53]. Specifically, there are genetic
links to the various roles of catecholaminergic-influenced
pathways in aberrant substance seeking behavior, in par-
ticular cravings for carbohydrates [14,50,53,54]. We pro-
pose that these various neurological factors involved in
the etiology of obesity, regulated by genetic predisposi-
tions, are a subtype of RDS. The treatment of obesity and
or metabolic syndrome genomic mechanisms may pave
the way for novel prescription pharmaceuticals as well as
nutritional and/or nutraceutical therapies. There is grow-
ing evidence to support the augmentation of precursor
amino acid therapy and enkephalinase and COMT inhibi-
tion leading to enhanced levels of neurotransmitters: sero-
tonin, enkephalins, GABA and dopamine/
norepinephrine [26]. Utilizing the combination of
nutraceuticals directed at replenishing the nutrigenomic
needs of multiple pathways, including brain reward/met-
abolic targets, mechanistically mimicking the brain
reward cascade as well as fat regulation and cell repair
(DRD2, 5-HTT2a. PPAR-Gamma, MTHFR and Leptin
genes) will provide significant anti-obesity benefits
[1,19,20,22,34,35].
Our laboratory recently presented evidence to support the
significant benefits of a DNA-directed personalized
weight management solution ([34,35]; see table 2). We
are proposing potential mechanisms herein, along with
the rationale for utilizing this multifaceted approach to
attenuate the pleiotropic defaults in obesity as well as
other addictions including alcohol, cocaine and nicotine.
In this regard, preliminary testing for the first time seems
to support a combination of neurotransmitter precursor
amino acids, enkephalinase inhibition, and catecho-
lamine 0-methyl-transferase (C.O.M.T.) inhibition ther-
apy. Components of a nutrigenomic formula are
modified based on the identification of specific gene pol-
ymorphisms resulting from genomic testing and the deter-
mination of correct dosage levels to promote successful
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and sustainable results in improved body recomposition
[55,56].
In summary, the impact of biomics technology and the
DNA directed nutraceutical targeting of the brain reward
circuitry may provide a customized approach to prevent
and treat high risk individuals who are carriers of a genetic
predisposition to obesity and related RDS behaviors.
While over 600 genes have been associated with obesity,
we believe that selective candidate genes could provide
useful information. Thus, we present the necessity of
exploiting systems biology and "omics" [34].
Relapse in addiction: anti-reward
"A neurobiological model of the brain emotional systems
has been proposed to explain the persistent changes in
motivation that are associated with vulnerability to
relapse in addiction, and this model may generalize to
other psychopathology associated with dysregulated
motivational systems" [57]. Addiction is conceptualized
as a cycle of decreased function of brain reward systems
and recruitment of antireward systems that progressively
worsen, resulting in the compulsive use of drugs. This
concept is similar to our concept of RDS which is counter
to the normal homeostatic limitation of reward function.
According to Koob and La Moal [57] "counteradaptive
processes, such as opponent processes that are part of the
normal homeostatic limitation of reward function, fail to
return within the normal homeostatic range and are
hypothesized to repeatedly drive the allostatic state. Exces-
sive drug taking thus results in not only the short-term
amelioration of the reward deficit but also suppression of
the antireward system. However, in the long term, there is
worsening of the underlying neurochemical dysregula-
tions that ultimately form an allostatic state (decreased
dopamine and opioid peptide function, increased cortico-
tropin-releasing factor activity). This allostatic state is
hypothesized to be reflected in a chronic deviation of
reward set point that is fueled not only by dysregulation
of reward circuits per se but also by recruitment of brain
and hormonal stress responses. Vulnerability to addiction
may involve genetic comorbidity (i.e. DRD2 gene A1
allele etc.) and developmental factors at the molecular,
cellular, or neurocircuitry levels that sensitize the brain
antireward systems."
Moreover, others have described relapse in specific terms
emphasizing the importance of dopaminergic function.
Volkow et al. [58] suggested that drug addiction is charac-
terized by a set of recurring processes (intoxication, with-
drawal, craving) that lead to the relapsing nature of the
disorder. These researchers have used positron emission
tomography to investigate in humans the role of
dopamine (DA) and the brain circuits it regulates in these
processes. They have shown that increases in DA are asso-
ciated with the subjective reports of drug reinforcement
corroborating the relevance of drug-induced DA increases
in the rewarding effects of drugs in humans. During with-
drawal they have shown significant reductions in DA D2
receptors and in DA release in drug abusers. They have
supported the original RDS concept [27] by postulating
that this hypodopaminergic state would result in a
decreased sensitivity to natural reinforcers, perpetuating
the use of the drug as a means to compensate for this def-
icit and contributing to the anhedonia and dysphoria seen
during withdrawal. Because the D2 reductions are associ-
ated with decreased activity in the anterior cingulate gyrus
and in the orbitofrontal cortex they postulate that this is
one of the mechanisms by which DA disruption leads to
compulsive drug administration and the lack of control
over drug intake in the drug-addicted individual. This is
supported by studies showing that during craving these
frontal regions become hyperactive in proportion to the
intensity of the craving. Therefore, Volkow et al [58] pos-
tulate that dopamine contributes to addiction by disrupt-
ing the frontal cortical circuits that regulate motivation,
drive, and self-control.
Linking attention deficit disorder with obesity
and dopamine
It is noteworthy that our laboratory has proposed that
Attention Deficit Disorder (ADHD) is a subtype of RDS,
having dopaminergic allelic associations among other
deficit genes. In fact, being carriers of specific polymor-
phisms of the dopaminergic system places these individu-
als, both children and adults, at high risk for RDS
behaviors (i.e. Substance Use Disorder [SUD] etc.)
