Endorphinergic Enhancement Attenuation of Post-traumatic Stress Disorder (PTSD) via Activation of Neuro-immunological Function in the Face of a Viral Pandemic

Abstract

Introduction:

Polymorphic gene variants, particularly the genetic determinants of low dopamine function (hypodopaminergia), are known to associate with Substance Use Disorder (SUD) and a predisposition to PTSD. Addiction research and molecular genetic applied technologies supported by the National Institutes of Health (NIH) have revealed the complex functions of brain reward circuitry and its crucial role in addiction and PTSD symptomatology.

Discussion:

It is noteworthy that Israeli researchers compared mice with a normal immune system with mice lacking adaptive immunity and found that the incidence of PTSD increased several-fold. It is well established that raising endorphinergic function increases immune response significantly. Along these lines, Blum’s work has shown that D-Phenylalanine (DPA), an enkephalinase inhibitor, increases brain endorphins in animal models and reduces stress in humans. Enkephalinase inhibition with DPA treats Post Traumatic Stress Disorder (PTSD) by restoring endorphin function. The Genetic Addiction Risk Severity (GARS) can characterize relevant phenotypes, genetic risk for stress vulnerability vs. resilience. GARS could be used to pre-test military enlistees for adaptive immunity or as part of PTSD management with customized neuronutrient supplementation upon return from deployment.

Conclusion:

Based on GARS values, with particular emphasis on enhancing immunological function, pro-dopamine regulation may restore dopamine homeostasis. Recognition of the immune system as a “sixth sense” and assisting adaptive immunity with Precision Behavioral Management (PBM), accompanied by other supportive interventions and therapies, may shift the paradigm in treating stress disorders.

1. BACKGROUND

The purpose of this review is to help understand the unfortunate fact that in the face of a worldwide viral pandemic, a large part of society has been in a state of extreme stress with insults to the brain reward system and potential induction of PTSD. It has become increasingly clear that PTSD may link to a compromised neuroimmune system. This review profiles some molecular neurobiological phenomena relevant to PTSD in the general population and may have particular importance to armed services.

Three decades of gene-based research identified and characterized the Reward Deficiency Syndrome (RDS) that includes impulsive, compulsive, and addictive behaviors. This article involves a new evidence-based model for the prevention and treatment of all RDS behavioral types, not just those for which there are known genetic causes. It is crucial to acknowledge that stress is indeed a primary culprit to altering normal brain function. The novel adoption of “Precision Behavioral Management” (PBM) seems imminent. Indeed, more research to pinpoint the most appropriate candidate genes related to addiction-prone risk is necessary, but the development of PBM has already begun. Personalized, precision medicine identifies Single Nucleotide Polymorphisms (SNPs) of candidate reward genes associated with populations with RDS [1].

The environment, manifest by an epigenetic switch that controls gene expression, is thought to contribute about fifty percent to the genetic risk for many psychological disorders. Post-traumatic Stress Disorder (PTSD) is a good example of environmental stress compounding the genetic risk. Individuals who have PTSD are also known to have hypodopaminergia, which triggers co-morbidity with (SUD) [2]. New research directed towards up-regulation of mesolimbic dopamine, as suggested by the NIDA aims to restore homeostasis [3] and eventually be supported in the scientific community.

The importance of core reward circuitry neurotransmitters in the brain’s prefrontal cortices was not well understood. The idea of addiction as a disease did not hit until the early 1960s. The discrete functions of acetylcholine, serotonin, cannabinoids, GABA, dopamine, and endorphins were unknown. In 1956, the alcoholism concept, introduced by Dr. Jellinek, without much scientific support, was shocking and not generally accepted [4]. However, at that time, most addiction scientists agreed that deficiencies or imbalances in brain chemistry-perhaps, genetic in origin-were at least in part the cause of alcoholism, and alcohol per se was an allergen.

