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Journal of Psychoactive Drugs, 44 (2), 134–143, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0279-1072 print / 2159-9777 online
DOI: 10.1080/02791072.2012.685407
The Addictive Brain:
All Roads Lead to Dopamine
Kenneth Blum, Ph.D.a,c,d,f,g,i,k; Amanda LC Chen, Ph.D.b; John Giordano, MAC, Ph.D. (Hon)c;
Joan Borsten, M.Sc.d; Thomas JH Chen, Ph.D.e; Mary Hauser, M.Sc.f; Thomas Simpatico, M.D.g;
John Femino, M.D.h; Eric R. Braverman, M.D.i,j & Debmalya Barh, Ph.D.k
Abstract —This article will touch on theories, scientific research and conjecture about the evolutionary
genetics of the brain function and the impact of genetic variants called polymorphisms on drug-seeking
behavior. It will cover the neurological basis of pleasure-seeking and addiction, which affects
multitudes in a global atmosphere where people are seeking “pleasure states.”
Keywords — brain reward cascade, dopamine, mesolimbic system, orbital prefrontal cortex-cingulate
gyrus, relapse, reward deficiency syndrome (RDS)
When almost half of the U.S. population have indulged
in illegal drug practices, when presidential candidates are
forced to dodge the tricky question of their past history
involving illegal drug use, and when most Americans have
sloshed down a martini or two in their lifetime, there must
be a reason, there must be a need—this must be a natural
response for people to imbibe at such high rates. Even more
compelling questions surround the millions who seek out
high-risk novelty. Why do millions of us have this innate
Excerpts from this article have been published in the April
2012 issue of Colliers Magazine. The authors appreciate the editorial
work of Margaret A. Madigan and comments from B. William Downs
and Roger L. Waite of LifeGen, Inc. Conflict of interest: Kenneth Blum
is an executive and owns stock in LifeGen Inc, the exclusive worldwide
distributor of patented KB220 products and the patented GARS test. Mary
Hauser, John Giordano and Joan Borsten are LifeGen partners in research
and development. There are no other conflicts.
aProfessor, Department of Psychiatry & Mcknight Brain Institute,
University of Florida, College of Medicine, Gainesville, FL.
bProfessor, Department Engineering and Management of Advanced
Technology, Chang Jung Christian University, Taiwan, ROC.
cPresident (JG), Chief Scientist(KB), Department of Holistic
Medicine G & G Holistic Addiction Treatment Center, North Miami
Beach, FL.
dCEO (JB), NeuroScience Advisor (KB), Department of Addiction
Research and Therapy, Malibu Beach Recovery Center, Malibu, CA.
eProfessor, Department of Occupational Safety and Health, Chang
Jung Christian University, Taiwan, ROC.
fVice President (MH), Ambassador of Molecular Biology (KB),
Dominion Diagnostics, LLC, North Kingstown, RI.
gProfessor, (TS, KB), Department of Psychiatry, University of
Vermont, Burlington, VT.
hPresident, Meadows Edge, North Kingstown, RI, USA.
iMedical Director (ERB), Scientific Director (KB), Path Research
Foundation New York, NY.
jDepartment of Neurological Surgery, Weill-Cornell College of
Medicine, New York, NY.
kDirector (DB), Faculty (KB), Centre for Genomics and
Applied Gene Therapy, Institute of Integrative Omics and Applied
Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West Bengal,
India.
Please address correspondence to Kenneth Blum, Ph.D., Department
of Psychiatry, University of Florida, PO Box 103424, Gainseville,
FL 32610-3424; phone: 352-392-3681; fax: 352-392-9887; e-mail:
drd2gene@aol.com; Co-correspondence: Amanda LC Chen; email:
tjhchen@yahoo.com.tw
drive in the face of putting themselves in harm’s way? Why
are millions paying the price of their indiscretions in jails,
hospitals, wheel chairs or cemeteries? What price must
be paid for pleasure seeking or just plain getting “high”?
Maybe the answer lies within the brain, and in particular
the genome.
