COMMENTS: This is a slightly easier article based on this review – FULL STUDY – from the Journal of Psychoactive Drugs, 44 (2), 134–143, 2012, Copyright © Taylor & Francis Group, LLC
J Psychoactive Drugs. 2012 Apr-Jun;44(2):134-43.
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.”
by Dr. Kenneth Blum
Collier’s Magazine April 2012
Almost half-of the U.S. population has indulged in illegal drug practices. Presidential candidates are forced to dodge tricky questions of their past history involving illegal drug use and almost every American has sloshed down a martini or two in their life time. There must be a reason, a need, or natural response for people to imbibe at such high rates. An even more compelling question surrounds the millions who seek out high risk novelty. Why do so many of us have this innate drive to place ourselves in harm’s way? Why are millions paying the price of their indiscretions in jails, hospitals, and wheel chairs or lying dead in our cemeteries. What price must we pay for pleasure seeking or just plain getting “high”? Maybe the answer lies within our brain. Maybe it is within our genome.
All Roads Lead to DOPAMINE
Once it was true, all roads lead to Rome. This simple truth is not too dissimilar from the reward circuitry of the brains of Homo sapiens. Numerous experiments have established that the brain’s major reward neurotransmitter pathway, the road to Rome, is indeed dopamine.
Reward circuitry, the cascade of neurotransmission in the brain that leads to the release of dopamine, is kicked off by any pleasurable experience. Everything from eating, to having sex and even skydiving can get it going. The point of the reward circuitry is to positively reinforce actions that promote the survival of the species. During what the brain perceives to be as beneficial actions, dopamine’s release makes our brains “happy,” thus encouraging us to do it again. Though “extreme actions” inherently don’t promote survival, and in fact endanger it, the rush to preserve life causes the release of dopamine and consequently pleasure.
Drugs play on this system and can destroy it with enough use, creating a permanent craving that results in addiction. Pleasure produced from drug abuse occurs because most of these drugs target the brain’s reward system by flooding the circuit with dopamine. When some drugs like cocaine are taken, they can release 2-10 times the amount of dopamine as natural responses. The resultant effects on the brain’s pleasure circuit dwarfs those produced by natural rewards such as food and even sex. Just this fact alone strongly motivates people to take drugs again and again, but for about 30% of the population, genetics is also a factor when it comes to the desire to take drugs.
Scientists now know that there are at least two variant forms of the human dopamine D2 receptor gene, (DRD2) which regulates the number of D2 receptors and how much dopamine is naturally fed to our brains. Consequently, DRD2 is the most widely studied gene in psychiatric genetics and what accounts for major aspects of modern human behavior. The DRD2 A2 form, which in today’s world is considered the “normal” variation, is carried by 2/3 of the U.S. population. People carrying this form have properly functioning reward circuitry, thus they won’t inherently crave artificial or alternate ways to induce dopamine release, such as drugs or thrills. Carriers of the DRD2 A1 form represent about one third of today’s U.S. population and have 30-40% lower D2 receptors. These men and women are prone to addiction, a subset of approximately 100 million people.
Given that about 30% of us are born with genetically induced low dopamine brain function how can we overcome this survival variant of human nature and prevent excessive craving behavior? Certainly, the human brain is the most complex organ in the body— a communications center consisting of billions of neurons, or nerve cells. Unfortunately drugs can alter brain areas such as the brain stem that is necessary for sustaining life through motor and sensory control, the limbic system that regulates our ability to feel pleasure, and the cerebral cortex that powers our ability to think. Independent of one’s genetic makeup, if an individual keeps taking drugs, the brain adjusts to the overwhelming surge in dopamine and other neurotransmitters causing a breakdown in the natural process of the brain reward by producing less dopamine or reducing the number of dopamine (D2) receptors. This causes abnormally low dopamine function, high cravings, and reduced ability to perceive pleasure, all contributing to a vicious cycle of addiction.
Evolutionary Genetics and a Theory About the Origins of the Dopamine Driven Society
Think about the characteristics of our current society—the driven, ever changing, exceedingly fast world of today. Now look back, a mere 80,000 years ago our ancestors walked the earth as equal parts predator and prey with a much narrower set of goals and limited understanding of the world around them. It is possible that those differences could be attributed to dopamine.