Virginia Davis, Michael Collins, Gerald Cohen, and others did initial work related to the interface of alcohol and opioid use disorders involving condensation of alcohol, acetaldehyde, and dopamine resulting in the novel substance class known as isoquinolines [5–9]. Blum investigated the neurochemical mechanisms of alcohol and opioids from the 1970s and, in the mid-1990s, developed the concept of Reward Deficiency Syndrome (RDS) published by The Royal Society of Medicine in 1996 [10]. There have been 1,328 (1/7/21) Reward Deficiency articles listed within PubMed, and The SAGE Encyclopedia of Abnormal and Clinical Psychology included the RDS concept in 2017 [1]. Cross-addictions occur, primarily, in psychiatric illnesses, including PTSD [11]. Cocaine use in PTSD is prevalent and associated with treatment failure, health, and societal consequences. Cocaine use and abuse appear to increase the risk of PTSD symptoms, especially in females [12]. This risk increase is not surprising since significant cocaine abuse leads to hypodopaminergia, which intensifies many PTSD symptoms, including nightmares. Mark Gold’s dopamine depletion hypothesis proposed a vital role for dopamine in the effects of cocaine. Dackis and Gold suggested that chronic Cocaine Use Disorder (CUD) development was due to the acute activation of central dopamine neurons and the euphoric properties of cocaine. Acute overstimulation of dopamine neurons and excessive synaptic metabolism responsible for depleting dopamine may bring about cocaine abstinence dysphoria and cocaine use urges [13], including an inability to cope with stressful events.

These neurochemical disruptions caused by cocaine were identified as “physical” rather than “psychological” addiction [14]. Dopamine depletion due to CUD was treated with dopamine agonist therapy. After a single dose of the potent dopamine D2 agonist, bromocriptine cocaine craving was significantly reduced [15]. Open trials of low dose implied that bromocriptine might be useful in cocaine detoxification and prove to be an effective, non-addictive pharmacological treatment for CUD. Ernest P. Nobel, now deceased, directed a placebo-controlled bromocriptine study to treat subjects with Alcohol Use Disorder (AUD) [16]. The best results occurred in the bromocriptine-treated subjects with the DRD2 A1 allele (first associated with severe alcoholism in 1990 by Blum et al. [17]), while the worst result occurred in the placebo-treated A1 subjects [16]. Unfortunately, this potent D2 agonist’s chronic administration induced significant down-regulation of D2 receptors, thereby negating its clinical usefulness [18, 19]. This lead to Blum et al. proposal that milder therapeutic, neuro-nutrient formulations could accomplish D2 receptor agonism to help attenuate stressful events [20].

Blum group favored encouraging dopamine release, using KB220; mild, neuro-nutrient formulations, to stimulate human mRNA expression and D2 receptor proliferation [21] to diminish craving and alleviate stress. Based on this model, research studies showed significant reductions in rodent alcohol craving behavior and craving in genetically bred alcohol-preferring rodents and reduced self-administration of cocaine following gene therapy involving overexpression of DRD2 receptors [22, 23]. Essentially, increasing D2 receptors caused craving for psychoactive substances and even non-drug addictive behaviors to abate.

The chronic promotion of dopaminergic activation by lower potency dopaminergic repletion therapy (KB220Z) has been a clinically effective treatment modality for RDS behaviors, including PTSD, SUD, Attention-deficit/Hyperactivity Disorder (ADHD), and obesity [24]. Experiments using fMRI in both animals and humans identified resting-state functional connectivity increases and neuronal recruitment, following acute doses of neuro-nutrients therapy, within 15 minutes (animal) to 60 minutes (human), post-administration of KB220Z. Additional dopamine neuronal firing reward processing areas of the brain indicated possible neuroplasticity [25, 26].

2. WHAT HAS NEUROIMAGING REVEALED ABOUT PTSD?

Neuroimaging techniques have identified the Default Mode Network (DMN), which includes the medial temporal regions, lateral parietal cortices, and the medial prefrontal cortex, posterior cingulate cortex/precuneus [27]. In healthy individuals, dopamine is a known substrate of the DMN, most active during rest from cognitive tasks like remembering. The DMN is involved in self-processing at rest, which can be perturbed by stress [28, 29].

PTSD psychopathology involves the amygdala (fear) and hippocampus (memory recall), and physiologically patients with severe PTSD symptoms presented with decreased neuronal tissue in the anterior right hippocampus [30] and the right amygdala (corresponding to the Centro-medial Amygdala) [31]. Akiki et al. followed up their neuroimaging research with a stepwise regression analysis, which indicated that arousal symptoms of PTSD were associated with tissue indentation in the hippocampus, and re-experiencing traumatic events explained amygdala abnormality [31].

Martindale et al. [32] reported that white matter hyperintensities correlated significantly with the blast intensity of the explosion; however, this finding was independent of diagnosis.