[59,60]. The linking of ADHD and obesity via a dopamin-
ergic mechanism has also been proposed by others
[61,62]. There is strong evidence indicating that
dopamine dysregulation is very important in the patho-
physiology of ADHD, as well as in the mechanism of the
therapeutic action of stimulant drugs. With regard to ther-
apeutic implications, recent studies indicate that methyl-
phenidate (MPH), a drug widely used for ADHD, reduced
overall energy intake with a selective reduction in dietary
fat [61]. The findings are consistent with a reward defi-
ciency model [34] of obesity whereby low brain
dopamine predicts overeating and obesity, and adminis-
tering agents that increase dopamine results in reduced
feeding behavior. The obesity epidemic has focused atten-
tion on obesity's health consequences beyond cardio-vas-
cular disease and diabetes. Current findings link both
obesity and ADHD to the dopamine system and implicate
dopamine genes in body weight, eating, and ADHD,
among others. Detailed consideration suggests that
dopaminergic changes in the prefrontal cortex among
individuals with the ADHD subtype Attention Deficit Dis-
order (ADD) may increase their risk for obesity. Thus,
individuals and populations with a high prevalence of
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hypodopaminergic genes may experience higher rates of
obesity in the presence of abundant food [62]. From an
evolutionary perspective, Campbell and Eisenberg [62]
suggest that alterations in the dopamine system appear to
affect a wide range of behavioral phenotypes. They suggest
that recent evolutionary changes in the dopamine recep-
tor genes selected to increase cognitive and behavioral
flexibility may now be associated with attention problems
and increased food consumption in an obesity gene envi-
ronment.
With this said we must consider these results with caution,
especially in terms of in vivo studies by Chen et al [63]
showing a down-regulation of D2 receptor density follow-
ing a 6 day infusion of the D2 agonist quinpirole [64].
Interestingly, continuous infusion of quinpirole caused a
significant down-regulation of striatal D2 dopamine
receptors without significantly changing the density of D1
receptors. This was accompanied by a decrease in the level
of D2 receptor messenger RNA in the striatum as meas-
ured by northern blotting. The down-regulation of
dopamine receptors was selective for D2 dopamine recep-
tors. Moreover, continuous treatment with quinpirole
resulted in a significant increase in striatal mu opioid
receptor levels without significant change in the delta opi-
oid receptors. This treatment also induced a significant
decrease in proenkephalin messenger RNA in the stria-
tum. Taken together, these results suggest that the down-
regulation of D2 dopamine receptor and D2 receptor mes-
senger RNA is the result of the persistent stimulation of
D2 receptors and that the up-regulation of mu opioid
receptors may be a compensatory response to a decreased
biosynthesis of enkephalin. While this appears at first
sight to contradict our suggestion, we theorize that the dif-
ference in continuous stimulation by a slow (more physi-
ological and natural) release of DA, as proposed herein,
will result in a proliferation in D2 receptors as seen in the
in vitro studies [28,29] and documented by the consistent
anti-craving effects observed in clinical trials [18,34-49].
It is noteworthy that diminished DA receptors are not
inevitably associated with depression or addictive behav-
iors. In fact, while the lower incidence of Parkinson's dis-
ease (PD) among smokers may be explained by a
protective effect of cigarette smoke, or by a tendency to
avoid addictive behaviors among future PD cases, this
does not hold true for alcoholism. Hernan et al [64] con-
ducted an indirect test of the latter hypothesis by compar-
ing the incidence of PD between alcoholics and
nonalcoholics in the General Practice Research Database
of the United Kingdom. Their case-control study included
1,019 cases and 10,123 matched controls. Overall, they
did not find a lower incidence of PD among alcoholics
compared with nonalcoholics (odds ratio: 1.09; 95 % CI:
0.67, 1.78). However, the contrary made be true. In Par-
kinson's disease, dopamine dysregulation syndrome
(DDS) is characterized by severe dopamine addiction and
behavioral disorders such as manic psychosis, hypersexu-
ality, pathological gambling, and mood swings or Reward
Deficiency Syndrome, as reported by Linazaroso et al [65].
In this regard, Witjas et al [66] describe the case of 2 young
parkinsonian patients suffering from disabling motor
fluctuations and dyskinesia associated with severe DDS.
In addition to alleviating the motor disability in both
patients, subthalamic nucleus (STN) deep brain stimula-
tion greatly reduced the behavioral disorders as well as
completely abolishing the addiction to dopaminergic
treatment. According to the authors [66], dopaminergic
addiction in patients with Parkinson's disease therefore
does not constitute an obstacle to high-frequency STN
stimulation, and this treatment may even cure the addic-
tion. These findings related to Parkinson's disease partly
support our proposal herein.
There is an abundance of studies showing that acute
blockade of DA receptors will result in an attenuation of
substance seeking as in the case observed for the Cannab-
inoid CB1 receptor antagonist, Rimonabant, which neu-
ronal blocks DA-release [67]. This and other work has
prompted Berridge [68] to rethink the role of DA as a so
called "well-being substance". According to Berridge there
are three competing explanatory categories: 'liking,' learn-
ing, and 'wanting.' Does dopamine mostly mediate the
hedonic impact of reward ('liking')? Does it instead mead-
iate learned predictions of future reward, and stamp in
associative links (learning)? Or does dopamine motivate
the pursuit of rewards by attributing incentive salience to
reward-related stimuli ('wanting')? In this regard, recent
evidence indicates that dopamine is not needed for new
learning, and is not sufficient to mediate learning directly
by causing teaching or prediction signals. By contrast,
growing evidence indicates that dopamine does contrib-
ute causally to incentive salience. Dopamine appears nec-
essary for normal 'wanting', and dopamine activation can
be sufficient to enhance cue-triggered incentive salience.
