Igor Elman

Fatty acid-binding proteins (FABPs) are a family of intracellular lipid chaperones that transport fatty acids and other hydrophobic molecules, playing essential roles in cellular lipid metabolism, signaling, and brain function. Within the central nervous system, FABP3, FABP5, and FABP7 facilitate the trafficking of long-chain polyunsaturated fatty acids and endocannabinoids, thereby modulating key regulatory pathways including the endocannabinoid system (ECS), peroxisome proliferator-activated receptor (PPAR) signaling, and dopaminergic neurotransmission. Peripherally, FABP1 and FABP4 contribute to hepatic drug metabolism, kidney excretion, and inflammatory processes in both tissues, with implications for the pharmacokinetics of substances of abuse. This narrative review synthesizes the current literature on FABPs and their involvement in substance use and addiction-related behaviors. Evidence from transgenic knockout models, pharmacological inhibition studies, and adeno-associated virus vector approaches demonstrates that manipulation of FABP subtypes can alter reward-related behaviors across multiple substances, including THC, ethanol, nicotine, and cocaine. Reduction or knockout of FABP7 alters THC metabolite levels in a sex-dependent manner. FABP3 shows involvement with dopamine receptor expression; however, interaction between FABP3 modulation and specific substances has sparsely been investigated. FABP5 has vastly diverging interactions with addictive behavior and appears to be substance dependent, as downregulation reduces cocaine self-administration, but knockout enhances nicotine conditioned place preference (CPP) and increases brain uptake of THC. Combined deletion of FABP5 and 7 additionally reduces cocaine CPP and reinstatement, while showing promising decreases in ethanol consumption paradigms. FABPs may be a potential therapeutic target for treating substance use disorders and underlying reward deficiency mechanisms underlying addiction and further research is required to elucidate specific mechanistic effects and eliminate potential adverse consequences of chronic FABP modulation.

Background/Objectives: Post-Traumatic Stress Disorder (PTSD) is a complex psychiatric condition with a strong polygenic and stress-related biological basis. Although Genome-Wide Association Studies (GWAS) have acknowledged abundant risk variants, translating these findings into biologically meaningful candidates remains challenging. This study introduces an integrative computational approach from raw file preparation by python-coded application into downstream in-depth silico analyses designed to systematically refine GWAS signals for PTSD using fine-mapping, linkage disequilibrium (LD), and haplotype analyses. Methods: GWAS source file for PTSD was obtained from the GWAS Catalog (EFO_0001358) and analyzed using a custom Python pipeline integrating data harmonization, genome-wide visualization, LD estimation via 1000 Genomes reference panels, approximate Bayesian fine-mapping, and Haploview-inspired haplotype inference. SNPs were filtered based on statistical significance, LD structure, and posterior inclusion probability. Downstream systems’ biology analyses included protein–protein interaction modeling and pharmacogenomics (PGx) annotations. Results: From the primary GWAS dataset, 100 top-ranked SNPs were selected, leading to the identification of 58 significant loci. LD and haplotype analyses refined these signals to 93 candidate SNPs (66 genes). Following the exclusion of non-protein-coding genes, 45 genes remained, and network-based prioritization generated a final list of 20 biologically connected and pharmacogenetically relevant genes associated with PTSD. Conclusions: This integrative approach provided a robust and reproducible framework for GWAS fine-mapping and variant prioritization, effectively reducing large-scale GWAS outputs to biologically interpretable PTSD risk loci and genes.

Addiction continues to be heavily stigmatized due to lingering misconceptions that frame substance use as a moral failing rather than a treatable neurobiological disorder. This stigma, when internalized, intensifies shame and obstructs recovery. Awareness Integration Theory, a multidisciplinary therapeutic model, addresses these internalized beliefs by identifying and integrating fragmented aspects of the self across thoughts, emotions, behaviors, and promotes self-awareness, emotional regulation, and cognitive restructuring, critical components in reducing shame and fostering resilience. This paper explores the interplay between self-perception, shame, resilience, and biological predisposition in addiction recovery. Research shows that shame-prone individuals are more likely to relapse, while guilt-prone individuals demonstrate greater capacity for change. Resilience, cultivated through self-forgiveness, social support, and neuroplastic interventions, mitigates the impact of shame. Genetic variants and epigenetic modifications influence reward deficiency syndrome, increasing vulnerability to addiction. The Genetic Addiction Risk Severity test can identify at-risk individuals, enabling precision-targeted interventions. Awareness Integration Therapy’s integrative framework complements genomic and neurobiological insights by fostering self-acceptance, enhancing insight into unconscious belief systems, and motivating purposeful action. Neuroimaging studies support the role of resilience-based practices, including those embedded in Alcoholics Anonymous, in promoting dopamine homeostasis and neural recovery. In conclusion, stigma reduction must advance alongside personalized medicine. Integrating Awareness Integration Therapy with genetic screening, trauma-informed care, and psychoeducation offers a comprehensive, compassionate approach. Reframing addiction as a brain-based, treatable condition empowers clients and families, facilitating sustainable recovery grounded in science and self-awareness.