Averill et al. [33] discovered reduced cortical thickness in the left temporal regions correlated with combat exposure severity. There was an interaction between combat exposure severity and PTSD diagnosis in the superior temporal/insular region and a stronger negative correlation between combat exposure severity and cortical thickness in the non-PTSD group [31].

Both van Wingen [34] and colleagues and Butler et al. [35] found that some of the physiological changes caused by prolonged stress can be reversed. Van Wingen et al. [34] found that attention deficits were normalized within 18 months and midbrain to prefrontal cortex functional connectivity deficits continued. Butler et al. [35] observed an increase in amygdala volume and an increase in hippocampal volume following six weeks of mental health treatment.

Executive functional deficits due to prolonged stress results from alterations within the mesofrontal circuit involving dopaminergic activation [29]. The neurotransmitter dopamine functions within the mesolimbic ventral tegmental area to relieve stress, enhance wellbeing, and provide motivation [36]. These alterations from combat stress may be partially reversible, and immediate treatment may result in epigenetic mitigation of PTSD symptoms [37].

3. NEURO-IMMUNOLOGICAL FUNCTION, ADAPTATION OF STRESS & SOCIAL BEHAVIOR

The goal is to understand how the immune system provides an enhanced defense against specific pathogens and how homeostatic immune surveillance of all tissues, including the brain, occurs. The Jonathan Kipnis group is the foremost authority on this remarkable new thinking that has profound promise for new therapeutic targets for cognitive and even social brain function [38]. They suggest that initially inflammatory cytokines increase a host-host transmission by exploiting the pro-social effects of interferon-regulated genes. Later the inflammatory cytokines were recycled by the host to form part of an immune defense program. Like a host pathogen’s arms race, this CNS immune surveillance is crucial for recovery from injury and healthy brain function [38].

A series of early investigations have suggested that the beneficial effect of T-cells after traumatic CNS injury is the mediation of autoreactive T-cells specific for brain antigens [39–43]. The immune system, mainly through T-cells, effects CNS function in health and disease. There is evidence that brain immune cells play a vital role in learning and memory. Early work revealed that Severe Combined Immunodeficiency (SCID) mice perform poorly in the Morris water maze and other memory and spatial learning tasks [44, 45]. Specifically, reconstituting the T cell compartment rescued learning and memory in SCID mice [45].

Moreover, in support of the specific influence of T cells on learning behavior, it is known that mice lacking B cells display no impairment of learning behavior [46]. It is noteworthy that SCID mice show impaired social behavior as indicated in the three-chamber sociability assay [47], which determines the preference of a test mouse to investigate a novel mouse over a novel object [48]. Notably, while we do not know how long the effect lasts, social behavior deficits were rescued four weeks after repopulation with wild-type lymphocytes.

Along these lines, mice that lack T cells in a model of PTSD also exhibit heightened susceptibility [49], impaired maternal behavior, and exhibit compulsive grooming behaviors [50], representative of reward deficiency. In terms of physiology, it is worth noting that while perivascular macrophages and microglia patrol the brain parenchyma, the meningeal spaces have a diverse immune repertoire dedicated to neuro-immune crosstalk allowing the brain to perform optimally [51–54].

According to most social scientists, social or aggregation behavior is critical not only for survival and evolution but also for the spread of infectious organisms. Thus, coordinated immunity and sickness behavior have evolved to limit the spread of pathogens. Hart [55] argued that sickness behavior is not a maladaptive response to infection but rather a coordinated behavioral plan to promote host survival. More recently, Shakhar and Shakhar attributed altruism and kin selection sickness behavior [56]. Another intriguing argument is that carriers of specific gene polymorphisms may flock together concerning sickness behavior or psychological or psychiatric disorders [57, 58]. In support of this notion, Blum’s group [59] has proposed that political, spiritual, and social behaviors may be tied to inheritable reward gene polymorphisms, as seen in addictions and PTSD. For example, both drinking (alcohol) and obesity seem to cluster in large social networks influenced by friends having the same genotype, such as the DRD2 A1 allele. This clustering effect may have an evolutionary advantage for the heard and general population. While many polymorphic risk alleles load onto the PTSD phenotype, Comings, Muhleman, and Gysin [60] provided the first genetic evidence that the DRD2 A1 allele associates with PTSD. Concerning the immune response, it is well-known that the inflammatory response promoted by TNF-alpha causes many clinical problems associated with autoimmune disorders and psychiatric issues. Indeed, Petrullj et al. [61] clearly showed that increases in systemic inflammation enhance stimulant-induced striatal dopamine elevation linked to higher TNF-alpha plasma levels. The question could augmented-neuroimmunological function be coupled with increased dopamine to attenuate stressful events, including trauma? While this question must await required basic research in animal models and humans, a more straightforward approach is to find ways to enhance the immune response by manipulating specific transduction signaling by targeting the endorphinergic system.