Drugs of abuse that promote dopamine signals short-cir-
cuit and sensitize the dynamic mesolimbic mechanisms
that evolved to attribute incentive salience to rewards.
Such drugs interact with incentive salience integrations of
Pavlovian associative information with physiological
state signals. In short, dopamine's contribution appears to
be chiefly to cause 'wanting' for hedonic rewards, more
than 'liking' or learning for those rewards. Interestingly,
Alcaro et al [69] agree with Berridge's view by suggesting
that the rewarding properties of drugs of abuse are, in
part, caused by the activation of the "SEEKING" disposi-
tion, ranging from appetitive drive to persistent craving
depending on the intensity of the affect. The implications
of such a view for understanding addiction are consid-
ered, with particular emphasis on factors predisposing
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individuals to develop compulsive drug seeking behav-
iors. In our view this predisposition is genetic and
involves among other candidate genes the DRD2 gene.
One important example of hedonic "wanting" and or
"SEEKING" predisposition involves polymorphisms of
the DRD 2 gene [70]. Statistical analysis revealed a signif-
icant association between the DRD2 TaqI A genotypes and
"Eros" (a loving style characterized by a tendency to
develop intense emotional experiences based on physical
attraction to the partner), thus supporting hedonism as a
"wanting" or "SEEKING" phenomena. Exploiting this
view one might argue that the "reward center" be simpli-
fied and termed "the well-being system".
Summary
In brief, the site of the brain where one experiences feel-
ings of well being is the mesolimbic system. This part of
the brain has been termed the "reward center". The chem-
ical messages include serotonin, enkephalins, GABA and
dopamine, all working in concert to provide a net release
of DA at the NAc (a region in the mesolimbic system). It
is well known that genes control the synthesis, vesicular
storage, metabolism, receptor formation and catabolism
of neurotransmitters. The polymorphic versions of these
genes have certain variations, which could lead to an
impairment of the neurochemical events involved in the
neuronal release of DA. The cascade of these neuronal
events has been termed "Brain Reward Cascade". A break-
down of this cascade will ultimately lead to a dysregula-
tion and dysfunction of DA. Since DA has been
established as the "pleasure molecule" and the "anti-stress
molecule," any reduction in function could lead to reward
deficiency and resultant aberrant substance seeking
behavior. Our physiology is motivationally programmed
to drink, eat, have sex and desire pleasurable experiences.
Impairment of the mechanisms involved in these natural
processes leads to multiple impulsive, compulsive and
addictive behaviors governed by genetic polymorphic
antecedents. While there are a plethora of genetic varia-
tions at the level of mesolimbic activity, polymorphisms
of the serotonergic-2A receptor (5-HTT2a), dopamine D2
receptor (DRD2) and catechol-o-methyl-transferase
(COMT) genes predispose individuals to excessive crav-
ings and resultant aberrant behaviors. An umbrella term
to describe common genetic antecedents of multiple
impulsive, compulsive and addictive behaviors is RDS.
Individuals possessing a paucity of serotonergic and/or
dopaminergic receptors and a increased rate of synaptic
DA catabolism due to a high catabolic genotype of the
COMT gene are predisposed to self-medicating with any
substance or behavior that will activate DA release, includ-
ing alcohol, opiates, psychostimulants, nicotine, gam-
bling, sex, and even excessive internet gaming, among
others. Acute utilization of these substances induces a
feeling of well being. But unfortunately, sustained and
prolonged abuse leads to a toxic pseudo feeling of well
being resulting in tolerance and disease or discomfort.
Thus, low DA receptor levels consequent on carrying the
DRD2 A1 allelic genotype result in excessive cravings and
consequential behavior, whereas normal or high DA
receptors levels result in low craving-induced behavior. In
terms of preventing substance abuse, one goal would be to
induce a proliferation of DA D2 receptors in genetically
prone individuals. Experiments in vitro have shown that
constant stimulation of the DA receptor system via a
known D2 agonist results in significant proliferation of
D2 receptors in spite of genetic antecedents. In essence,
D2 receptor stimulation signals negative feedback mecha-
nisms in the mesolimbic system to induce mRNA expres-
sion, causing proliferation of D2 receptors. This molecular
finding serves as the basis for inducing DA release natu-
rally, also causing the same induction of D2-directed
mRNA and thus proliferation of D2 receptors in the
human. This proliferation of D2 receptors will in turn
induce the attenuation of craving behavior. In fact, as
mentioned earlier, this has been proven with work show-
ing DNA-directed overexpression (a form of gene therapy)
of the DRD2 receptors and significant reduction in alco-
hol craving-induced behavior in animals [50]. Finally, uti-
lizing long term dopaminergic activation will modify
behaviors including Substance Use Disorders (SUD),
Attention Deficit Hyperactivity Disorder (ADHD) and
Obesity among other reward deficient aberrant behaviors.
Support for the impulsive nature of individuals possessing
dopaminergic gene variants is derived from a recent article
suggesting that variants in the COMT gene predicts impul-
sive choice behavior, and may shed light on treatment tar-
gets [71].
A new but emerging concept provides a more comprehen-
sive understanding of reward behaviors and the role of
DA. In fact, interfering with accumbens DA appears par-
tially to dissociate the process of primary reinforcement
from processes regulating instrumental response initia-
tion, maintenance and selection [72]. The fact that DA in
the accumbens is involved with seeking maintenance sug-
gests that activating the DA system over long periods of
time rather than blocking DA receptors should result in
attenuation of substance seeking behavior. This idea does
not negate the important use of early detoxification
whereby opioid receptors are blocked with Naloxone
(Trexan/Rivera) [73], or DA activity is reduced with Acom-
posate [74] or with CB1 receptor blockers like Acomplia
[75] among other similar approaches. It is noteworthy
that assessment of 42 studies led to the conclusion that
short-term administration of naltrexone significantly
reduced the relapse rate, but was not associated with mod-
ification in the abstinence rate, suggesting the need for
additional approaches [74].
