Table 2.

The Molecular Neurobiological Summary of the 12 Steps (taken with permission from Blum et al. [46]).

STEP	Summary with References
First-Powerless	While the concept of POWERLESSNESS may be controversial in the field, the first step admitting personal powerlessness over addiction is supported by the actual mechanisms involved in the neurobiological circuits of our brain. It begins with genetic vulnerability to addiction and compounded by epigenetically induced environmental elements. Stress and the toxic effects of the drugs and compulsive behaviors themselves induce changes in the neuroanatomy, neurophysiology, and neurochemistry of the brain that effect hedonic tone, physical dependence, craving and relapse. Although genetic factors play a very significant role in the process of addiction and especially in risk for developing reward dependence behaviors, there are strong epigenetic effects of powerful substances. Those substances like alcohol etc. profoundly affect brain reward homeostasis and an unmanageable desire to self-administer drugs of abuse. This leads to powerlessness, an inability to control behaviors in face of harm that ultimately influences every aspect of one’s life [4, 104, 107–135].
Second-Restore Us to Sanity	Sanity (sound judgment) or insanity (repetitive behavior in spite of harm) may be impaired even at birth and could be due to deficient brain reward circuitry function especially resulting in a hypodopaminergic trait. This poor judgment could be a root cause for aberrant substance-seeking behavior in the face of harm’s way. This becomes further complicated when other environmental factors are present including drug availability, non-nurturing parents, social economic burdens and stress. Importantly the ability to behave sanely also may be impacted by an individual’s relationship with a power greater than themselves. In terms of relapse, it is well known that the prefrontal cortex and cingulate gyrus are very important brain regions that could regulate relapse. Poor judgment stemming from impairments in the neurochemical functioning of these regions due to genes and/or toxic substances and/or behaviors, impedes recovery and induces relapse. Understanding the molecular biology of the brain reward system (genes and environment) highlights the importance of positive input from fellowship (self-help) programs and other treatment modalities that can offset unwanted gene expression, lift spirits, and assist in enabling the individual to achieve a state of sanity and make good choices [5, 9, 16, 74, 78, 79, 104, 136–179].
Third-Turn our lives over to GOD	Will-power is not simple to control, especially if you are born with a compromised reward system, especially low levels of endorphins. Genetically predisposed individuals seek out drugs such as alcohol, heroin, cocaine, nicotine, and even sugar, because these substances all activate reward substrates (i.e., enkephalins, DA pathways) and provide a pseudo temporary feeling of well-being (so called “normalization”). Will power is based on both the interplay of genes and environmental elements in society. This includes stress as an adult and surprising during the prenatal phase. This early stress could lead to aberrant substance use disorders in adult life. Since it is not easy to fight the hard wiring of our brain reward circuitry, for the recovering addict it seems obvious to look for reward outside of our genome [i.e. alcohol, drugs, sex, and food] [180–186].
Fourth-Fearless & Moral Inventory of Ourselves	Fearless moral inventory must include not only the drug of choice but other Reward Deficiency Syndrome related behaviors. This is so because the phenotype is not any particular drug or behavior of choice; it is indeed Reward Deficiency Syndrome. However, the inventory the individual is completing cannot be “right” or “wrong,” because it his/her own list of resentments, and evaluation of self. Moreover, the Big Book states, “No one among us has been able to maintain perfect adherence to any of these principles. The point is that we are willing to grow along spiritual lines. The principles we have set down are guides to progress. We claim spiritual progress rather than spiritual perfection.” Several fourth steps may be taken by an individual over the course of his/her sobriety. Moreover, it is literally almost impossible for early recovering addicts to embrace Step 4 due to protracted abstinent impairments of brain reward circuitry, for example, in alcoholics, heroin addicts, and cocaine addicts. Unfortunately this could be due to the chronic abuse of these powerful substances as an epigenetic phenomena, as well as possible inherited reward gene polymorphisms that occur at birth. It has been reasoned that one therapeutic target involves continued natural DA D2 activation as reflected in the preliminary fMRI research being conducted in China using KB220Z [51, 15, 24, 29, 31, 41, 67, 102, 106, 115, 187–195].
Fifth-Admitted Exact Nature of our Wrong Doings	Understanding our natural desire to obtain pleasure states and to admit “wrong doing” to God, ourselves, and those around us is no simple task and involves the consideration of not just our issue with “getting high” but rather with the toxic effects produced in the brain by continual exposure to these powerful substances. Their impact on brain reward networks is indeed physiological (e.g., increase in brain DBI). This can result in mental effects (anxiety and aggression) that also result in harmful behaviors with harmful and sometimes fatal consequences not only to one-self but to others [187, 196–208].
Sixth-Removing Defects in Character	Although it is possible to define character in a moralistic sense, it is very difficult to assign responsibility for defects of character and the bad decisions and consequence since character is shaped by genetic (evolutionary) forces far beyond a person’s control. With this stated it is argued that environmental elements especially in childhood may also require rethinking in terms of blame and or even praise of an individual act. This idea supports the idea in the sixth step that the removal of character defects is the province of a higher power. Clinicians should be cognizant that for the individual, achievement of this step requires deep character analysis, painful realization, and ability to dissociate oneself (present) from the past self. It should also be noted that carriers of the DRD2 gene polymorphism (risk for addiction) will have great difficulty in achieving honesty [209–225].