4. ENDORPHINS AND ENHANCEMENT OF IMMUNE FUNCTION AND STRESS

It is well-known that the Corticotropin-Releasing Factor (CRF), synthesized in the hypothalamus, stimulates the release of pituitary peptides derived from the precursor molecule, Proopiomelanocortin (POMC). These peptides not only include Adrenocorticotropic Hormone (ACTH), but a variety of Endogenous Opiate Peptides (EOP) from the endorphin family. Chemically, endorphin is a 31 amino acid molecule, with specific fragments such as 5 (Met-enkephalin) and other endorphins. The resting circulating concentration of endorphin lies in the low picomolar range and increases following various forms of stress [62].

B-endorphins binds to opiate receptors through its N-terminal sequence, and N-terminal acetylation blocks this binding. The C-terminal sequence binds to different non-opiate receptors [63]. Importantly, there is evidence that lymphocytes have receptors for these EOP. Moreover, the binding of Met-enkephalin and morphine to T-cells prevented by naloxone, suggesting that T-lymphocytes express opiate receptors [64]. The link between the central nervous system and the immune system may be the surface receptor-like structures for morphine, dextromoramide, and methionine-enkephalin observed on normal human blood T-lymphocytes.

The endogenous opioid peptides have many significant effects on immune function. For a few examples, in vivo, treatment of mice with Met and Leu-enkephalin protects against challenge with L1210 leukemic cells [65]. Also, endorphins modulate proliferative responses to mitogens in vitro [66]. McCain, Lamster, and Bilotta [67] claim that at specific concentrations, endorphins also inhibit the induction of suppression by Concanavalin A (ConA), which functions as a T cell regulator in humans. According to Wybran [68], EOP also enhances Natural Killing (NK) cells, and the enhancement can be reversed by naloxone. Johnson, Smith, Torres & Blalock [69] showed that endorphins block specific antibody production in rodents.

In summary, it is noteworthy that stress rapidly increases the secretion of B-endorphin from the pituitary gland [62, 70]. Soldiers who had higher numbers of glucocorticoid receptors (involved in stress response) on their leukocytes were more likely to develop PTSD after experiencing traumatic stress [71]. Since stress and trauma effect the immune response, these changes in the immune response may correlate to changes in circulating endorphins. Smith, Morrill, Meyer & Blalock [72] suggested that lymphocytes can synthesize immunoreactive ACTH and endorphin-like peptides. The importance here is that EOP produced by activated lymphocytes themselves may be highly potent modulators of the final immune effector response. Moreover, the opioid peptide-induced immuno-stimulating effect may involve the dopaminergic system [73, 74]. These endorphinergic effects on the immune system [75] and its potential enhancement of the immune response, especially under stressful conditions, provide the rationale to increase endorphinergic function epigenetically by inhibiting the enzyme enkephalinase [76].

4.1. Raising the Endorphin Function via Enkephalinase Inhibition

The carboxypeptidase enzyme (enkephalinase) cleaves methionine-enkephalin into non-opioid fragments, and as such, the activity of the parent compound finishes. The enkephalinergic neuroendocrine-immune regulatory system is well known as one of the most critical neuroendocrine-immune systems in humans. The neurotransmitter [Met5]-enkephalin released by the neuroendocrine system regulates the developing immune system. An enzyme enkephalinase inhibitor reduces the activity of the enkephalinase class that breaks down the endogenous enkephalin-opioid-peptides. A few examples include racecadotril, bestatin, RB-101, D-phenylalanine, opioid peptides, opiorphin, thiorphin, and spinorphin [77].