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(page number not for citation purposes)
We therefore suggest further that the biochemical and
molecular changes that take place in dopaminergic and
enkephalinergic systems following continuous neutraceu-
tical treatment with dopamine agonists may underlie the
mechanisms by which certain dopamine-mediated behav-
iors may be influenced. It is our intention to perform
micro-dialysis studies showing that precursor amino acid
therapy and enkephalinase inhibition induce DA release
at the nucleus accumbens of both animals and humans, as
well to perform additional clinical trials using nutrige-
nomic principles [76,77]. Finally our concept is supported
by other work involving glutamate neurotoxicity. Preincu-
bation with the D2 type dopamine agonists provides neu-
roprotection against glutamate neurotoxicity and the
protective effects blocked by a D2 antagonist, indicating
that D2 agonists provide protection mediated not only by
the inhibition of dopamine turnover, but also via D2 type
dopamine receptor [78]. While we caution interpretation
our laboratory is encouraged that long -term dopaminer-
gic agonistic therapy seems warranted.
Competing interests
Kenneth Blum, Lonna Williams, B William Downs, and
Roger Waite are officers of LifeGen Inc. and current stock
holders. LifeGen, Inc. is the worldwide distributor of Syn-
aptamine.™
Authors' contributions
KB Investigator and major contributor to writing of
manuscript; ALHCC – Co-investigator and contributor to
hypothesis; TJHC – Editorial contributions; ERB – Co-
writer and editorial support; SHB – Literature search; KC
– Editorial review; BWD – Major editor and co-writer;
RLW – Contributor to clinical aspects of the commentary;
LW – Editorial contributions; TJP – Statistical contribu-
tions and co-contributor to overall concept; MK – Edito-
rial assistant and scientific review; TP – Editorial review;
DEC – Contributor to scientific validity and editorial; HT
– Editorial review; JR – Editorial review; PR – Editorial
review; MOB – Contributor to writing manuscript and
editorial and literature review.
Acknowledgements
The authors would like to thank LifeGen, Inc. Electronic Waveform Lab,
Huntington Beach and Path Research Foundation for their financial support
in the development of this article.
References
1. Blum K, Kozlowski GP: Ethanol and neuromodulator interac-
tions: a cascade model of reward. In Alcohol and Behavior Edited
by: Ollat H, Parvez S, Parvez H. Utrecht, Netherlands: VSP Press;
1990:131-149.
2. Malhotra AK, Lencz T, Correll CU, Kane JM: Genomics and the
future of pharmacotherapy in psychiatry. Int Rev Psychiatry
2007, 19:523-530.
3. Koob GF, Le Moal M: Addiction and the Brain Antireward Sys-
tem. Annu Rev Psychol 2008, 59:29-53.
4. Volkow ND, Fowler JS, Wang GJ, Goldstein RZ: Role of dopamine,
the frontal cortex and memory circuits in drug addiction:
insight from imaging studies. Neurobiol Learn Mem 2002,
78:610-624.
5. Radwan GN, Setouhy ME, Mohamed MK, Hamid MA, Israel E, Azem
SA, Kamel O, Loffredo CA: DRD2/ANKK1 TaqI polymorphism
and smoking behavior of Egyptian male cigarette smokers.
Nicotine Tob Res 2007, 9:1325-1329.
6. da Silva Lobo DS, Vallada HP, Knight J, Martins SS, Tavares H, Gentil
V, Kennedy JL: Dopamine genes and pathological gambling in
discordant sib-pairs. J Gambl Stud 2007, 23:421-33.
7. Kirsch P, Reuter M, Mier D, Lonsdorf T, Stark R, Gallhofer B, Vaitl D,
Hennig J: Imaging gene-substance interactions: the effect of
the DRD2 TaqIA polymorphism and the dopamine agonist
bromocriptine on the brain activation during the anticipa-
tion of reward. Neurosci Lett 2006, 405:196-201.
8. Costa-Mallen P, Costa LG, Checkoway H: Genotype combina-
tions for monoamine oxidase-B intron 13 polymorphism and
dopamine D2 receptor TaqIB polymorphism are associated
with ever-smoking status among men. Neurosci Lett 2005,
385:158-162.
9. Shahmoradgoli Najafabadi M, Ohadi M, Joghataie MT, Valaie F, Riazal-
hosseini Y, Mostafavi H, Mohammadbeigi F, Najmabadi H: Associa-
tion between the DRD2 A1 allele and opium addiction in the
Iranian population. Am J Med Genet B Neuropsychiatr Genet 2005,
134B(1):39-41.
10. Swan GE, Jack LM, Valdes AM, Ring HZ, Ton CC, Curry SJ, McAfee
T: Joint effect of dopaminergic genes on likelihood of smok-
ing following treatment with bupropion SR. Health Psychol
2007, 26:361-368.
11. Xu K, Lichtermann D, Lipsky RH, Franke P, Liu X, Hu Y, Cao L,
Schwab SG, Wildenauer DB, Bau CH, Ferro E, Astor W, Finch T,
Terry J, Taubman J, Maier W, Goldman D: Association of specific
haplotypes of D2 dopamine receptor gene with vulnerability
to heroin dependence in 2 distinct populations. Arch Gen Psy-
chiatry 2004, 61:597-606.
12. Spangler R, Wittkowski KM, Goddard NL, Avena NM, Hoebel BG,
Leibowitz SF: Opiate-like effects of sugar on gene expression
in reward areas of the rat brain. Brain Res Mol Brain Res 2004,
124:134-142.