Once it was true that all roads led to Rome. Recently it
has been said (with regard to understanding the brain) that
all roads lead to dopamine. Thus, this simple truth is not
Journal of Psychoactive Drugs 134 Volume 44 (2), April – June 2012
Blum et al. The Addictive Brain
too dissimilar to considerations of the reward circuitry of
the brains of homo sapiens. Numerous experiments in the
scientific literature have established that the brain’s major
reward neurotransmitter pathway —the road to Rome—is
indeed dopamine (Kirsch et al. 2006).
Dopamine was first synthesized in 1910 by George
Barger and James Ewens at the Wellcome Laboratories in
London, England. It was named dopamine because it is a
monoamine whose precursor is levodopamine. In 1958 at
the National Heart Institute of Sweden, Arvid Carlsson and
Nils-Ake Hillarp were the first to recognize dopamine’s
function as a neurotransmitter (Benes 2001). In 1978 one
of the present authors (KB) invited Arvid to present
at the first Gordon Conference on Alcoholism in Santa
Barbara, California, for a discussion of the important role
of dopamine in alcoholism. Twenty-two years later in
2000 Carlsson was awarded the Nobel Prize for Physiology
or Medicine.
EVOLUTIONARY GENETICS OF DOPAMINE
Currently throughout the neuroscience literature
dopamine is considered both a “pleasure molecule” and
an “antistress molecule.” The role of dopamine in brain
function has been fraught with controversy but is arguably
very interesting and mind expanding (Blum et al. 2000).
There are many unanswered questions related to what
makes us human and what drives our unique behaviors.
While many brain theories have focused on the role of
brain size and genetic adaptations, Fred Previc (2009),
explored the provocative concept of a “dopaminergic soci-
ety.” According to Previc, the dopaminergic mind hypoth-
esis seeks to explain the differences between modern
humans and their hominid relatives by focusing on changes
in dopamine. It theorizes that increased levels of dopamine
were part of a general physiological adaptation due to an
increased consumption of meat around two million years
ago by homo habilis and later (beginning approximately
80,000 years ago) by dietary changes and other environ-
mental and social factors. This theory is supported by
recent discoveries about the seaside settlements of early
man where evidence of dietary changes, like the inclusion
of fish oils—known to increase dopamine receptors—could
have further enhanced dopamine function (Kuperstein et al.
2005).
Previc’s theory is that the “high-dopamine” society
is characterized by high intelligence, a sense of personal
destiny, a religious/cosmic preoccupation, and an obses-
sion with achieving goals and conquests. High levels of
dopamine are proposed to underlie increased psychologi-
cal disorders in industrialized societies. According to this
hypothesis, a “dopaminergic society” is an extremely goal-
oriented, fast-paced, and even manic society, “given that
dopamine is known to increase activity levels, speed up
our internal clocks and create a preference for novel over
unchanging environments”(Previc 2009).
Although behavioral evidence and some indirect
anatomical evidence like the enlargement of the dopamine-
rich striatum in humans revealed by the work of S.I.
Rapoport (1990) support a dopaminergic expansion in
humans, according to M.A. Raghanti and associates (2008)
there is still no direct evidence that dopamine levels are
markedly higher in humans relative to apes. However, the
recent discoveries about seaside settlements of early man
may provide evidence of dietary changes consistent with
this hypothesis.
There are a number of studies that report the posi-
tive relationship between omega 3 fish oil and dopamine
D2 receptor density. Specifically, decreased tissue levels
of n-3 (omega-3) fatty acids, particularly docosahexaenoic
acid (DHA), are implicated in the etiologies of nonpuer-
peral and postpartum depression. Davis and colleagues
(2010) examined the effects of a diet-induced loss of
brain DHA content and concurrent reproductive status on
dopaminergic parameters in adult female Long-Evans rats.
Decreased brain DHA produced a significant main effect
of decreased density of ventral striatal D(2)-like recep-
tors. Virgin females with decreased DHA also exhibited
higher density of D(1)-like receptors in the caudate nucleus
than virgin females with normal DHA. These receptor
alterations are similar to those found in several rodent mod-
els of depression, and are consistent with the proposed
hypodopaminergic basis for anhedonia and motivational
deficits in depression.