Background: There are important gaps in describing the associations between variants found by GWAS and various phenotypes. Prior reports suggest that SNPs in regulatory regions should be further investigated to uncover these associations. Thus, this study involved a novel approach, along with Pharmacoepigenomics, prompting a new coined term “CpG-PGx SNP”. Methods: The rationale behind our analysis strategy was based on the impact of SNPs playing dual roles both in the CpG site disruption/formation and having PGx associations. Thus, we employed GeneCards (relevance score), PharmGKB (significant p-value), and GWAS catalog data for each gene (p < 5 × 10⁻⁸). Following the obtainment of the 25 best-scored genes of four major epigenetic processes (methylation, demethylation, acetylation, and deacetylation), we generated two lists of candidate genes, including potential CpG-PGx SNPs and possible CpG-PGx SNPs. Results: Among 2900 significant PGx annotations, we found 99 potential CpG-PGx SNPs related to 16 genes. CYP2B6, CYP2C19, CYP2D6, and COMT genes were the top genes. Additionally, we found 1230 significant GWAS-based SNPs, among them 329 CpG-SNPs related to 48 genes with at least one CpG site disruption/formation. The top gene with the highest CpG-SNPs was TET2, followed by JMJD1C and HDAC9. Importantly, we detected some synonymous variants in the Epigenetically Modifiable Accessible Region (EMAR), which can provide insights into undiscovered roles of these SNPs. We identified 173 CpG-Disruptive SNPs, 155 CpG-Forming SNPs, and just 1 CpG SNP with both impacts. Conclusions: In conclusion, here we introduce CpG-PGx SNP for the first time and suggest three major genes playing crucial roles in Pharmacoepigenomics (PEpGx), CYP2D6 as the heart of PEpGx, and TET2 with the highest possibility of having CPG-PGx SNPs. We believe that this approach will help the scientific community to utilize “CpG-PGx SNP” to unravel complex disease-driven genetic and epigenetic interactions, yielding therapeutic opportunities.

Background: GLP‑1 receptor agonists (GLP‑1RAs) are effective for type 2 diabetes and obesity and engage central stress and reward pathways (HPA axis; mesolimbic dopamine). Psychiatric signals have been reported in some settings. Objective :To narratively synthesize evidence on neuropsychiatric effects of GLP‑1RAs—mood, anxiety, suicidality, reward processing, substance use, and migraine—and to consider genetic/epigenetic moderators (e.g., hypodopaminergia/reward deficiency syndrome).Evidence: Mechanistic and imaging studies demonstrate GLP‑1 engagement of HPA and reward circuitry; animal work suggests acute anxiogenic responses with mixed chronic effects. Pharmacovigilance datasets (FAERS/EudraVigilance) show signals for headache, dizziness, sensory changes, and less consistently for depression/anxiety/suicidality; such data are hypothesis‑generating and not causal. Clinical trials and meta‑analyses report heterogeneous outcomes, including small antidepressant effects in some T2DM cohorts. Conclusions: Neuropsychiatric outcomes with GLP‑1RAs appear context‑dependent. Individuals with hypodopaminergic biology may be vulnerable to reward blunting/anxiety, whereas others may experience mood benefits. A pragmatic approach is screen–stratify–monitor, with slow titration and prompt adjustment if psychiatric signals emerge. Prospective, genotype‑informed studies are needed to identify who benefits or is harmed and why.

Stress is often mentioned as a factor in the development of drug abuse. Twelve cocaine-dependent individuals were administered a stress hormone, cortisol, along with cocaine and saline via intravenous boluses in a double-blind, counterbalanced fashion. Self-reports of mood states were collected prior to, during, and 20 minutes after each bolus was administered. Cortisol produced significant increases in craving, while cocaine significantly elevated all subjective ratings (i.e., craving, high, rush, and low). These pilot data suggest that cortisol can induce a state associated with drug abuse. Psychopharmacology Bulletin. 2003;37(3):84-89