13. Ponce G, Jimenez-Arriero MA, Rubio G, Hoenicka J, Ampuero I,
Ramos JA, Palomo T: The A1 allele of the DRD2 gene (TaqI A
polymorphisms) is associated with antisocial personality in a
sample of alcohol-dependent patients. Eur Psychiatry 2003,
18:356-360.
14. Spitz MR, Shi H, Yang F, Hudmon KS, Jiang H, Chamberlain RM, Amos
CI, Wan Y, Cinciripini P, Hong WK, Wu X: Case-control study of
the D2 dopamine receptor gene and smoking status in lung
cancer patients. J Natl Cancer Inst 1998, 90:358-363.
15. Comings DE, Muhleman D, Gysin R: Dopamine D2 receptor
(DRD2) gene and susceptibility to posttraumatic stress dis-
order: a study and replication. Biol Psychiatry 1996, 40:368-372.
16. Epstein LH, Temple JL, Neaderhiser BJ, Salis RJ, Erbe RW, Leddy JJ:
Food reinforcement, the dopamine D2 receptor genotype,
and energy intake in obese and nonobese humans. Behav Neu-
rosci 2007, 121:877-889.
17. Xiao C, Zhang J, Krnjeviæ K, Ye JH: Effects of ethanol on mid-
brain neurons: role of opioid receptors. Alcohol Clin Exp Res
2007, 31:1106-1113.
18. Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D,
Lubar JO, Chen TJ, Comings DE: Reward deficiency syndrome: a
biogenetic model for the diagnosis and treatment of impul-
sive, addictive, and compulsive behaviors. J Psychoactive Drugs
2000, 32(Suppl):i-iv.
19. Comings DE, Blum K: Reward deficiency syndrome: genetic
aspects of behavioral disorders. Prog Brain Res 2000,
126:325-341.
20. Bowirrat A, Oscar-Berman M: Relationship between dopaminer-
gic neurotransmission, alcoholism, and Reward Deficiency
Syndrome.
Am J Med Genet B Neuropsychiatr Genet 2005,
132B(1):29-37.
21. Green AI, Zimmet SV, Strous RD, Schildkraut JJ: Clozapine for
comorbid substance use disorder and schizophrenia: do
patients with schizophrenia have a reward-deficiency syn-
drome that can be ameliorated by clozapine? Harv Rev Psychi-
atry 1999, 6:287-296.
22. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Jayne M, Ma Y,
Pradhan K, Wong C: Profound decreases in dopamine release
Page 14
Theoretical Biology and Medical Modelling 2008, 5:24 http://www.tbiomed.com/content/5/1/24
Page 15 of 16
(page number not for citation purposes)
in striatum in detoxified alcoholics: possible orbitofrontal
involvement. J Neurosci 2007, 27:12700-12706.
23. Carelli RM: The nucleus accumbens and reward: neurophysio-
logical investigations in behaving animals. Behav Cogn Neurosci
Rev 2002, 1:281-296.
24. Pohjalainen T, Rinne JO, Någren K, Lehikoinen P, Anttila K, Syvälahti
EK, Hietala J: The A1 allele of the human D2 dopamine recep-
tor gene predicts low D2 receptor availability in healthy vol-
unteers. Mol Psychiatry 1998, 3:256-260.
25. Noble EP, Blum K, Ritchie T, Montgomery A, Sheridan PJ: Allelic
association of the D2 dopamine receptor gene with recep-
tor-binding characteristics in alcoholism. Arch Gen Psychiatry
1991, 48:648-654.
26. Blum K, Chen TJ, Meshkin B, Waite RL, Downs BW, Blum SH, Men-
gucci JF, Arcuri V, Braverman ER, Palomo T: Manipulation of cate-
chol-O-methyl-transferase (COMT) activity to influence the
attenuation of substance seeking behavior, a subtype of
Reward Deficiency Syndrome (RDS), is dependent upon
gene polymorphisms: a hypothesis. Med Hypotheses 2007,
69:1054-1060.
27. Blum K, Sheridan PJ, Wood RC, Braverman ER, Chen TJ, Cull JG,
Comings DE: The D2 dopamine receptor gene as a determi-
nant of reward deficiency syndrome. J R Soc Med 1996,
89:396-400.
28. Boundy VA, Pacheco MA, Guan W, Molinoff PB: Agonists and
antagonists differentially regulate the high affinity state of
the D2L receptor in human embryonic kidney 293 cells. Mol
Pharmacol 1995, 48:956-964.
29. Boundy VA, Lu L, Molinoff PB: Differential coupling of rat D2
dopamine receptor isoforms expressed in Spodoptera fru-
giperda insect cells. J Pharmacol Exp Ther 1996, 276:784-794.
30. Lawford BR, Young RM, Rowell JA, Qualichefski J, Fletcher BH, Syn-
dulko K, Ritchie T, Noble EP: Bromocriptine in the treatment of
alcoholics with the D2 dopamine receptor A1 allele. Nat Med
1995, 1:337-341.
31. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A: Effi-
cacy and safety of the weight-loss drug rimonabant: a meta-
analysis of randomised trials.
Lancet 2007, 370:1671-1672.
32. Peng XQ, Li X, Li J, Ramachandran PV, Gagare PD, Pratihar D, Ashby
CR Jr, Gardner EL, Xi ZX: 97(3). Drug Alcohol Depend 2008,
97(3):207-15.
33. Rothman RB, Blough BE, Baumann MH: Dual dopamine/serotonin
releasers as potential medications for stimulant and alcohol
addictions. AAPS J 2007, 9:E1-10.