While many theories about brain evolution have focused on the role of brain size and genetic adaptations Fred Previc6 explored the provocative concept of a “Dopaminergic Society” based on changes in dopamine. The consumption of meat and fish oils is known to increase dopamine receptors. According to Previc6 the differences between modern humans and their hominid relatives resulted from increased levels of dopamine that were part of a general physiological adaptation due to an increase in meat consumption, beginning around two million years ago.
It is prudent to speculate that DRD2-A1, the older gene form still seen in 30% of people today, was vital to the survival of early man. For these ancestors of ours, a shortage of dopamine receptors was useful in their struggle to survive, the rush of constantly striving to live providing all the dopamine they would need. However, about 80,000 years ago dopamine receptors may have been further enhanced by other factors. Recent discoveries detailing the seaside settlements of early man show environmental, social, and dietary changes, like the inclusion of fish oils, provide evidence for enhanced dopamine function at this time in human history. From this enhancement, a new society was born – the “high dopamine society” carrying the DRD2 A2 form of this gene that most people currently carry. Conversely, those left with the older gene form must deal with the void in dopamine release left when danger was removed from the everyday life of humans.
According to Previc’s theory, the “high-dopamine” society is characterized by high intelligence, a sense of personal destiny, a religious/cosmic preoccupation, and an obsession with achieving goals and conquests. This “dopaminergic society” is fast-paced or even manic, which is not surprising, “given that dopamine is known to increase activity levels, speed up our internal clocks and create a preference for novel over unchanging environments.” High levels of dopamine are also proposed to underlie increased psychological disorders in industrialized nations. 6 David Comings, writing in his popular book The Gene Bomb, pointed out that while it may be true that genetic adaptations are very slow, there may be some exceptions that show the rapid change like this is also possible, particularly the Tibetan altitude gene that allowed for adaptation to high altitudes.
Comings also discussed the future of the DRD2 gene from an evolutionary perspective, demonstrating how the dynamics of the human population with respect to this gene may change. 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, (“Birds of a Feather Flock together”, another characteristic of the DRD2 A1) 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 is 25 years. As a result, the X form of the gene will reproduce faster at a ratio of 1.25 to 1, which can add up over time. 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, risk taking leading to greater survival, as it did in the past. Bottom line, addiction is not a problem that going away.
Probing the Mysteries of Relapse and Recovery
“Can you imagine jumping out of a plane without a parachute?” – John Giordano, president of G & G Holistic Addiction Treatment Center, North Miami Beach
Addiction is a global and widespread problem in today’s society. At the turn of the twenty-first century, the total population of the United States was 281 million with 249 million above the age of 12. A survey of persons aged 12 years or older by The National Institutes on Drug Abuse and the Substance Abuse and Mental Health Services Administration in 2001 found that 104 million people have used illegal drugs in their life, 32 million used a psychoactive drug in the past year (2000-2001) and 18 million used a psychoactive drug in the past 30 days. Interestingly, this does not include alcohol.
On top of those numbers, children of alcoholics are 50-60 percent more likely to develop alcohol use disorder than people in the general population. Similarly, children of parents who abuse illicit drugs may be 45-79 % more likely to abuse drugs themselves than the general population. In 2008, Americans aged 18-24 had the highest rate of alcohol use disorder at 18.4% and drug use disorder at 7%. Men are more likely than women to have problems with alcohol, drugs, or two substances combined. 2007 saw 182 million prescriptions written for pain medications, furthering concern among addiction professionals about a new epidemic in America involving prescription pain medications. We must ask then, who are the people that could just say “NO”?
Science Meets Recovery
Though 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 century, there was no knowledge of how the disease might be acquired or treated. The good news today is the acceptance of “Reward Deficiency Syndrome” (RDS) as an umbrella term for a predisposition to obsessive, compulsive, and impulsive behaviors that are associated with genetic differences that can lead to addiction , paves the way to defining addiction as a brain disorder involving impairments in so called “reward circuitry.” This definition of addiction has now been adopted by the American Society of Addiction Medicine and is a realization that encouraged changes and advancements in treatment options.