EVOLUTIONARY GENETICS AND THE
DRD2 GENE
The possibility does exist that prehistoric ances-
tral species over two million years ago carried the
low dopamine brain function due to low dopamine
receptors (Blum et al. 2012). Dopamine functions as
a neurotransmitter, activating the five known types of
dopamine receptors (D1 through D5) and their variants.
Dopamine from l-tyrosine, abundant in meat, is produced
in several areas of the brain, including the brain reward
site in the nucleus accumbens (NAc) which is located in
the reptilian, old brain region called the mesolimbic sys-
tem (see Figure 1). It now well known that there are two
major variant forms of the human dopamine D2 receptor
gene (DRD2) that regulate the synthesis of D2 receptors;
they are the A1 and A2 alleles. As these forms (poly-
morphisms) exist in pairs, there at least are three variants
of the dopamine D2 receptors: the A1/A1, the A1/A2,
and the A2/A2. DRD2, the most widely studied gene,
accounts for major aspects of modern human behavior.
The DRD2 A2 form, which in today’s world is con-
sidered the “normal” variation, is carried by 2/3ofthe
United States population. Carriers of the DRD2 A1 form
Journal of Psychoactive Drugs 135 Volume 44 (2), April – June 2012
Blum et al. The Addictive Brain
FIGURE 1
The Brain Reward Site∗
∗Modified from Comings 2008 with permission
about 1/3 of today’s U.S. population and have 30% to
40% lower D2receptors; this is a subset of approxi-
mately 100 million people (Blum 2011). However, within
this subset, the prevalence varies significantly between
Caucasians, African Americans, Hispanics, Asians and
Native Americans (Castiglione et al. 1995). It is prudent to
speculate that the older gene form (DRD2-A1) leading to
low dopamine function may have afforded certain survival
benefits. But as homo habilis or Australopithecus sediba
(Berger et al. 2010) increased their meat consumption,
feeding the brain with the needed l-tyrosine to synthe-
size more dopamine required to overcome the D2receptor
deficit (competitive edge), a new society was born—the
“high dopamine society” carrying the DRD2 A2 form of
this gene (Blum et al. 1996a, b).
David Comings (1996) writing in his popular book The
Gene Bomb suggests that while it may be true that genetic
adaptations are very slow there may be some exceptions
like the Tibetan altitude gene that allowed for adaptation
to high altitudes. Comings also discussed the future of the
DRD2 gene. Let us assume that the a gene variant called X
causes addiction, and that individuals with this X gene drop
out of school earlier, cohabitate with others carrying the
same genotype (this is known as “birds of a feather flock
together,” another characteristic of the DRD2 A1 form;
Fowler, Settle & Christakis 2011) and start having children
earlier than individuals who do not carry that gene. Let us
also assume that the average age at birth of the first child
of X gene carriers is 20 years, while for those not carrying
the variation it is 25 years. As a result, the X form of the
gene will reproduce faster, namely every 20 years, while
the normal form of the gene will reproduce every 25 years.
The ratio of 25/20 is 1.25. Although this gene X may seem
to not have any selective benefit one must consider the
fact that having low D2 receptors in our current society
may confer certain competitive advantages like enhanced
aggression, novelty seeking and risk taking, leading to
greater survival as it did in the past (Comings 1996).
WHAT IS THE DOPAMINE-ADDICTION
CONNECTION?
The conviction that drug and alcohol dependence was
a disease rather than a symptom of moral weakness was
growing in the late nineteenth and early twentieth cen-
tury, there was no knowledge of how the disease might
be acquired or treated. Importantly, the therapies used to
treat this disease remained focused solely on psychological
factors and lifestyle behavior modification (with the help
of drugs) as if it were still a psychiatric condition rooted
in moral weakness. The good news today is that under-
standing that low dopamine function leads to impulsive,
compulsive and addictive behaviors paves the way to defin-
ing addiction as a brain disorder involving impairments in
so-called “reward circuitry” (Blum et al. 2000). This defi-
nition of addiction has now been adopted by the American
Society of Addiction Medicine (ASAM 2011), which was
founded by the San Franciscan visionary David E. Smith
(Sturges 1993).