34. Chen TJH, Blum K, Kaats G, Braverman E, Pullin D, Downs BW, Mar-
tinez-Pons M, Blum SH, Mengucci J, Bagchi D, Bagchi M, Robarge A,
Meshkin B, Arcuri V, Varshavskiy M, Notaro A, Comings DE, White
L: Reviewing the role of putative candidate genes in "Neu-
robesigenics" a clinical subtype of Reward Deficiency Syn-
drome (RDS). Gene Ther Mol Biol 2007, 11:61-74.
35. Blum K, Chen TJ, Meshkin B, Downs BW, Gordon CA, Blum S, Men-
gucci JF, Braverman ER, Arcuri V, Deutsch R, Pons MM: Genotrim,
a DNA -customized nutrigenomic product, targets genetic
factors of obesity: hypothesizing a dopamine-glucose corre-
lation demonstrating reward deficiency syndrome (RDS).
Medical Hypotheses 2007, 68:844-852.
36. Blum K, Chen TJH, Downs BW, Meshkin B, Blum SH, Martinez-Pons
M, Mengucci JF, Waite RL, Arcuri V, Varshavskiy M, Braverman ER:
Synaptamine (Sg8839): an amino-acid enkephalinase inhibi-
tion nutraceutical improves recovery of alcoholics, a subtype
of Reward Deficiency Syndrome (RDS). Trends in Applied Sci-
ences Res 2007, 2:132-138.
37. Blum K, Chen TJH, Meshkin B, Downs BW, Gordon CA, Blum SH,
Mengucci JF, Braverman ER, Arcuri V, Varshavskiy M, Deutsch R, Mar-
tinez-Pons M: Reward Deficiency Syndrome in Obesity: a pre-
liminary cross-sectional trial with a Genotrim variant. Adv
Ther 2006, 23:1040-1051.
38. Chen TJH, Blum K, Kaats G, Braverman ER, Eisenberg A, Sherman M,
Davis K, Comings DE, Wood R, Pullin D, Arcuri V, Varshavskiy M,
Mengucci JF, Blum SH, Downs BW, Meshkin B, Waite RL, Williams L,
Schoolfield J, White L: Chromium Picolinate (CrP) a putative
anti-obesity nutrient induces changes in body composition as
a function of Taq1 dopamine D2 receptor polymorphisms in
a randomized double-blind placebo controlled study. Gene
Ther Mol Biol 2007, 11:161-170.
39. Chen TJ, Blum K, Payte JT, Schoolfield J, Hopper D, Stanford M,
Braverman ER:
Narcotic antagonists in drug dependence: pilot
study showing enhancement of compliance with SYN-10,
amino-acid precursors and enkephalinase inhibition therapy.
Med Hypotheses 2004, 63:538-548.
40. Chen TJ, Blum K, Waite RL, Meshkin B, Schoolfield J, Downs BW,
Braverman EE, Arcuri V, Varshavskiy M, Blum SH, Mengucci J, Reuben
C, Palomo T: Gene\Narcotic Attenuation Program attenuates
substance use disorder, a clinical subtype of reward defi-
ciency syndrome. Adv Ther 2007, 24:402-414.
41. Blum K, Chen TJ, Meshkin B, Downs BW, Gordon CA, Blum S, Men-
gucci JF, Braverman ER, Arcuri V, Deutsch R, Pons MM: Genotrim,
a DNA-customized nutrigenomic product, targets genetic
factors of obesity: hypothesizing a dopamine-glucose corre-
lation demonstrating reward deficiency syndrome (RDS).
Med Hypotheses 2007, 68:844-852.
42. Brown RJ, Blum K, Trachtenberg MC: Neurodynamics of relapse
prevention: a neuronutrient approach to outpatient DUI
offenders. J Psychoactive Drugs 1990, 22:173-187.
43. Blum K, Trachtenberg MC, Elliott CE, Dingler ML, Sexton RL, Samuels
AI, Cataldie L: Enkephalinase inhibition and precursor amino
acid loading improves inpatient treatment of alcohol and
polydrug abusers: double-blind placebo-controlled study of
the nutritional adjunct SAAVE. Alcohol 1988, 5:481-493.
44. Blum K, Trachtenberg MC, Ramsay JC: Improvement of inpatient
treatment of the alcoholic as a function of neurotransmitter
restoration: a pilot study. Int J Addict 1988, 23:991-998.
45. Blum K, Trachtenberg MC: Neurogenetic deficits caused by
alcoholism: restoration by SAAVE, a neuronutrient inter-
vention adjunct. J Psychoactive Drugs 1988, 20:297-313.
46. DeFrance JF, Hymel C, Trachtenberg MC, Ginsberg LD, Schweitzer
FC, Estes S, Chen TJ, Braverman ER, Cull JG, Blum K: Enhancement
of attention processing by Kantroll in healthy humans: a pilot
study. Clin Electroencephalogr 1997, 28:68-75.
47. Blum K, Trachtenberg MC, Cook DW: Neuronutrient effects on
weight loss in carbohydrate bingers: an open clinical trial.
Curr Ther Res 1990, 43:217-233.
48. Blum K, Cull JG, Chen TJH, Garcia-Swan S, Holder JM, Wood RC,
Braverman ER, Bucci LR, Trachtenberg MC: Clinical evidence for
effectiveness of PhenCal in maintaining weight loss in an
open-label, controlled, 2 year study. Curr Ther Res 1997,
58:745-763.
49. Thanos PK, Volkow ND, Freimuth P, Umegaki H, Ikari H, Roth G,
Ingram DK, Hitzemann R: Overexpression of dopamine D2
receptors reduces alcohol self-administration. J Neurochem
2001, 78:1094-1103.
50. Noble EP, Noble RE, Ritchie T, Grandy DK, Sparks RS: D2
dopamine receptor gene and obesity. J Eating Disorders 1994,
15:205-217.
51. Maes HH, Neale Mc, Eaves IJ: Genetic and environmental factors
in relative body weight and human adiposity. Behav Gen 1997,
27(4):325-351.
