So, what is this molecule [NAD+] with the power to heal? How does it work? Where does it come from and how important is it? Why do we see such remarkable, “too good to be true” outcomes with our patients? What do we need to convince the skeptics and be embraced by the American Medical Association?
Empirical evidence! Large-scale, double-blind studies, or peer-accepted, reproducible laboratory results showing the one or more mechanisms by which NAD+ works to restore the brain. These are the keys that unlock the door to credibility within the international medical establishment.
Fortunately, and at long last, this evidence is coming—building upon a foundation laid down by researchers more than 100 years ago.
On January 26, 1907, a baby was born in Vienna, Austria-Hungary, who became a world-renowned endocrinologist. His investigations led him to coin the term “stress,” which is now a common household word. His name was Hans Selye, and I was introduced to his work during my internship in graduate school. What I remember most from those days is that, as a young medical resident in Canada, Dr. Selye noticed something interesting about all the patients in the hospital. Irrespective of their “diagnosis,” he observed that people had similar symptoms. He first described the similarities as “noxious agents,” which he later referred to as “stress.” He developed a theory of stress he called the “general adaptation syndrome,” which was foundational to his work on biological stress. Dr. Selye noticed that stress was different from other physical responses because stress induces biochemical changes in the body regardless of whether the stressor is good or bad, positive or negative. Dr. Selye called positive stress (getting married, giving birth, or winning the lottery, for example) “eustress” and negative stress he called “distress.” Both kinds involve the hypothalamic-pituitary-adrenal axis (HPA axis), which governs how the body copes with stress. He identified three ascending stress states: the “alarm state,” the “resistance state,” and the “exhaustion state.” (You don’t want to spend a lot of time in the “exhaustion state” because the next state is death!)
It’s clear that stress has become an even greater health issue today than it was in the early 1900s when Dr. Selye was writing, lecturing, and researching the stresses of life. That’s because, for most people, the stress of modern living is constant—and the human body did not evolve to handle constant stress. As a result, the body’s normal ability to deal with occasional stress situations is being overwhelmed, and a new illness precursor has been identified: oxidative stress.
Oxidative stress is a term to describe an imbalance to cellular structure that exceeds the body’s ability to repair. In most cases, oxidative stress is caused by reactive oxygen species (ROS) free radicals, which, at low levels perform essential cellular functions. However, the overproduction of ROS can damage DNA, proteins, and fats, which promotes aging and the development of diseases ranging from cancer to dementia. Oxidative stress also appears to be a major factor in the disease we call addiction.
Years ago, while in my internship, I saw a documentary showing what happens to the brain of cocaine addicts when shown a variety of pictures on a computer screen while fastened to cranial electrodes. This was new science at the time because being able to see the functionality of the brain was now possible and it was a big deal. It made a strong impression on me for two reasons: one, because we could actually see the brain respond, and two, because of how dramatically the brain responded. Seeing people with electrodes on their heads calmly watching benign images of flowers, birds, ocean views, a car, a boat, etc. was interesting only because of what happened when an occasional line of cocaine, or a needle, or other drug paraphernalia was randomly shown. Shockingly, the midbrain of each participant lit up like a flashlight! What did that mean?
I recently watched a lecture given by Dr. Kevin McCauley that I found very helpful. His presentation was entertaining and informative, which is always advantageous for attention-deficit sufferers like me. He was addressing the disease model of addiction, which was first embraced by the American Medical Association in 1956. That was a long time ago, but I can tell you from my clinical experience that the needle hasn’t moved much in a positive direction since then. Here we are, 61 years later, and we are still debating whether addiction is a “choice” or a “disease.”
Dr. McCauley humorously and logically presented his defense of the “disease” model, which interestingly centers on the midbrain.