In 1987, Blum et al. provided the first report showing that in alcohol-preferring mice, with concomitant genetically compromised innate brain enkephalin deficiencies, raising brain enkephalins using acute and chronic treatment with D-phenylalanine (an enkephalinase inhibitor) significantly attenuate both volitional and forced ethanol intake. Since these agents, through their enkephalinase inhibitory activity, raise brain enkephalin levels, Blum et al. proposed that alteration of endogenous brain opioid peptides can regulate excessive alcohol intake. Understanding that both drug-seeking behavior and PTSD have a common neurochemical and genetic mechanism, and as proposed in this review, neuroimmunological regulation is tantamount to overcoming PTSD symptoms. This novel proposal of raising endorphin function by inhibition of the enkephalinase enzyme seems prudent. Studies have demonstrated the anti-inflammatory activity of D-phenylalanine in the rat paw test [76, 78].

It is noteworthy that Nagarjun et al. [79], as recently as 2017, showed that a chromium complex of D-phenylalanine [complex (Cr (d-phe)3)] demonstrated the protective effect of Cr (d-phe)3 against indomethacin-induced Irritable Bowel Disorder (IBD) in rats. The anti-inflammatory and antioxidant properties of Cr (d-phe)3 might be responsible for this protective effect. This finding is of particular interest since Febo, Blum, Badgaiyan, Perez, Colon-Perez et al. [80] provided resting-state Functional Magnetic Resonance Imagining (rsfMRI) evidence for BOLD activation of the dopaminergic pathways in the brain reward circuitry with a complex KB220Z containing both Cr and D-phenylalanine.

5. UNDERSTANDING GENETICS OF PTSD

As mentioned earlier, the first study to show an association between a reward gene, the A1 allele form of the dopamine D2-receptor gene, and military veterans diagnosed with PTSD was carried out by David Comings from the City of Hope [60]. Carriers of this gene form associated with severe alcoholism by the Noble, Blum group have 30–40 percent less dopamine D2 receptors in the brain [81].

Along these lines, low dopamine-function is associated with increased risk for PTSD [37]. Dopamine is released from neurons 100 times above the resting state to cope with the extreme stress of combat [82–84]. This insult release depletes dopamine, combined with trait hypodopaminergia (fewer dopamine D2 receptors), or chronic repeated insult, can cause PTSD. Post-traumatic stress disorder is hereditary. Compared to non-identical (dizygotic) twins, identical (monozygotic) twins with PTSD, associated with an increased risk of their co-twins having PTSD following combat exposure in Vietnam [85].

Moreover, there is evidence that those with smaller hippocampi (a region of the brain involving memory), perhaps due to genetic differences, are more likely to develop PTSD following traumatic stress [30]. Post-traumatic stress disorder shares many genetic influences with other psychiatric disorders; for example, 60% of the genetic variance of panic and generalized anxiety disorders and substance addictions share greater than 40% genetic similarity [86].

Most importantly, environmental insults like childhood abuse induce epigenetic changes that impact brain chemistry. Instead of being caused by differences within the DNA sequence, epigenetic changes caused by external or environmental factors that switch genes on and off and phenotypic traits; cellular, physiological, and behavioral characteristics that can continue for at least two subsequent generations [87]. These environmentally induced epigenetic changes in DNA chromatin structure can reduce dopamine D2 receptor gene expression and function, leading to PTSD symptoms.

Genetic polymorphisms that regulate gene expression within the serotonergic and dopaminergic pathways are evident in the development of PTSD. The 5-HTTLPR (promoter region of SLC6A4, which encodes the serotonin transporter) is a genetic candidate region responsible for modulating emotional responses to traumatic events. Furthermore, the variation of the 5HTTLPR gene coupled with stressful life events can predict depression and PTSD. The dopaminergic pathway, specifically, the A1 allele coding the type 2 dopaminergic receptor, is associated with severe co-morbidity of PTSD, with many reward deficiency behaviors. For example, the polymorphism of the GABRA2 gene is associated with the occurrence of PTSD. The Val (158)Met polymorphism of the gene coding for catecholamine-o-methyltransferase is associated with the number of traumatic events [2]. Also, other genes include polymorphisms in FKBP5 (a co-chaperone of hsp 90, which binds to the glucocorticoid receptor) predicts risk for PTSD, with a gene-by-environment interaction [88].