52. Schoushoe K, Visscher PM, Erbas B, Kyvik KO, Hopper Jl, Henriksen
JE, Heitman BL: Twin study of genetic and environmental influ-
ences on adult body size, shape, and composition. Int J Obes
Relat Metab Disord 2004, 28(1):39-48.
53. Blum K, Braverman ER, Wood RC, Gill J, Li C, Chen TJ, Taub M,
Montgomery AR, Sheridan PJ, Cull JG: Increased prevalence of
the Taq I A1 allele of the dopamine receptor gene (DRD2) in
obesity with comorbid substance use disorder: a preliminary
report. Pharmacogenetics 1996, 6:297-305.
54. Comings DE, Flanagan SD, Dietz G, Muhlman D, Knell E, Gysin R:
The dopamine D2 receptor (DRD2) as a major in obesity and
height. Biochem Med Metab Biol 1993, 50:176-185.
55. Comings DE, Gade R, McMurray JP, Muhlman D, Johnson P, Verde R,
Peters WR: Genetic variants of the human obesity (OB) gene
: association with body mass index in young women : psychi-
atric symptoms and interactions with the dopamine D2
receptor(DRD2) gene. Mol Psychiatry 1996, 1:325-335.
56. Blum K, Meshkin B, Prihoda TJ, Downs BW, Waite RL, Braverman ER,
White L: DNA-Customized Genotrim
®
induces significant
reductions in weight, appetite and sugar cravings in the
D.I.E.T. study: Polymorphic correlates involving five candi-
date genes in Obesity, a clinical subtype of Reward Defi-
ciency Syndrome (RDS). Presented at the Natural Products
Association Scientific Session, 2007, July 21, Las Vegas, NV (abstract) .
Page 15
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Theoretical Biology and Medical Modelling 2008, 5:24 http://www.tbiomed.com/content/5/1/24
Page 16 of 16
(page number not for citation purposes)
57. Koob GF, Le Moal M: Addiction and the Brain Antireward Sys-
tem. Annu Rev Psychol 2008, 59:29-53.
58. Volkow ND, Fowler JS, Wang GJ, Goldstein RZ: Role of dopamine,
the frontal cortex and memory circuits in drug addiction:
insight from imaging studies. Neurobiol Learn Mem 2002,
78:610-624.
59. Comings DE, Chen TJ, Blum K, Mengucci JF, Blum SH, Meshkin B:
Neurogenetic interactions and aberrant behavioral co-mor-
bidity of attention deficit hyperactivity disorder (ADHD):
dispelling myths. Theor Biol Med Model 2005, 23(2):50.
60. Blum K, Chen ALC, Braverman ER, Comings DE, Chen TJH, Arcuri
V, Blum SH, Meshkin Downs BW, Waite RL, Notaro A, Lubar J, Wil-
liams L, Prihoda TJ, Palomo T, Oscar Berman M: Attention-Deficit-
Hyperactivity Disorder and Reward Deficiency Syndrome. J
Neuropsychiat Diseas Diag Treatment in press.
61. Liu LL, Li BM, Yang J, Wang YW: Does dopaminergic reward sys-
tem contribute to explaining comorbidity obesity and
ADHD? Med Hypotheses 2008, 70(6):1118-20.
62. Campbell BC, Eisenberg D: Obesity, attention deficit-hyperac-
tivity disorder and the dopaminergic reward system. Coll
Antropol 2007, 31:33-38.
63. Hernán MA, Logroscino G, Rodríguez LA: A prospective study of
alcoholism and the risk of Parkinson's disease. J Neurol 2004,
251(Suppl 7):vII14-7.
64. Chen JF, Aloyo VJ, Weiss B: Continuous treatment with the D2
dopamine receptor agonist quinpirole decreases D2
dopamine receptors, D2 dopamine receptor messenger
RNA and proenkephalin messenger RNA, and increases mu
opioid receptors in mouse striatum. Neuroscience 1993,
54:669-80.
65. Linazaroso G, van Blercom N, Lasa A: Hypothesis: Parkinson's
disease, reward deficiency syndrome and addictive effects of
levodopa. Neurologia 2004, 19:117-27.
66. Witjas T, Baunez C, Henry JM, Delfini M, Regis J, Cherif AA, Peragut
JC, Azulay JP: Addiction in Parkinson's disease: impact of sub-
thalamic nucleus deep brain stimulation. Mov Disord 2005,
20:1052-5.
67. Le Foll B, Goldberg SR: Cannabinoid CB1 receptor antagonists
as promising new medications for drug dependence. J Phar-
macol Exp Ther
2005, 312:875-83.
68. Berridge KC: The debate over dopamine's role in reward: the
case for incentive salience. Psychopharmacology (Berl) 2007,
191:391-431.
69. Alcaro A, Huber R, Panksepp J: Behavioral functions of the mes-
olimbic dopaminergic system: an affective neuroethological
perspective. Brain Res Rev 2007, 56:283-321.
70. Emanuele E, Brondino N, Pesenti S, Re S, Geroldi D: Genetic load-
ing on human loving styles. Neuro Endocrinol Lett 2007, 28:815-21.
71. Boettiger CA, Mitchell JM, Tavares VC, Robertson M, Joslyn G,
D'Esposito M, Fields HL: Immediate reward bias in humans:
fronto-parietal networks and a role for the catechol-O-
methyltransferase 158(Val/Val) genotype. J Neurosci 2007,
27:14383-14391.
72. Salamone JD, Cousins MS, Snyder BJ: Behavioral functions of
nucleus accumbens dopamine: empirical and conceptual
problems with the anhedonia hypothesis. Neurosci Biobehav Rev
1997, 21:341-59.