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 (home, family, availability of drugs, stress, peer pressure in school, early use, and method of administration) that predict not only addictive behaviors in general, but specificity of the type of drug or behavior of choice. A Bayesian mathematical formulation was used to predict the lifetime risk for any RDS behavior if you carry the A1 version of the DRD2 gene at birth. Total risk for any behavior was predicted to be as high as 74%. However, as Steve Sussman of the University of Southern California points out, rather than being victim to our genetic factors based on our DNA, RDS is highly impacted by environmental (epigenetic) factors affecting our RNA. Scientists estimate that genetic factors account for between 40-60 percent of a person’s vulnerability to addiction, with the rest being environmental factors that can affect how those genes are expressed. The take home message is one is not doomed because of their genes to become addicted, but definitely at high risk. Genetic knowledge earlier rather than later in life becomes exceedingly valuable in such cases.
Despite this truth, Mark Gold, chairman of the Department of Psychiatry at the University of Florida, College of Medicine in Gainesville, 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 incorporate well established, evidence-based medical modalities into treatment, especially as it relates to relapse prevention.”
I am encouraged that for the first time in this millennium, the addiction community is prepared to embrace newer scientific and clinically proven modalities. In this regard, the following areas must be adequately addressed by treatment providers going forward:
- Genetic test to determine risk for RDS
- Safe and effective non-addictive D2 agonist known as KB220 to activate dopaminergic pathways in the brain
- Holistic modalities that promote well-being
- Drug testing to assist in 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.
Understanding Diagnosis, Prevention, and Treatment strategies
In general, people begin taking drugs for a variety of reasons: to feel good, to do better, and to fit in. Importantly, at first, people may experience what they perceive to be positive effects of drug use and also may believe that they can control their use. However, when drug abuse takes over, a person’s ability to 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. An example is cocaine which 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 levels. Again, the result is over-stimulation of these pleasure-pathway nerves in the brain.
Genetic Test to Determine Risk for RDS
A very important preventive tactic is to develop a genetic-based test to determine risk and vulnerability to substance abuse and harmful behaviors during adolescence. One of the brain areas still maturing during adolescence (from age 5-20) is the prefrontal-cortex—the part of the brain that enables us to assess situations, make sound judgments, and maintain our emotions the prefrontal cortex and . Thus use of drugs while the brain is still developing may have profound and long-term consequences on these vital abilities. Drug abuse often starts as early as 12 years and peaks in the teen years, adding real impetus to the development of a test to determine a Genetic Addiction Risk Score (GARS) as an early preventive tool. The GARS test will also have relevance for treatment of addicted patients to reduce both guilt and denial to determine levels of support required for maintenance and relapse prevention. Coupled with the message that drugs are harmful to the brain, this test should lead to a reduction of youthful drug use or abuse.
Safe and Effective Non-addictive Dopamine Agonist Therapy
No matter if a person has been sober or clean for 5, 10, or 20 years there is still always that propensity toward drug abuse perhaps coming from their genes or damage done to their dopamine receptors by years of abuse. “White knuckle sobriety” is abstinence through sheer will power—determination being the main factor keeping a former user away from the syringe or opening a bottle.
Dopamine agonist therapy has emerged as the most effective treatment for alleviating the “white knuckle” aspects of abstinence. The most exciting facet of this sort of therapy is that it actually brings neurotransmitters back to life—kick starting the brain reward cascade and providing dopamine to the brain again. Scientists across the globe, including Dr. Nora Volkow, the director of National Institute on Drug Abuse (NIDA), have suggested that dopamine agonist therapy would reduce cravings, prevent relapses, and drug seeking behavior.
The bottleneck to date is that typical pharmaceutical agents that have activation qualities are too powerful and have profound side effects. The good news is that the dopaminergic system can be stimulated with a patented natural, non-addictive D2 agonist known as KB220. Neuroimaging tools (qEEG, PET, and fMRI) are being used to demonstrate the impact of KB220IV and KB220Z oral (SynaptaGenX™) as a safe activator of brain reward dopamine. Only one hour after administration KB220Z “normalizes” irregular electro-physiological activity in subjects undergoing prolonged abstinence from alcohol, heroin, and cocaine in the site of the brain for relapse, by increasing alpha and low beta waves similar to 10-20 sessions of neuro-feedback therapy. Moreover, preliminary data from China is showing that KB220Z induces activation of dopamine pathways in the reward site of the brain.