What constitutes a disease? Dr. McCauley presented the 100-plus-year old medical model of disease as having an organ, having a defect, having symptoms, and a cause. One dictionary defines disease as an incorrectly functioning organ or system of the body having a defect with symptoms caused by genetics, infections, poisons, nutritional deficiency, toxicity, or environmental factors or illness. Before this medical model was used, the doctor would spend a lot of time focusing on the symptoms, which might or might not respond to treatment because the “cause” of the defect was not first identified. The symptoms could span numerous diseases so knowing the “cause” helps in diagnosing and treatment.
Choice vs. Disease
In the debate between “choice” vs. “disease” in addiction medicine, a distinction needs to be made between “behaviors” vs. “symptoms.” The “choice” model argues that addiction cannot be a disease because it is caused by behavior and behavior is a “choice.” The “disease” model argues that the symptoms are not actually a choice, but the result of a biological impairment to the midbrain. Just as a diabetic cannot change his or her blood-sugar level at will, an addict cannot stop craving at will. In the diabetic, the body’s inability to produce or effectively utilize insulin is the cause. In the addict, improper functioning of the midbrain is the cause. Both diseases produce symptoms that can cause unwanted behaviors. But as my friend and colleague, Dr. Liz Stuller, emphasizes to her residents in training, “You must find the root cause if you are going to successfully treat a patient. Identify the root cause!”
McCauley’s definition of addiction is, “The dysregulation of the midbrain dopamine system due to unmanaged stress resulting in symptoms of decreased functioning—specifically loss of control, cravings, and persistent drug use despite negative consequences.”
Although there are other organs involved in addiction, like the liver, pancreas, and more, the brain is our focus because this is where we will find the root cause. Addiction is first a brain disease and here is why.
The prefrontal cortex is associated with what we call “executive” functions like reasoning, abstract thought, self-control, planning and organization, emotional meaning such as love, and morality, spirituality, ethics, and responsibility. Some consider it the “seat of the self,” where personality and conscious awareness reside. Interestingly, drugs don’t work in the prefrontal cortex; they work in the midbrain. This was first demonstrated by a series of experiments conducted in the ‘60s called the Olds Experiments, in which a probe the diameter of a hair was used to determine which area of the brain was affected by drug use (specifically, the drug cocaine). The Olds Experiments inserted probes to every possible region of the brain of rats, but the areas that resulted in addictive behavior—continual self-administration of additional doses of the drug—were the lateral hypothalamus, the nucleus accumbens, and the ventral tegmental areas (VTA) of the midbrain. Test animals would work continuously—lever-pressing at rates of several thousand responses per hour—for days to obtain direct electrical stimulation of the lateral hypothalamus and related brain regions.. The animals did so to the exclusion of other behaviors, starving themselves for the opportunity to self-stimulate if food and stimulation were concurrently available for only a limited portion of each day. (ibid, Routtenberg and Lindy, 1965) Once experienced with the stimulation, rats would cross electrified grids to gain access to the lever, accepting higher shocks to obtain stimulation than they were willing to accept to obtain food, even when deprived for 24 hours. (ibid, Olds, 1959) (What person familiar with addiction doubts this result?)
Subsequent research has demonstrated that not only rats, but monkeys as well, will work similarly compulsively for intravenous stimulants to the midbrain. If given unlimited access, they will self-administer intravenous injections of these drugs to the point of severe weight loss and death. (ibid, Johanson et al. 1976, Bozarth and Wise 1985) What begins as a tentative response tendency becomes a compulsive habit very quickly.
The drug apparently convinces the midbrain that obtaining more of the drug is more important than anything and everything. The drug becomes tantamount to survival.
That’s because the midbrain is where your survival instinct resides. Your midbrain is unconscious and reacts to sensory information all day, every day. It processes the life or death signaling messages, with the fight-flight-or-freeze mechanism on stand-by. These are the areas where addiction is processed, not the prefrontal cortex. The midbrain is also where reward and pleasure are processed. Addiction causes a defect in the midbrain long before the prefrontal cortex is affected. In fact, when the midbrain is activated to go into survival mode, it shuts down the prefrontal cortex. Brain imaging studies have shown this: when the midbrain is lit up, the prefrontal cortex is dark.