We previously theorized that Attention-Deficit Hyperactivity Disorder (ADHD) may increase susceptibility to narcolepsy and hypersomnia, potentially sharing genomic and pathophysiological features with addictive behaviours linked to Reward Deficiency Syndrome (RDS). We further suggested that the emergence of narcolepsy in individuals with underlying ADHD or RDS may place additional stress on the dopaminergic reward system. To explore this, we conducted comprehensive data mining using GWAS catalog databases focused on ADHD and narcolepsy, identifying three relevant datasets. These were individually analyzed in GWAS meta-analyses, followed by a combined GWAS meta-meta-analysis. From this, we derived a Primary Gene List (PGL) of 512 genes and a Secondary Gene List (SGL) of 42 genes, which were further examined through in-depth silico, systems biology, and pharmacogenomic (PGx) approaches. Our findings revealed a fully connected protein–protein interaction (PPI) network between ADHD and narcolepsy, with FOXP2 and RBFOX1 emerging as shared genes. We also identified schizophrenia as a potential endophenotype linking ADHD and narcolepsy. PGx analysis revealed pharmacogenomic relevance for seven genes from the SGL. To further investigate PGx–PPI relationships, we incorporated ten GARS family genes along with eight identified pharmacogenes in PGx-PPIs, and included FOXP2, RBFOX1, and GRIN2A, despite the absence of PGx data for the latter three. This analysis highlighted DRD2 and NRXN1 as central components of the dopaminergic [Genetic Addiction Risk Severity (GARS)] pathway, forming critical connections in the ADHD–schizophrenia–narcolepsy axis. These results support our initial hypothesis of a shared genetic basis between ADHD and narcolepsy. Additionally, we identified potentially overlapping genes with schizophrenia and highlighted dopaminergic regulatory variants of FOXP2, RBFOX1, and GRIN2A as promising diagnostic markers and therapeutic targets for future research.

Background: There are important gaps in describing the associations between variants found by GWAS and various phenotypes. Prior reports suggested that SNPs in regulatory regions should be more investigated to uncover these associations. Thus, this study initiated a novel method along with Pharmacoepigenomics suggesting a new coined term “CpG-PGx SNP”. Methods: The rationale behind our analysis strategy was based on the impact of SNPs playing dual roles both in the CpG site disruption/formation and having PGx associations. Thus, we employed GeneCards (relevance score), PharmGKB (significant p-value), and GWAS catalog data for each gene (p<E-8). Following obtaining the 25 best-scored genes of four major epigenetic processes (methylation, demethylation, acetylation, and deacetylation), we generated two lists of candidate genes including potential CpG-PGx SNPs 2 of 22 and possible CpG-PGx SNPs. Results: Among 2,900 significant PGx annotations, we found 99 potential CpG-PGx SNPs related to 16 genes. CYP2B6, CYP2C19, CYP2D6, and COMT genes were the top genes. Additionally, we found 1,230 significant GWAS-based SNPs, among them 329 CpG-SNPs related to 48 genes with at least one CpG site disruption/formation. The top gene with the highest CpG-SNPs was TET2, followed by JMJD1C, and HDAC9. Importantly, we detected some synonymous variants in Epigenetically Modifiable Accessible Region (EMAR) which can open new insights into undiscovered roles of these SNPs. We identified 173 CpG-Disruptive SNPs, 155 CpG-Forming SNPs, and just 1 CpG SNP with both impacts. Conclusion: In conclusion, here we introduced CpG-PGx SNP for the first time, suggested 3 major genes playing crucial roles in Pharmacoepigenomics (PEpGx), CYP2D6 as the heart of PEpGx, and TET2 with the highest possibility of having CPG-PGx SNPs. We believe that his novel technological advance potentially will help the scientific community to utilize “CpG-PGx SNP” to unravel complex disease driven genetic and epigenetic interactions yielding therapeutic opportunities.

Background The management of spine-related pain with narcotics, both before and after surgery, poses major challenges, including drug diversion, limited effectiveness, and worsening of pain symptoms over time. Chronic opioid use is associated with hypodopaminergia-induced hyperalgesia, whereby dopamine depletion increases pain sensitivity. Patients with inherently low dopaminergic function are particularly predisposed to hyperalgesia and reduced pain tolerance. Methods An alternative therapeutic strategy centers on genetically guided pro-dopamine regulation, which aims to transmodulate dopaminergic signaling to mitigate hyperalgesia. Early identification of predisposition through genetic testing, combined with pharmacogenetic and pharmacogenomic monitoring, is proposed to optimize treatment approaches. Results Pro-dopamine regulators have demonstrated promising results across 43 clinical studies, showing potential to reduce stress, craving, and relapse rates, while improving emotional well-being and attenuating pain sensitivity. These findings suggest that pro-dopamine regulation may serve as a viable frontline therapy for managing chronic pain and associated Reward Deficiency Syndrome behaviors, offering a significant reduction in the adverse effects commonly observed with chronic opioid therapy. Conclusions Given the limitations of dopaminergic blockade through chronic opioid agonist therapy, there is a critical need to reevaluate current pain management practices. The induction of dopamine homeostasis via pro-dopamine regulation represents a novel and potentially transformative strategy. Spine surgeons, pain specialists, and addiction medicine practitioners are urged to consider this approach as a promising alternative for improving long-term outcomes in patients suffering from chronic pain.