Zhang, Wang, Cao, Li, Fang, et al. [89] analyzed the association of the DRD2/ANNK1-COMT genes located at (rs1800497 × rs6269) with PTSD diagnosis (p-interaction = 0.0008055 and p-corrected = 0.0169155). The Chinese earthquake exposed female-cohort (32 cases and 581 controls), p-interaction = 0.01329) results suggested that rs1800497 is related to the dopamine receptor D2 density and rs6269-rs4633-rs4818-rs4680 haplotypes affect the catechol O-methyltransferase level and enzyme activity. These genotypes may be a possible origin of dopamine homeostasis abnormalities in PTSD.

Identification of individuals faced with military combat who carry high-risk alleles for PTSD is a persuasive potential use of the GARS test. One of the polymorphic variants measured in GARS, specifically the DRD2 A1 allele, has been associated with PTSD and comorbid substance use disorder [60]. Of 24 patients in an addiction treatment unit who met the diagnostic criteria for PTSD after exposure to severe combat conditions in Vietnam, 58.3% carried the D2A1 allele. 12.5% of the eight patients without PTSD were carriers of the D2A1 allele (p< 0.04). Subsequently, in a replication study, using 13 PTSD patients, 61.5% carried the D2A1 allele, 11 without PTSD did not carry the allele D2A1 (p< 0.002). For the combined group, 5.3% of those who did not have PTSD compared to 59.5% with PTSD carried the D2A1 (p< 0.0001) [60]. These results suggest that the DRD2 variant in linkage disequilibrium with the D2A1 allele confers an increased risk for PTSD, and the absence of the variant confers relative resistance to PTSD.

6. CAN WE PREVENT OR TREAT PTSD?

Galatzer-Levy et al. [87] used Latent Growth Mixture Modeling (LGMM) supervised Machine Learning (ML) to identify individuals by clustering them into symptom progression trajectories. The trajectories and graphic algorithms examined causal paths to data from a large (n = 153) longitudinal study of the neuroendocrine response to a traumatic event, from ER endocrine markers and PTSD status at ten days, one month, five months later. Saliva and blood samples each morning of follow-up assessment included lymphocytes glucocorticoid-receptor density, saliva cortisol plasma cortisol, Norepinephrine (NE), and Adrenocorticotropic Hormone (ACTH). They found that reduced neuroendocrine response in the ER was dependent on a report of early childhood trauma exposure; this was consistent with evidence that early life abuse produces a blunted cortisol response to trauma in animal models. The authors suggest that this predictive of abnormal stress responses and implicates to genomic and molecular mechanisms for further investigation, and those abnormal cortisol responses to trauma associate with multiple genetic, epigenetic, and proteomic elements, including FKBP5 among many others, and maybe manageable therapeutic targets in the context of traumatic emergencies including military personnel deployed to war zones.

Certainty, early identification of PTSD risk will have preventative benefits if adopted by the Department of Defense (DOD). With that stated, early access to trauma and cognitive behavioral therapy has been modestly beneficial in treating PTSD [90]. Also, Critical Incident Stress Management (CISM) suggested as a means of preventing PTSD is “an integrated, multi-component continuum of psychological interventions to be provided in the context of acute adversity, trauma, and disaster on an, as needed, basis to appropriate recipient populations [91].” Critical Incident Stress Management is either a technique or a treatment for acute stress disorder, PTSD, post-traumatic depression, bereavement, or grief [91]. The World Health Organization (WHO) explicitly recommends against treatment with benzodiazepines and antidepressants in trauma victims. Some evidence supports the use of hydrocortisone for its anti-inflammatory effect in preventing PTSD symptoms in adults, which dovetails with the proposal herein to use endorphins for their anti-inflammatory effects to combat the development of PTSD. There is scant evidence to support other drugs, like propranolol, escitalopram, temazepam, or gabapentin. Indeed, gabapentin stimulates the neurotransmitter GABA and reduces dopamine effects should not be used to treat PTSD, especially in the long-term [92].