The tendency to label an addict or an alcoholic by the behaviors they exhibit while “under the influence” is understandable. If you have been on the receiving end of that behavior, without having the awareness or restraint to keep from lashing out with labels such as selfish, lying, cheating, stealing, criminal, sociopathic, entitled brat, loser, and “in denial,” then welcome to the human race. Unfortunately, that type of interaction only makes matters worse. Why? Because the addict’s prefrontal cortex has been high-jacked by the midbrain. To the non-addicted, those of us with access to the executive functioning of the prefrontal cortex, it’s absolutely clear what addicts need to do: change their behavior. But as a practical medical matter, the only way an addict can successfully use the prefrontal cortex to address his or her addiction is by first addressing the defect in the midbrain. Moreover, I question the therapeutic value of labeling someone an addict or alcoholic when the label carries such negative connotations—generating guilt, shame, insecurity, and self-doubt. These, in turn, spark anxiety, depression, insomnia, and fatigue—increasing the stress that, in the addict’s brain, can only be relieved by drugs. Dopamine gets the credit for relieving stress and the blame when addiction neutralizes the dopamine response, but there are other neurotransmitters like glutamine, serotonin, GABA and some we haven’t yet discovered that may also be involved. Moreover, there is some data to suggest that NAD+ itself may function as a neurotransmitter, implying that if NAD+ levels are low, the addicted patient is further prevented from stress relief. However, this warrants further examination.
Stress? We ALL have stress!
Critics of the disease model of addiction like to say that stress comes in different sizes: severe, traumatic, chronic, moderate, or mild. Stress changes the physiology of the midbrain. We each experience stress differently depending on our coping mechanisms, some of which are hereditable—the genetic and epigenetic ones. However, above a certain threshold that is unique to each individual, the midbrain processes stress as a threat to survival, commanding the body to remain in constant “fight-flight-or-freeze” mode until dopamine, the body’s stress-reliever, is released, which enables it to relax. An addict has learned to get that dopamine release from a drug. That strategy makes sense because an addicted brain’s dopamine-production ability has been shut down—by the drug.
For those addicted to opiates or other painkillers, the same dynamic functions with endorphins, the body’s natural painkiller. The brain’s production capacity has been replaced by the drug, leaving a single pathway to pain relief: the narcotic. (A secondary reason for an addict to seek a drug is to get relief from excruciating withdrawals.)
The truth is that being under the influence of a substance is not limited only to the state of intoxication. A person is still under the influence of the drug even after they sober up because their brain is still impaired. The midbrain continues to insist that survival is at stake, and only a dopamine release will change that. At this point, addicts are no longer seeking to get “high,” but to relieve the agony produced by stress and the cortisol-releasing factor (CRF) in the midbrain. In fact, the limited success of most drug treatment programs is based on substituting one (legal) drug for the illegal one that has caused the addiction in the first place. Whether the replacement drug is methadone, Suboxone, caffeine, nicotine, or sugar, its biochemical role is the same: to quiet the midbrain with a dopamine release. Twelve-step programs like AA and NA attempt to augment biochemical coping strategies with social and emotional support—because these, too, reduce anxiety. But none of them do what intravenous NAD appears to do: reset the brain to its pre-addicted state.
 Olds 1958b, Annau et al. 1974 http://www.cell.com/neuron/pdf/S0896-6273(02)00965-0.pdf
 Wise, Roy A. Brain Reward Circuitry: Review Insights from Unsensed Incentives, Neuron, Vol. 36, 229–240, October 10, 2002, Cell Press. http://www.cell.com/neuron/pdf/S0896-6273(02)00965-0.pdf
Paula Norris Mestayer, M.Ed, LPC, FAPA, is the founder of Springfield Wellness Center, a mental health clinic that specializes in treatment for addiction and other brain diseases. She is the author of Addiction: Dark Night of the Soul; NAD+: The Light of Hope, Balboa Press, 2019, from which this essay is excerpted.
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