This new definition is based in part on our initial con-
ceptualization of the “brain reward cascade” (see Figures 2
and 3 and Blum 2011) and the discovery in 1990 in col-
laboration with Earnest Noble of the genetic association
between alcohol addiction and the reward gene DRD2
(Blum et al. 1996a,b, 1990). This was the first evidence
of the link between addictive behavior genes and neuro-
transmitters. Subsequently, in 1995 Blum coined the term
“reward deficiency syndrome” (RDS), an umbrella term
for behaviors that are associated with genetic antecedents
that result in a hypodopaminergic state and a predisposi-
tion to obsessive, compulsive and impulsive behaviors (see
Table 1). All of these behaviors have been linked with low
dopamine function due to an association with the pres-
ence of the DRD2-A1 gene form (Blum et al. 2012, 2011b,
1996 a, b).
Based on an abundance of literature indicating that
low brain dopamine function confers a high vulnerabil-
ity to substance use and aberrant behavior seeking, it is
not surprising that every known abusable drug as well as
gaming, sex and even music all cause the neuronal release
of dopamine at the brain reward site. In essence this helps
explain the concept of self-medication. An individual with
low dopamine function will seek out substances and/or
behaviors known to boost dopamine function. This can be
temporarily achieved through alcohol, drugs, food, smok-
ing, sex and gaming. These drugs and behaviors provide a
pseudo feeling of well-being that could in the short-term
asymptotically reach a so-called feeling of “normalization”
Journal of Psychoactive Drugs 136 Volume 44 (2), April – June 2012
Blum et al. The Addictive Brain
FIGURE 2
The Interaction of Various Neurotransmitter Including Serotonin, Enkephalins, GABA and Dopamine
Constitute the “Brain Reward Cascade”
The brain reward cascade starts in the hypothalamus of the brain sitting in the midbrain called the mesolimbic system where serotonin acts as the
neurotransmitter activating the enkephalins (one type of brain endorphin); the enkephalins are released in the hypothalamus and stimulate mu receptors
in another part of the brain called substania nigra that contains the neurotransmitter GABA (an inhibitory neurotransmitter) that stimulates GABAB
receptors that projects to the ventral tegmental area (VTA) brain region where dopamine neurons are inhibited to allow for just the right amount of
dopamine to released at the nucleus accumbens (reward site of brain).
(Blum et al. 2012). This fact is coupled with the under-
standing that dopamine functions in the brain to provide
a feeling of pleasure and promotes general well-being and
happiness (Blum et al. 2012; see Figure 3).
An orgasm is the primary natural blast of dopamine
available to all of us. Accordingly, J.R. Georgiadis (2006)
scanned the brains of people having orgasm. He said they
resembled scans of heroin rushes. These individuals expe-
rienced one of the most addictive substance ever produced:
dopamine. Orgasms and addictive substances or behav-
iors have two things in common. They produce an initial
pleasurable experience, and both are followed by neuro-
chemical fluctuations that appear to continue for a week
or two. According to some sexual satisfaction is innate,
or what we have always experienced. That is one rea-
son many never notice its effects—they have always been
there.
“What goes up must come down.” It’s simple: bio-
logical systems must return to balance, or homeostasis.
In this case dopamine (or sensitivity to dopamine) ris-
ing and falling that can play around with your mood and
most importantly, your love life, including the way in
which you perceive and treat your partner. In terms of love
and relationships there are two brain chemical messengers
involved: oxytocin and dopamine (Ross & Young 2009).
In fact, oxytocin and dopamine are the yin and yang of
bonding and love. Dopamine furnishes the kick, oxytocin
makes a particular mate appealing, in part by triggering
feelings of comfort. It is necessary to have both acting
on the reward circuitry at ideal levels to stay in love.
In animal experiments, if scientists block either oxytocin
or dopamine, mothers will ignore their offspring (Heather
et al. 2009).
While having any genetic deficit in the reward site of
the brain may predispose an individual to a higher risk for
RDS, it is always the combination of our genes and their
interaction with environmental elements that predict not
only addictive behaviors in general but specificity of the
type of drug or behavior of choice. A Bayesian mathemati-
cal formulation developed by a sixteenth century monk was
used to predict the life-time risk for any RDS behavior for
those carrying the A1 polymorphism of the DRD2 gene,
which causes low D2receptors in the reward site. The total
risk for any behavior was predicted to be as high as 74%
(Blum et al. 1996a). However, as Steve Sussman of the
University of Southern California points out, RDS is highly
Journal of Psychoactive Drugs 137 Volume 44 (2), April – June 2012
Blum et al. The Addictive Brain
FIGURE 3
Brain Reward Cascade∗
Happy Brain A represents the normal physiologic state of the
neurotransmitter interaction at the mesolimbic region of the brain.