In response to these recommendations and therapeutic evidence, this proposal uses a pro-dopamine regulator (KB220Z). Thomas McLaughlin and others have published studies that showed that chronic administration of a nutraceutical, KB220Z, eliminated terrifying, lucid nightmares in at least 83% of patients with PTSD and comorbid ADHD [93, 94]. The voluntary withdrawal of the pro-dopamine regulator resulted in the reinstatement of the terrifying, non-pleasant nature of the dreams signifying that the reduction or elimination of terrifying nightmares depended on KB220Z. Most of the patients reported gradual, and then complete, amelioration of their long-term, terrifying nightmares (lucid dreams) while taking KB220Z [95]. Remarkably, we show that in at least four cases, the amelioration of nightmares persisted for up to 12 months after a self-initiated withdrawal of the use of KB220Z [93]. Increased connectivity volume and recruitment of more dopamine neurons and neuronal dopamine firing in the brain reward site in rodents suggests the induction of epigenetic changes (neuroplastic adaptation). These adaptations may be involved in the cessation of human lucid dreaming and nightmares [95].

7. ETHICAL ISSUES IN GENOMIC TESTING IN MILITARY

There have been several articles related to the ethics of performing genomic or genetic testing in the military. There are controversies and different schools of thought related to this interesting topic. One important article in 2014 by Mehlman and Li suggested that utilizing genomic or genetic testing of soldiers before military entry may have heuristic value in terms of PTSD vulnerability and peripheral issues, including traumatic bone fracture and blood loss [96]. There are currently discussions in military circles about the idea that genetic testing may result in better performance. Indeed, the addition of genetic testing may augment current selection procedures used to identify particular roles or positions within military services. However, there are crucial issues that must be addressed before genetic testing in this vital cohort. These include the following: a) one’s genes may determine 50% of any phenotype; when it relates to strength, the capacity to develop muscle or retain body fat, intelligence, or memory recall-these are functions of the environment (epigenetic) as much as they are of genetics; b) in terms of performance, a genetic test may not provide data to help select appropriate skills required in the military; c); there may also be both economic and ethical issues to overcome; d) the push for $100 genomic test while seems to be cost-effective may impose a burden in terms of interpretation of any military-related trait. Finally, while these caveats represent ethical and economic issues, the authors of this article believe that a simple GARS test to understand the vulnerability of soldiers faced with extremely stressful conditions and the potential induction of PTSD may be informative as one way to reduce harm [97–100].

CONCLUSION

Thus, neuroimmunological function enhancement through enkephalinase inhibition using the mechanism of action of KB220 variants, especially as customized through recently introduced Precision Behavioral Management (PBM), is recommended [96]. In order to assist us in identifying potential military candidates who would be less well suited for combat than those without high-risk alleles, the suggestion is that, before combat, soldiers with a background of childhood violence within the family would benefit from being tested for high-risk genetic variants. Also, using safe methods to treat individuals at high risk prophylactically and those already exposed to combat and known to have PTSD. This proposed process would also greatly benefit individuals returning from deployment to help diminish triggering traumatic experiences and foster societal reassimilation. Based on the fact that the immune system plays a critical role in regulating social behavior as discussed above, the proposal of enhancing neuroimmunological function by raising endorphin activity via enkephalinase inhibitors such as D-phenylalanine as utilized in PMB seems prudent (Fig. 1).

Fig. (1).

Healthy immune system function increases endorphinergic activity, which treats PTSD.

Finally, following a GARS test to identify gene polymorphisms (variations) known to increase the risk for substance use disorder in individuals with PTSD, due to hypodopaminergic reward circuitry function, administration of precision, pro-dopamine regulators, like KB220, might be a reasonable way to provoke epigenetic reward gene expression (mRNA) to overcome this deficiency (Fig. 2) [56, 101–105].

Fig. (2).

Maps PTSD, stress, endorphins, immune system, GARS, KB220 variants, and precision behavioral management.

In Fig. (2), neurochemical measurement showed that the enkephalinase inhibitor D-Phenylalanine (DPA) not only increased brain endorphins but also reduced stress in humans. Considering these and other facts, it seems prudent that one way to treat PTSD is to enhance endorphin function by utilizing enkephalinase inhibitors like DPA. Moreover, using the (GARS) test, the relevant genotype-phenotype relationships can be characterized and Psychosocial tools. GARS could be used to pre-test military enlistees for adaptive immunity or as part of PTSD management. Based on the GARS test values, customized supplementation of neuro-nutrients may achieve dopamine homeostasis, emphasizing the enhancement of immunological function. “Precision Behavioral Management” (PBM) and putative pro-dopamine regulation should be accompanied by interventions like mindfulness and trauma therapy and all types of psychological and behavioral modalities. The suggestion that the immune response requires reconsideration in this severe resistant disorder responsible for PTSD induced unwanted deaths seems prudent.