Seventh-Removing Shortcomings	Being humble must be accompanied with both gratitude and grace. The concept of ‘turning it over’ and let GOD remove our shortcomings is not easily accomplished. To be humble is akin to having gratitude for the things we have the idea of moving forward. Statements of spiritual faith and being humble challenge the recovering person to face the fact that good intentions and honest effort alone will not always succeed in getting him or her what is truly wanted from life. I n turn and supported by genetic predisposition, this could lead to chronic depression and relapse. However, the 12-step program and the traditions together ask the person to believe that evil and brutishness, injustice and cruelty will not necessarily win out in the end. Being humble and having faith advocates neither passivity nor hopelessness; on the contrary, they express the belief that our shortcomings can be removed by our willingness to believe that things can work out for the best in the long term. Having positive feelings about GOD translates to positive epigenetics which enhance the chances that we could remove our shortcomings by expressing “good” genes rather than “bad genes” [10, 11, 99, 226–244].
Eighth-Making Amends of Harms	It is not easy to make amends especially to people who are not only our friends but people whom we love. Step 8 does not come early in one’s sobriety but only after periods of being clean and sober. However, once an individual accomplishes this arduous task he or she will be able to move forward in the path of recovery. In terms of connecting the dots, it is important for clinicians to realize that the old adage of “Birds of a feather flock together” may be inheritable by virtue of friends seeking friends who not only have similar characteristic (maybe even drinking, drugging, and eating), but similar genotypes, such as the DRD2 A1 allele. So that when the alcoholic, for example, is asked to make amends and also eliminate certain friends that would not be conducive to their recovery, we need to be cognizant about going against the genetic grain. Thus, on a molecular neurobiological level, it is easily said but not easily done. A form of happiness is that people live in social networks that are comfortable. Making amends for the hurt may not reestablish trust but may help assuage guilt and shame. Here it may be helpful to consider the genetic predisposition of families to Reward Deficiency Syndrome behaviors [46, 104, 165, 216, 245–267].
Ninth-Direct Amends to Such People without Injury to Them	It is not easy to achieve happiness and peace especially when the alcoholic or addict is faced with taking responsibility for hurting others with whom he or she has relationships while drinking and drugging. An obvious source of injury to relationships caused by addiction is the “abandonment” of a spouse or significant other for alcohol and/or drugs. Victims of Reward Deficiency Syndrome must take responsibility for this abandonment of loved ones. Furthermore, addicts may have been very abusive (both physically and emotionally) during their active addiction. Before any amends can be made, the addict is asked in Step 8 to take an inventory of all persons harmed, which can easily evoke intense feelings of guilt and shame. It also requires overcoming denial and being willing to make amends. In Step 9, the achievement of making amends (except where doing so would cause no further injury) is subject to correlations among genes, friendships, and relationships. As noted in the research summarized above, relationships and happiness are based on neuronal hard wiring, and this presents both a formidable challenge and clarity as to how to achieve effective healing in recovery. The degree to which the person can make amends to others (without harm or hurt) is tantamount to a healthy recovery, and importantly, the attainment of happiness. This can be facilitated through the positive natural release of DA in reward centers of the brain [34, 137, 268–271].
Tenth-Take Personal Inventory and Admit to being wrong	The tenth step can be a pressure-relief valve. Addicts work this step while the day’s ups and downs are still fresh in mind. They list what they have done and try not to rationalize their actions. The first thing they must do is stop! Then they must take the time to allow themselves the privilege of thinking. They work this step continuously. It presents a way of avoiding grief. The individual monitors feelings, emotions, fantasies, and actions. By constantly looking at these things they may be able to avoid repeating the actions that make them feel bad (Narcotics Anonymous Basic Text, Chapter 4/Step 10). Step 10 is the maintenance step for Steps 4 and 5 and encourages the taking of a personal inventory, which, for recovering persons, should be a daily process. It is important that addicts realize that if they do carry a genetic risk, for example the DRD2 A1 allele among other gene deficits with 30–40 % less D2 receptor density, taking inventory and feeling good about it is a temporarily “dopamine fix.” As such, addicts must continue to “work the steps” on a day-to-day basis to replenish DA. [25, 272–274].
Eleventh-Prayer & Meditation to Contact God	Doing the work required in Step 11 continuously through both the meditative and prayer process increases the release of DA at the synaptic level. In addition, working Step 11 on a daily basis will offset the genetically induced “hypodopaminergic brain function” by continued DA release in the synapse. Increased DA will result in a subsequent proliferation of DA D2 receptors even in carriers of the DRD2 A1 allele and other reward gene polymorphisms. The increase in D2 receptors translates to enhanced DA function, which will ultimately promote greater confidence in the recovering addict, enabling a better understanding of the written word of the twelve-step fellowship. This will lead to an anti-stress effect and as such reduce the chance for relapse especially in dysfunctional and co-dependent families [25, 32, 42, 156, 169, 258, 272, 274, 275–278].
Twelfth-Spiritual Awakening & Carrying the Message to Others	Step 12-occurs when the recovering person had done the work, and truly understands all the preceding steps in the program. It has been said that working all the steps will allow an individual to have spiritual awakening. We point out that for people who have addiction is dependent on both genes and environmental conditions, attaining this awakening may be more or less difficult. One of the most fulfilling experiences one could get is sharing emotions with others especially as it relates to carrying the message of the fellowship to other addicts. It is important to realize this experience maybe impacted by the synthesis and release of the brain chemical oxytocin. Unfortunately, independent of one’s genetic makeup, alcohol and opiates significantly impair the synthesis and release of this important human bonding neuropeptide. Finally, clinicians should be cognizant that any lifestyle change is significantly impacted by both polymorphic genes and traumatic events [79, 279–286].