Briefly, serotonin in the hypothalamus stimulates neuronal projec-
tions of methionine enkephalin in the hypothalamus that, in turn,
inhibits the release of GABA in the substania nigra, thereby allow-
ing for the normal amount of dopamine to be released at the nucleus
accumbens (NAc), reward site of the brain.
Unhappy Brain B represents hypodopaminergic function of the
mesolimbic region of the brain. The hypodopaminergic state is
due to gene polymorphisms as well as environmental elements,
including both stress and neurotoxicity from aberrant abuse of
psychoactive drugs (i.e. alcohol, heroin, cocaine etc) and genetic
variables.
∗Adapted from Blum et al. 2010 with permission.
impacted by environmental epigenetic factors affecting our
RNA rather than just genetic factors involving our DNA
(Sussman & Sussman 2011). While one is not doomed
because of their genes to become addicted, they are def-
initely at high risk and as such may require this genetic
knowledge earlier rather than later in life.
PROBING THE MYSTERIES OF RECOVERY
The problem regarding addiction in society is global
and widespread. The total population of the United States
at the turn of the twenty-first century was 281,421,906. The
total number of people above the age of 12 was estimated
at 249 million (US Census Bureau 2011). The National
Institutes on Drug Abuse and the Substance Abuse and
Mental Health Services Administration (SAMHSA) have
surveyed persons age 12 and older and found that in the
year 2001, a total of 104 million people had ever used ille-
gal drugs in their life, 32 million had used a psychoactive
drug in the past year (2000–2001) and 18 million had used
a psychoactive drug in the past 30 days (NIDA 2010).
Interestingly this does not include alcohol. Children of
alcoholics are 50% to 60% more likely to develop alco-
hol use disorder than people in the general population.
Similarly children of parents who abuse illicit drugs may
be 45% to 79% more likely to abuse drugs themselves than
the general population. In the United States in 2008 the
highest percent prevalence of any alcohol use disorder
was 18.4 and any drug use disorder was 7.0 at ages
18–24. Men are more likely than women to have prob-
lems with alcohol, drugs or two substances combined (US
DHHS 2008). In 2007, 182 million prescriptions were
written for pain meds. (NIDA 2010). There is a grow-
ing concern among addiction professionals about a new
epidemic in America involving prescription of pain medi-
cation. We must ask then, who are the people that could just
say “no.”
John Giordano, in thinking about the recovery pro-
cess, emphatically stated, “Can you imagine jumping out
of a plane without a parachute?” (Giordano & Blum 2010).
Mark Gold accurately stated, “In spite of all the effort and
progress made by the addiction community, as a whole,
it has failed to both comprehend and willingly incorpo-
rate well established, evidence-based medical modalities
into treatment, especially as it relates to relapse prevention”
(Blum et al. 2011b).
We now know that the patient who carries certain
high-risk genetic deficits, such as low dopamine func-
tion (“dopamine resistance”) in the brain reward site, is
at a high risk of relapse. Following treatment—residential
or nonresidential—where no attempt is made to enhance
the function of brain dopamine, the patients who most
likely carry gene variants that cause low dopamine func-
tion in the brain are released back into society and
are probably doomed to relapse. Are we approaching
the time when, along with “love needs care” (coined
by David Smith), providers can supply a much-needed
parachute?
Science Meets Recovery
It is encouraging that for the first time in this millen-
nium the addiction community is about to embrace newer
scientific and clinically proven modalities. In this regard the
following areas must be adequately addressed by treatment
providers:
• Genetic testing to determine risk for RDS
• Safe and effective nutrigenomic and neuromodula-
tion solutions to activate dopaminergic pathways in
the brain
• Holistic modalities that promote well-being
• Drug testing to assist in determining medication
adherence and use as outcome measures
• Tests related to alterations of reward gene expression
as a molecular outcome measure
• Continued utilization of self-help organizations
• Psychological, behavioral and spiritual therapy
While this is a profound wish list, significant progress is
being made in a global thrust to characterize, delineate
and develop through necessary rigorous investigation those
elements required to translate research from the bench to
bedside.
