The functional neuroimaging techniques, such as resting-state functional magnetic resonance imaging (rsfMRI), have shown that acute exposure to cannabis reduces the neuronal activity in the nucleus accumbens (NAc) and prefrontal cortex (PFC), anterior cingulate gyrus (ACG), striatum, and thalamus. In contrast, chronic cannabis exposure increases the rsfMRI in these brain regions, and in adolescents' chronic use of high Δ9-THC content cannabis results in impaired motivation with depression, anhedonia, low academic achievement, and reduced functional connectivity in the brain reward circuitry (22, 23). The primary neurochemical insult is an altered dopaminergic function across mesolimbic pathways requiring neurotransmitter balance across the brain reward system. Nestor et al. (24) found that in chronic cannabis users (with an average of 6.1 [range = 2.5–17] lifetime years of cannabis use and with the consumption of 7,258-lifetime cannabis joints), there is an increased ventral striatal (VS) blood-oxygen-level-dependent (BOLD) response to stimuli predicted potential non-drug rewards. Importantly, VS hyperactivity is seen during reward anticipation associated with years of cannabis use and the lifetime estimation of numbers of cannabis joints consumed. Another known impairment related to chronic cannabis use relates to compulsive drug use with NMDA receptor-dependent synaptic depression located at the ventral tegmental area (VTA) linked to dopamine circuitry. Chronic cannabis exposure also activates VTA cannabinoid CB1 receptors and reduces transient neurotransmission at VTA local Glu-DA synapses by activating NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits (25).

This evidence provides possible new targets in obviating chronic addiction learning, specifically with chronic cannabis use in humans. Dopamine augmentation is difficult to achieve, especially after the development of a substance use disorder (SUD). Vigorous physical exercise, like Eminem, TMS, and nutraceuticals, have been proposed as viable options. Our proposal herein of incorporating genetic risk allelic testing related to reward pathways along with potential induction of dopamine homeostasis seems logical. This concept takes on even more importance when we consider that the onset and peak use of cannabis occur during brain development in teenagers and, as such, represents an unwanted window of liability (26, 27). The onset of cannabis use begins in the mid-teens and peaks by the age of 25, with the development of cannabis use disorder between 15 and 20. In order to either prevent or treat the high dose Δ9-THC-induced hypodopaminergic anhedonia and cognitive decline, it may be possible to combine the non-invasive testing for the genetic addiction risk score (GARS) with pro-dopamine regulation and restore the dopamine function (26–58). A novel model (Figure 1) espouses a reasonable biphasic approach; a short-term blockade followed by long-term dopaminergic upregulation with KB220Z^* primarily for reward deficiency syndrome (RDS) behaviors (29–38).

“^*KB220Z Components, The most recent variant of KB220Z (powdered form), is composed of the following ingredients: Vitamin B6, 10 mg (500%); Thiamine, 15 mg (1,033% of Daily Value); and Chromium poly nicotinate, 200 mcg (166%). A fixed-dose of synaptose is included as well, which is a combination of amino acids and herbs that contains DL-Phenylalanine, L-Tyrosine, Passion-Flower Extract; a Complex containing Arabinogalactans, N-Acetylglucosamine, Astragalus, Aloe Vera, Frankincense Resin, White Pine Bark Extract, and Spirulina; Rhodiola; L-Glutamine; 5-Hydroxytryptophan (5-HTP); Thiamine Hydrochloride; Pyroxidal-5-phosphate and Pyridoxine HCl, CoQ10, NADH, and N-Acetyl Cysteine (NAC); (59). The powder was manufactured by Cephram, Inc. (New Jersey)”.

However, in chronic cannabis-using adolescents, the goal would be to enhance brain reward functional connectivity [measures the degree of synchrony of the BOLD time-series between different brain regions] and connectivity volume [Voxel-based morphology (VBM)], attenuate depression-like symptoms (anhedonia), and target stress-like anti-reward drug dependence symptoms. Using fMRI of both naïve animals (60) and heroin abstinent subjects (61), we confirmed blood-oxygen-level-dependent (BOLD) activation of dopaminergic reward pathways and recruitment of dopamine neuronal firing with KB220Z. These types of fMRI results provide some evidence for dopaminergic activation.

Millions of individuals worldwide struggle to combat their frustrating and even fatal romance with getting high daily. The neuroscience community conducts and funds incredible research using sophisticated molecular-genetic applied technology in animal experiments and humans using neuroimaging to advance our understanding of brain reward circuitry's complex functions that play a vital role in the expressed symptoms found in addictions. Although dopamine is known as a major neurotransmitter involved in addictions, many disagree about how to deal with dopamine dysregulation clinically to prevent and treat addictive disorders, including cannabis use disorder (CUD). An alternative approach could include two phases; a brief blockade followed by stable dopaminergic upregulation. The treatment goal would be to augment brain reward functional connectivity volume by targeting reward deficiency and the stress-like anti reward symptomatology of addiction. These phenotypes can be characterized using the Genetic Addiction Risk Score (GARS). Dopamine homeostasis may thus be achieved via “Precision Addiction Management” (PAM)®, the customization of neuronutrient supplementation based on the GARS test result, along with a behavioral intervention (29).

Dopaminergic homeostasis could be achieved by genetic testing for addiction risk and administering precursor amino acid and enkephalinase inhibitory, non-addictive, natural complex pro-dopamine regulator (KB220), matching to one's neurotransmitter pathways associated reward gene polymorphisms, as previously proposed. Fried et al. (59) reported a case series about the novel treatment of screening with GARS and utilizing a customized pro-dopamine regulator matched to polymorphic reward genes with a hypodopaminergic risk. The proband was a female of 34 years with a history of cannabis abuse and alcoholism. She voluntarily entered treatment after experiencing a car accident while driving under the influence. Following an assessment, she was genotyped using the GARS and given a polymorphic matched neuro-nutrient with a KB220Z base. She successfully recovered from Substance Use Disorder (SUD) and experienced improved socialization, family, economic status, well-being, and attenuation of major depression. She tested urine negative over the first 2 months in treatment and a recent screening. Following ~2 months into the program, her parents also decided to take the GARS and started taking the recommended variants. The proband's father (a binge drinker) and mother (no SUD) showed improvement in various behaviors. Finally, the proband's biological children were also GARS tested, showing a high risk for SUD. This three-generation case series represents an example of the impact of genetic information coupled with an appropriate DNA guided “Pro-Dopamine Regulator” to recover and enhance life.

Over the many years of the development of the putative pro-dopamine regulator, with the research ID code of KB220Z, there have been a plethora of studies showing remarkable benefits related to reward deficiency behaviors and associated drug and non-drug phenotypes (26, 27, 29, 51, 55, 56, 59, 60, 62–93).

This KB220Z variant has been the subject of at least 43 clinical and pre-clinical studies showing anti-RDS addictive behaviors via dopaminergic mechanisms [see Annotated Bibliography and review by Blum et al. (30)] and Figure 2.

Manza et al. (94) suggest that chronic cannabis abuse is associated with resting-state brain function changes, particularly in dopaminergic nuclei implicated in psychosis, habit formation, and reward processing. Is it possible that by utilizing GARS-guided precision, KB220Z could help restore the normal functioning of reward processing and connectivity in cannabis-using subjects, especially in our youth and high-risk populations?