1 1091 114 COGNITIVE ENHANCERS AS A TREATMENT FOR HEROIN RELAPSE AND ADDICTION. HEROIN ADDICTION IS A DISORDER THAT STEMS FROM MALADAPTIVE PLASTICITY WITHIN NEURAL CIRCUITS AND PRODUCES BROAD COGNITIVE DEFICITS. DESPITE CONSIDERABLE ADVANCES IN PSYCHOTHERAPY AND PHARMACOTHERAPY FOR HEROIN RELAPSE AND ADDICTION, EFFECTIVE TREATMENTS FOR HEROIN USE DISORDER ARE STILL LACKING. INCREASING PRECLINICAL EVIDENCE INDICATES THAT HEROIN SEEKING BEHAVIOR IS PERSISTENT AFTER WITHDRAWAL, WHILE COGNITIVE DYSFUNCTIONS ASSOCIATED WITH CHRONIC HEROIN USE ARE AN IMPORTANT CONTRIBUTING FACTOR TO RISK OF HEROIN RELAPSE AND ADDICTION. COGNITIVE ENHANCERS MAY BE USED TO STIMULATE TREATMENT SUCCESS AND ENHANCE TREATMENT EFFICACY. THE PURPOSE OF THIS REVIEW IS TO OUTLINE THE LITERATURE THAT DEMONSTRATES THE COGNITIVE DEFICITS DURING THE DEVELOPMENT OF HEROIN ADDICTION AND WITHDRAWAL PROCESS, AND SEVERAL FACTORS THAT UNDERLINE THE EFFICACY OF COGNITIVE ENHANCERS FOR HEROIN USE DISORDERS. THE REVIEW, THEN, EXAMINES THE POTENTIAL USE AND PHARMACOLOGICAL MECHANISMS OF COGNITIVE ENHANCERS THAT ACT ON CHOLINERGIC, GLUTAMATERGIC, DOPAMINERGIC OR ADRENERGIC PATHWAYS. IT ALSO EXAMINES THE EFFECTS OF COMPOUNDS THAT ALTER CREB SIGNALING AND EPIGENETIC MECHANISMS IN ANIMAL MODEL OF HEROIN RELAPSE. THE CURRENT BODY OF RESEARCH REVEALS THE NEW INSIGHTS INTO THE PHARMACOLOGICAL MECHANISMS UNDERLYING HEROIN ADDICTION AND HOLDS A SIGNIFICANT PROMISE FOR COGNITIVE ENHANCERS AS AN IMPROVED APPROACH TO TREAT HEROIN USE DISORDER IN A MORE EFFICIENT AND PERSISTENT WAY. 2019 2 856 29 CHROMATIN ACCESSIBILITY MAPPING OF THE STRIATUM IDENTIFIES TYROSINE KINASE FYN AS A THERAPEUTIC TARGET FOR HEROIN USE DISORDER. THE CURRENT OPIOID EPIDEMIC NECESSITATES A BETTER UNDERSTANDING OF HUMAN ADDICTION NEUROBIOLOGY TO DEVELOP EFFICACIOUS TREATMENT APPROACHES. HERE, WE PERFORM GENOME-WIDE ASSESSMENT OF CHROMATIN ACCESSIBILITY OF THE HUMAN STRIATUM IN HEROIN USERS AND MATCHED CONTROLS. OUR STUDY REVEALS DISTINCT NEURONAL AND NON-NEURONAL EPIGENETIC SIGNATURES, AND IDENTIFIES A LOCUS IN THE PROXIMITY OF THE GENE ENCODING TYROSINE KINASE FYN AS THE MOST AFFECTED REGION IN NEURONS. FYN EXPRESSION, KINASE ACTIVITY AND THE PHOSPHORYLATION OF ITS TARGET TAU ARE INCREASED BY HEROIN USE IN THE POST-MORTEM HUMAN STRIATUM, AS WELL AS IN RATS TRAINED TO SELF-ADMINISTER HEROIN AND PRIMARY STRIATAL NEURONS TREATED WITH CHRONIC MORPHINE IN VITRO. PHARMACOLOGICAL OR GENETIC MANIPULATION OF FYN ACTIVITY SIGNIFICANTLY ATTENUATES HEROIN SELF-ADMINISTRATION AND RESPONDING FOR DRUG-PAIRED CUES IN RODENTS. OUR FINDINGS SUGGEST THAT STRIATAL FYN IS AN IMPORTANT DRIVER OF HEROIN-RELATED NEURODEGENERATIVE-LIKE PATHOLOGY AND DRUG-TAKING BEHAVIOR, MAKING FYN A PROMISING THERAPEUTIC TARGET FOR HEROIN USE DISORDER. 