Journal of Psychoactive Drugs 138 Volume 44 (2), April – June 2012
Blum et al. The Addictive Brain
TABLE 1
The Reward Deficiency Syndrome Behaviors (RDS)∗
Addictive Behaviors Impulsive Behaviors Compulsive Behaviors Personality Disorders
Severe Alcoholism Attention-Deficit
Disorder &
Hyperactivity
Aberrant Sexual Behavior Conduct Disorder
Polysubstance Abuse Tourette Syndrome Internet Gaming Antisocial Personality
Smoking Autism Pathological Gambling Aggressive Behavior
Obesity Generalized Anxiety
∗Reproduced from Blum et al. 1996a with permission
Understanding Diagnosis, Prevention and
Treatment Strategies
In general people begin taking drugs for a variety
of reasons: to feel good, to feel better, to do better, and
because others are doing it. Importantly, at first, peo-
ple may perceive what seem to be positive effects from
drug use. They also may believe that they can control
their use; however, when drug abuse takes over, a per-
son’s ability to maintain prudent executive function and
exert self-control can become seriously impaired. Brain
imaging studies from drug-addicted subjects show physical
changes in areas of the brain that are critical to judgment,
decision-making, learning, memory and behavior control
(see Figure 4). Cocaine prevents dopamine reuptake by
binding to proteins that normally transport dopamine. Not
only does cocaine “bully” dopamine out of the way, it hangs
on to the transport proteins much longer than dopamine
does. As a result, more dopamine remains to stimulate
neurons, which causes prolonged feelings of pleasure and
excitement. Amphetamine also increases dopamine lev-
els. Again, the result is overstimulation of these pleasure
pathway nerves in the brain (NIH/NIDA 2010).
Why do some people become addicted to drugs,
(or any aberrant RDS behavior noted in Table 1 above)
while others do not? As mentioned earlier, vulnerability
to addiction differs from person to person and is influ-
enced by both environmental (home, family, nutrition,
availability of drugs, stress, and peer pressure in school,
early use and method of administration) and genetic risk
factors. Researchers estimate that genetic factors account
for between 40% to 60% of a person’s vulnerability to
addiction, (especially alcoholism) including the effects of
environment on gene expression and function. It is note-
worthy that both adolescents and individuals with comor-
bid mental disorders are at greater risk of drug abuse and
addiction than the general population (Pickens et al. 1991).
Genetic Test to Determine Risk for RDS
One very important preventive tactic is to develop a
genetic-based test to determine risk and vulnerability to
substance abuse and harmful behaviors during adolescence.
FIGURE 4
Brain Images Showing Decreased Dopamine (D2)
Receptors in the Brain of a Person Addicted to
Cocaine Versus a Nondrug User (color figure
available online)
The dopamine system is important for conditioning and motiva-
tion, and alterations such as this are likely responsible, in part,
for the diminished sensitivity to natural rewards that develops with
addiction (NIDA 2010).
One of the brain areas still maturing during adolescence
(from age five to 20) is the prefrontal cortex—the part
of the brain that enables one to assess situations, make
sound judgments, and maintain emotions. Thus use of
drugs while the brain is still developing may have pro-
found and long-term consequences. Drug abuse often starts
as early as 12 years and peaks in the teen years. This
has added real impetus for the development of a test to
determine a “genetic addiction risk score” (GARS) as an
early preventive tool. The GARS test will also have rele-
vance for treatment of addicted patients to reduce both guilt
and denial and to determine levels of support required for
maintenance and relapse prevention. This test coupled with
the message that drugs are harmful to the brain (having
both short and long-term consequences) should lead to a
reduction of youthful drug use or abuse (Blum et al. 2010).
