Are We Getting High Cause the Thrill is Gone?

Abstract

In the USA alone, opioid use disorder (OUD) affects approximately 27 million people. While the number of prescriptions may be declining due to increased CDC guidance and prescriber education, fatalities due to fentanyl-laced street heroin are still rising. Our laboratory has extended the overall concept of both substance and non-substance addictive behaviors, calling it "Reward Deficiency Syndrome (RDS)." Who are its victims, and how do we get this unwanted disorder? Is RDS caused by genes (Nature), environment (Neuro-epigenetics, Nurture), or both? Recent research identifies resting-state functional connectivity in the brain reward circuitry as a crucial factor. Analogously, it is of importance to acknowledge that the cumulative discharge of dopamine, governed by the nucleus accumbens (NAc) and modulated by an array of additional neurotransmitters, constitutes a cornerstone of an individual's overall well-being. Neuroimaging reveals that high-risk individuals exhibit a blunted response to stimuli, potentially due to DNA polymorphisms or epigenetic alterations. This discovery has given rise to the idea of a diminished 'thrill,' though we must consider whether this 'thrill' may have been absent from birth due to high-risk genetic predispositions for addiction. This article reviews this issue and suggests the general concept of the importance of "induction of dopamine homeostasis." We suggest coupling a validated genetic assessment (e.g., GARS) with pro-dopamine regulation (KB220) as one possible frontline modality in place of prescribing potent addictive opioids for OUD except for short time harm reduction. Could gene editing offer a 'cure' for this undesirable genetic modification at birth, influenced by the environment and carried over generations, leading to impaired dopamine and other neurotransmitter imbalances, as seen in RDS? Through dedicated global scientific exploration, we hope for a future where individuals are liberated from pain and disease, achieving an optimal state of well-being akin to the proverbial 'Garden of Eden'.

Keywords: Dopamine; Functional connectivity; Genetic addiction risk severity; Neurotransmitters; Pro-dopamine regulation; Reward brain circuitry; Thrill is gone.

Figure 1:

Illustration of the lock and key principle (standard free stock internet).

Figure 2:

Dopamine chemical structure. The chemical structure of the compound dopamine, the happiness molecule is C₈H₁₁NO₂. Dopamine affects the brain processes that control emotional responses and ability to experience pleasure, desire, and motivation [26].

Figure 3:

A metaphor showing that RDS in terms of the population of 100,000 million is akin to the entire state of California.

Figure 4:

RDS: The behavioral octopus. Schematics show many arms of individual disorders with unique characteristics that share a common foundation of low dopamine signaling tone (hypodopaminergia); a foundational cause/consequence of reward deficiency (original artwork by Steven Gondre-Lewis).

Figure 5:

Mechanisms of epigenetics [36].

Figure 6:

Schematic representation of Brain Reward Cascade. (a) Abnormal unbalanced neurotransmission showing high GABA transmission with reduced dopamine release: Unhappy Brain. (b) Normal balanced neurotransmission showing appropriate amount of dopamine release: Happy Brain feeling of well-being [26].

Figure 7:

Functioning brain connections represented by cheese. Addictive Brain: lacks connectivity at rest represented by holes (no crosstalk) compared to Non-Addictive Brain. KB220Z helps restore resting state functional connectivity and consequentially better decision making (with permission from Blum et al.).

Figure 8:. Composite 3D functional connectivity maps comparing KB220Z and placebo.

The top row shows the segmented 3D ROI used as seed for the placebo and KB220Z maps seen below them. High clustering of voxels occurs within the seed regions for both placebo and KB220Z groups. Greater connectivity based on the number of voxels showing high correlation coefficient values is observed in the KB220Z maps. Difference maps (KB220Z minus placebo) are shown in the bottom row. Maps are set at a lower statistical threshold of p < 0.005 (voxel cluster size corrected) (with permission from Febo et al.).

Figure 9:

Resting-state fMRI 1 hour after one dose KB220Z. Placebo left side vs KB220Z right side (with permission from Blum et al.).