For those with genetically induced low D2 receptors, we believe that long-term activation of dopaminergic receptors with this natural substance will result in the creation of D2 receptors leading to enhanced dopamine sensitivity and thus, an increased sense of happiness.
Following treatment—residential or non-residential—where no attempt is made to enhance the function of brain dopamine, the patient, who most likely carries the low dopamine function gene, are released back into society, doomed to relapse. In such cases KB220Z can be very helpful. Are we approaching the time when, along with, “love needs care” (coined by David Smith), providers can supply a much needed parachute.
Beyond Medication: Embracing Holistic Modalities
Breakthroughs when it comes to addiction medication are of course exciting. However, the struggle for sobriety is nothing new and some, particularly those without a genetic deficit, have been successful. In many cases, a big part of that success was the use of holistic modalities. Dopamine is released in many ways and there are other activities someone in recovery can engage in to help them stave off relapse. Meditation, yoga, exercise, diet, music therapy, relaxation using Audio Therapy, acupuncture, and potentially hyperbaric oxygen therapy (HBOT) are known practices that could induce dopamine release. Over time, they can even regenerate receptors destroyed by drug use. Talk therapy, cognitive behavioral therapy, motivational incentives, motivational interviewing or group therapy coupled with treatment medications and whole body testing for peripheral markers (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 to many in recovery is the understanding of the 12-step program. However, some individuals are conflicted about the acceptance of spirituality and the “higher power” concepts that are a big part of the program. It is not the intent of this article to address the existence or non-existence of God, but it is important to realize the benefits of such a belief. A quality cognizant connection and dependence on such a belief system can be significantly influential in an individual’s ability to achieve a state of peace and happiness.
Comings’ research group was the first to identify the role of a specific gene in spirituality. Specifically, it is the dopamine D4 receptor gene (DRD4), 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. In fact those individuals that scored high on self-transcendence are less likely to abuse alcohol or drugs. Dopamine’s characterization as the “feel good” neuro-chemical may help explain why spirituality plays a powerful role in the human condition and the majority of people derive great comfort and happiness from a belief in a God.
Assisting in Recovery and Ensuring Success
Drug and urine testing are important to determine treatment outcomes and compliance. Different types of medications may be useful at different stages of treatment to help a patient stop abusing drugs, stay in treatment, and avoid relapse. Relapse rates are similar across Type 2 diabetes, hypertension, asthma and drug addiction. Avoiding relapse in each case is dependent in part on adherence to treatment medication. Unexpected use of drugs during treatment is another trigger for relapse. Recently, utilizing the Comprehensive Analysis of Reported Drugs (CARD™) exclusively offered by Dominion Diagnostics, it was discovered that there was a significant adherence to treatment medication, but also considerable unexpected drug use across all six east coast states evaluated.
Acceptance and Advancement
Our society is driven by dopamine. The scotch you crave after work, the feeling you get when a man or woman across the bar looks your way, the rush that hits during the roller coaster’s first big drop all trace back to it. For many, the above simple pleasures must come in droves for their brains to be satisfied and the price of that deficiency is addiction.
Understanding the inherent Impairment in reward circuitry millions are born with is responsible for addiction in a great number of people has been an important first step. Dopamine agonists, like KB220Z™, being used in treatment facilities to assist in adherence to acceptance of the 12-step program is the second. Together, these should enhance well-being, improve cognition and judgment, but most importantly facilitate stress reduction should be the result, which will impact one’s state of happiness and spirituality. Ultimately it should have benefits in the form of craving reduction, prevention of relapse, and quite possibly prevention of RDS behaviors, especially in adolescents.
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, most importantly, enhance quality of life for our recovering heroes.
John Giordano, Joan Borsten, Mary Hauser, B. William Downs, Margaret A. Madigan, and Eric R. Braverman assisted in writing this article and it is gratefully acknowledged.