Journal of Psychoactive Drugs 139 Volume 44 (2), April – June 2012
Blum et al. The Addictive Brain
Given that about 30% of people in the U.S. are born
with genetically induced low dopamine brain function
(Noble et al. 1991), how can we overcome this survival
variant of human nature and prevent excessive craving
behavior? Certainly, the human brain is the most com-
plex organ in the body. The brain is a communications
center consisting of billions of neurons, or nerve cells.
Unfortunately drugs can alter brain areas: the brain stem
that is necessary for sustaining life through motor and sen-
sory control, the limbic system that regulates the ability to
feel pleasure, and the cerebral cortex that powers the abil-
ity to think. Pleasure produced from drugs of abuse occurs
because most of these drugs target the brain’s reward sys-
tem by flooding the circuit with dopamine (Budygin et al.
2012). When some drugs like cocaine are taken, they can
release two to ten times the amount of dopamine; the resul-
tant effects on the brain’s pleasure circuit dwarfs those
produced by natural rewards such as food and even sex.
This fact alone strongly motivates people to take drugs
again and again. Independent of one’s genetic makeup,
if one keeps taking drugs the brain adjusts to the over-
whelming surge in dopamine and other neurotransmitters
causing a breakdown in the natural process of brain reward
by producing less dopamine or by reducing the number of
dopamine (D2) receptors. This process causes abnormally
low dopamine function, high cravings and reduced ability
to perceive pleasure (Chen et al. 2011).
Dopamine Agonist Therapy
Scientists across the globe, including Dr. Nora Volkow
the director of NIDA, have suggested that dopamine
agonist therapy would reduce cravings and prevent relapse
and drug-seeking behavior (Thanos et al. 2008). The bot-
tleneck to date is that typical pharmaceutical agents that
have dopaminergic activation qualities are too powerful
and as such have profound side effects. Studies are begin-
ning to support the idea that the dopaminergic system
can be stimulated with a patented natural, nonaddictive
D2 agonist KB220 neuroadaptogen. Neuroimaging tools
(qEEG, PET, and fMRI) are being used to demonstrate the
impact of KB220IV and KB220Z oral (SynaptaGenXTM;
see Table 2) as a safe activator of brain reward dopamine.
One hour after administration KB220Z “normalizes” aber-
rant electrophysiological activity in subjects undergoing
protracted abstinence from alcohol, heroin and cocaine
at the prefrontal cortex–cingulate gyrus, the site in the
brain for relapse, by increasing alpha and low beta waves
with effects similar to ten to 20 sessions of neurofeedback
(Figure 5). Moreover, preliminary data from China using
fMRI imaging is showing that KB220Z induces activation
of dopamine pathways in the reward site of the brain (Blum
et al. 2012; Chen et al. 2011).
In terms of genetically-induced low D2 receptors, we
believe that based on 26 clinical trials with KB220 vari-
ants, long-term activation of dopaminergic receptors with
TABLE 2
KB220Z (SynaptaGenXTM) Ingredients∗
Gras Nutrients Neurotransmitter Pathway
D-Phenylalanine Opioid Peptides
L-Phenylalanine Dopamine
L Tryptophane Serotonin
L-Tyrosine Dopamine
L-Glutamine GABA
Chromium Serotonin
Rhodiola rosea COMT and MOA
Pyridoxine Enzyme catalyst
∗Reproduced from Chen et al. 2011 with permission.
FIGURE 5
KB220Z Normalizes qEEG Dysregulation by
Increasing Alpha and Low Beta Bands
Modified from Blum et al. 2011 with permission.
this natural substance will result in the proliferation of
D2 receptors leading to enhanced “dopamine sensitivity”
and thus, an increased sense of happiness, particularly for
carriers of the DRD2 A1 gene form who have 30% to 40
% less D2 receptors (Chen et al. 2011). This is also true for
certain brain-stimulating devices such as Trans-Magnetic
Stimulator (TMS) and a newly developed neuro-modulator
–NEAT 12 (cranial electrical stimulator) in unpublished
research showing dopamine activation in the brain reward
site and relapse site respectively.