73. Blum K, Futterman S, Wallace JE, Schwertner HA: Naloxone-
induced inhibition of ethanol dependence in mice. Nature
1977, 265:49-51.
74. Snyder JL, Bowers TG: The efficacy of acamprosate and nal-
trexone in the treatment of alcohol dependence: a relative
benefits analysis of randomized controlled trials. Am J Drug
Alcohol Abuse 2008, 34:449-61.
75. Parolaro D, Rubino T: The role of the endogenous cannabinoid
system in drug addiction. Drug News Perspect 2008,
21(5):149-157.
76. Blum K, Chen ALC, Chen TLC, Rhoades P, Prihoda P, Downs BW,
Bagchi D, Bagchi M, Blum S, Williams L, Braverman ER, Kerner M,
Waite RL, Quirk B, White L: Dopamine D2 Receptor Taq A1
allele predicts treatment compliance of LG839 in a subset
analysis of a pilot study in the Netherlands. Gene Therapy and
Molecular Biology 2008 in press.
77. Blum K, Chen ALC, Chen TJH, Rhoades P, Prihoda P, Downs BW,
Waite RL, Williams L, Braverman ER, Braverman D, Arcuri , Kerner
M, Blum SH, Reinking J, Palomo T: LG839 (an experimental
DNA-Customized neutraceutical): Anti-obesity effects and
polymorphic gene correlates of Reward Deficiency Syn-
drome. Adv Ther
in press.
78. Sawada S, Shimohama S: MPP(+) and glutamate in the degener-
ation of nigral dopaminergic neurons. Parkinsonism Relat Disord
1999, 5(4):209-215.
Page 16
    • "In turn, the increased glutamatergic transmission modulates dopaminergic cell activity in rewarding processes, leading to alcohol addiction. [1, 9,[49][50]DA-Phen could play a critical role for alcohol-induced reinstatement, probably due to DA-ergic inputs within the basolateral amygdala complex [58][59][60]or acting on VTA DA-receptors, so suppressing alcohol seeking [1,[14][15] 17]. Furthermore, our results agree with findings from other studies on drug-induced reinstatement, like cocaine or morphine, in which D1-like agonists do not generate or promote additive effects, further supporting the use of DA-agonists in treatment of addiction [17][18][19]. "
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    • "However, an impairment of the mechanisms involved in these natural processes (e.g., a genetic hypodopaminergic activity of the brain) predisposes individuals to seek artificial stimulants and/or pleasure-seeking behaviors that will overcome this hedonic state by triggering dopaminergic centers, creating an artificial state of pleasure (Blum et al., 2008; Esch & Stefano, 2004). The chronic abuse of substances or the systematic display of thrill seeking behaviors can be seriously detrimental, and according to some researchers may lead to the inactivation of the brain reward system -Reward Deficiency Syndrome (Blum et al., 2008; Blum et al., 2012; Esch & Stefano, 2004). When balanced with the other systems, the drive system is a clearly advantage, guiding us toward important life goals (Depue & Morrone-Strupinsky, 2005; Gilbert, 2005 Gilbert, , 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: There is a growing interest in the study of psychopathic traits from an evolutionary framework; however, there is a lack of comprehensive reviews regarding this issue. To address this gap in the literature, the current paper examines the evolutionary roots of psychopathy by reviewing previous research on this topic. Specifically, the potentially adaptive role of psychopathic traits during human evolution through the lifespan is highlighted. Key areas covered include the evolution of the brain (“old brain, new brain” and the emotion-logic lag), emotion regulation, aggression and its potential adaptive function, and emotions specific to psychopathy including anger and shame/dishonor. This paper (mainly in the light of the Adaptive Calibration Model) discusses how psychopathic features can be seen as a useful heritage, especially for people who have grown in harsh psychosocial backgrounds. The implications of an evolutionary approach for the comprehension and treatment of children, youth, and adults with psychopathic traits are suggested, along with directions for future research.
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    • "Nicotine replacement therapies were the first pharmacological treatments approved by the Food and Drug Administration (FDA) for use in smoking cessation therapy, followed by bupropion and varenicline. Even if the effectiveness of nicotine replacement therapies, bupropion and varenicline appear to be high (Blum et al., 2008), doubling or tripling the smoking cessation rates in controlled studies (Le Foll and George, 2007), the real impact of these therapies has been questioned due to high rates of relapse in the long term (Alpert et al., 2013). There may be multiple reasons explaining those discrepancies such as the fact that clinical trial inclusion criteria do not always allow for generalization of results to the overall population of smokers. "
    [Show abstract] [Hide abstract] ABSTRACT: Tobacco produces an impressive burden of disease resulting in premature death in half of users. Despite effective smoking cessation medications (nicotine replacement therapies, bupropion and varenicline), there is a very high rate of relapse following quit attempts. The use of efficient strategies for the development of novel treatments is a necessity. A 'bench to bedside strategy' was initially used to develop cannabinoid CB1 receptor antagonists for the treatment of nicotine addiction. Unfortunately, after being tested on experimental animals, what seemed to be an interesting approach for the treatment of nicotine addiction resulted in serious unwanted side effects when tested in humans. Current research is focusing again on pre-clinical models in an effort to eliminate unwanted side effects while preserving the initially observed efficacy. A 'bed side to bench strategy' was used to study the role of the insula (part of the frontal cortex) in nicotine addiction. This line of research started based on clinical observations that patients suffering stroke-induced lesions to the insula showed a greater likelihood to report immediate smoking cessation without craving or relapse. Subsequently, animal models of addiction are used to explore the role of insula in addiction. Due to the inherent limitations existing in clinical versus preclinical studies, the possibility of close interaction between both models seems to be critical for the successful development of novel therapeutic strategies for nicotine dependence.
    Full-text · Article · Oct 2013 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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