Journal of Psychoactive Drugs 140 Volume 44 (2), April – June 2012
Blum et al. The Addictive Brain
TABLE 3
FDA Approved Addiction Medications
Drug and Alcohol Tobacco
Naltrexone Bupropion
Acamposate Varenicline
Campral Chantix
Disulfirm
Opioids Nicotine Replacement
Methodone Patches
Buprenorphine Inhaler
Naltrexone Gum
Holistic Modalities that Promote Well-Being
Moreover, meditation (Kjaer et al. 2002), yoga, exer-
cise, diet, music therapy, relaxation using Audio Therapy
(Morse et al. 2011), acupuncture (Blum et al. 2011a) and
potentially hyperbaric oxygen therapy (HBOT) are known
holistic modalities that could induce dopamine release.
Coupling talk therapy, behavioral therapy (cognitive behav-
ioral therapy, motivational incentives, motivational inter-
viewing, and group therapy) with treatment medications
(see Table 3) and whole body testing for peripheral mark-
ers (i.e. adrenal function, thyroid function, tissue levels of
heavy metals, hormones and brain mapping) provides the
clinician with a blueprint for successful treatment.
One of the most powerful elements about recovery
is the understanding of the 12-Step program. To many
in recovery this is essential. However, some individuals
are conflicted about the acceptance of spirituality and the
“higher power” concepts. Nevertheless, it is important to
realize that the quality of and dependence on the cognisant
connection to such a belief system can be significantly
influential in an individual’s ability to achieve a state of
peace and happiness.
Comings and associates (2008) were the first group to
identify the role of a specific gene in spirituality. The gene
was the dopamine D4 receptor gene (DRD4) gene, which
was found to play a role in novelty seeking. Others have
also found evidence for what was called the “God gene” or
the dopamine vesicular transporter gene (VMAT2), which
was reported to be associated with spirituality (Hamer
2005). In fact those individuals who scored high on self-
transcendence are less likely to abuse alcohol or drugs.
That dopamine is the “feel good” neurochemical may help
explain why spirituality plays a powerful role in the human
condition and why the majority of people derive great com-
fort and happiness from a belief in a God (Comings 2008).
Drug Testing to Assist in Medication Adherence and
Overall Outcome Measures
Drug and urine testing are important to determine
treatment outcomes and compliance. Different types of
FIGURE 6
Addiction Relapse Rates Compared to Other
Chronic Illnesses
Numbers shown are range in percents.
medications may be useful at different stages of treatment
to help a patient stop abusing drugs, stay in treatment
and avoid relapse. Figure 6 illustrates a comparison of
relapse rates between drug addiction and other chronic
illnesses. Relapse rates for drug-addicted patients are com-
pared with rates for those suffering from other chronic
illnesses (McLellan et al. 2000). Relapse is common and
is similar across Type 2 diabetes, hypertension and asthma
and is dependent in part to adherence to treatment medica-
tion. Certainly the relapse rates of approximately 22% for
physicians due to mandates of potentially losing a profes-
sional license is better than the general population, which
is much higher and varies across different drugs of abuse
(DuPont et al. 2009). Thus it is very important to determine
not only adherence to medication but unexpected use of
drugs during treatment, which is a trigger for relapse. Most
recently utilizing the Comprehensive Analysis of Reported
Drugs (CARDTM; Dominion Diagnostics), in unpublished
work it was discovered that in at least six east coast states
there was a significant nonadherence to treatment medi-
cation, but significant use of unexpected drugs was noted
across all states evaluated.
Self-help Organizations, Psychological and
Spiritual Therapy
The use of KB220ZTM in treatment facilities should
enhance well-being, improve cognition and judgment, and
most importantly, facilitate adherence for acceptance of
the 12-Step program. It is important to find dopamine
D2 activators that will not down regulate D2 receptors
like bromocryptine. We propose that a reduction in stress
will impact one’s state of happiness and spirituality. Thus
agents that reduce stress such as known natural dopamine
agonists should have benefits for craving reduction, relapse
prevention and quite possibly prevention of other RDS
behaviors, especially in adolescents.
Journal of Psychoactive Drugs 141 Volume 44 (2), April – June 2012
Blum et al. The Addictive Brain
CONCLUSION
Finally, the scientific understanding of addiction and
all its ramifications and the incorporation of these new
techniques and concepts into diagnosis, treatment, and
most importantly prevention strategies may ultimately lead
to not only reduced relapse but importantly enhance quality
of life for many.
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