2020 3 5684 33 SHOULD WE EMBRACE THE INCORPORATION OF GENETICALLY GUIDED "DOPAMINE HOMEOSTASIS" IN THE TREATMENT OF REWARD DEFICIENCY SYNDROME (RSD) AS A FRONTLINE THERAPEUTIC MODALITY? IN 2019, THE US CENTER FOR DISEASE CONTROL AND PREVENTION PROVIDED VITAL STATISTICS RELATED TO DRUG OVERDOSES IN THE UNITED STATE1. THEY CONCLUDED THAT IN THE USA THE NUMBER OF DEATHS AT ALMOST 72,000 WAS DUE TO 66.6% OF OPIOID OVERDOSES. IN FACT, THE RATE IS ALARMING AND INCREASING YEARLY. TO MAKE 2021 EVEN MORE SCARY IS THE DAUNTING EFFECT ON INCREASED DRUG USAGE DUE TO COVID 19 AS A PANDEMIC, ALBEIT THE NEW VACCINES. SPECIFICALLY, IN 2020, THE DEATH RATE FROM OPIOID OVERDOSES ROSE TO 13% NATIONALLY AND IN SOME SATES 30%. THE COMMON NEUROMODULATING ASPECTS OF NEUROTRANSMISSION, AND ITS DISRUPTION VIA CHRONIC EXPOSURE OF DRUGS AND BEHAVIORAL ADDICTIONS, REQUIRES FURTHER INTENSE RESEARCH FOCUS ON DEVELOPING NOVEL STRATEGIES TO COMBAT THESE UNWANTED GENETIC AND EPIGENIC INFRACTIONS AS ACCOMPLISHED WITH HEROIN ADDICTION BY OUR GROUP. THE TAKE HOME MESSAGE IS THE PLAUSIBLE ACCEPTANCE OF THE WELL-ESTABLISHED EVIDENCE FOR HYPODOPAMINERGIA, A BLUNTED REWARD PROCESSING SYSTEM, REDUCED RESTING STATE FUNCTIONAL CONNECTIVITY, GENETIC ANTECEDENTS, ANTI- REWARD SYMPTOMATOLOGY, POOR COMPLIANCE WITH MAT, AND GENERALIZED RDS. WITH THIS EVIDENCE IT IS CONCEIVABLE THAT PURSUIT THROUGH INTENSIVE FUTURE RESEARCH SHOULD INVOLVE AN APPROACH THAT INCORPORATES "DOPAMINE HOMEOSTASIS". THIS REQUIRED PARADIGM SHIFT MAY CONSIST OF MANY BENEFICIAL MODALITIES INCLUDING BUT NOT LIMITED TO: EXERCISE, PRO-DOPAMINE REGULATION, NUTRIGENOMICS, COGNITIVE BEHAVIORAL THERAPY, HEDONIC HOT SPOT TARGETS BRAIN, RTMRS, DEEP BRAIN STIMULATION, DIET, GENETIC EDITS, GENETIC GUIDED THERAPEUTICS, EPIGENETIC REPAIR, AMONGST OTHERS. IT IS OUR OPINION THAT NUTRIGENOMICS MAY ASSIST THE MILLIONS OF PEOPLE OF GETTING OUT OF A" HYPODOPAMINERGIC DITCH" WC 250. 2021 4 4846 22 OPIATE ADDICTION AND COCAINE ADDICTION: UNDERLYING MOLECULAR NEUROBIOLOGY AND GENETICS. ADDICTIVE DISEASES, INCLUDING ADDICTION TO HEROIN, PRESCRIPTION OPIOIDS, OR COCAINE, POSE MASSIVE PERSONAL AND PUBLIC HEALTH COSTS. ADDICTIONS ARE CHRONIC RELAPSING DISEASES OF THE BRAIN CAUSED BY DRUG-INDUCED DIRECT EFFECTS AND PERSISTING NEUROADAPTATIONS AT THE EPIGENETIC, MRNA, NEUROPEPTIDE, NEUROTRANSMITTER, OR PROTEIN LEVELS. THESE NEUROADAPTATIONS, WHICH CAN BE SPECIFIC TO DRUG TYPE, AND THEIR RESULTANT BEHAVIORS ARE MODIFIED BY VARIOUS INTERNAL AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING STRESS RESPONSIVITY, ADDICT MINDSET, AND SOCIAL SETTING. SPECIFIC GENE VARIANTS, INCLUDING VARIANTS ENCODING PHARMACOLOGICAL TARGET PROTEINS OR GENES MEDIATING NEUROADAPTATIONS, ALSO MODIFY VULNERABILITY AT PARTICULAR STAGES OF ADDICTION. GREATER UNDERSTANDING OF THESE INTERACTING FACTORS THROUGH LABORATORY-BASED AND TRANSLATIONAL STUDIES HAVE THE POTENTIAL TO OPTIMIZE EARLY INTERVENTIONS FOR THE THERAPY OF CHRONIC ADDICTIVE DISEASES AND TO REDUCE THE BURDEN OF RELAPSE. HERE, WE REVIEW THE MOLECULAR NEUROBIOLOGY AND GENETICS OF OPIATE ADDICTION, INCLUDING HEROIN AND PRESCRIPTION OPIOIDS, AND COCAINE ADDICTION. 2012 5 2841 35 FREQUENCY OF THE DOPAMINE RECEPTOR D3 (RS6280) VS. OPIOID RECEPTOR MICRO1 (RS1799971) POLYMORPHIC RISK ALLELES IN PATIENTS WITH OPIOID USE DISORDER: A PREPONDERANCE OF DOPAMINERGIC MECHANISMS? WHILE OPIOIDS ARE A POWERFUL CLASS OF DRUGS THAT INHIBIT TRANSMISSION OF PAIN SIGNALS, THEIR USE IS TARNISHED BY THE CURRENT EPIDEMIC OF OPIOID USE DISORDER (OUD) AND OVERDOSE DEATHS. NOTWITHSTANDING PUBLISHED REPORTS, THERE REMAIN GAPS IN OUR KNOWLEDGE OF OPIOID RECEPTOR MECHANISMS AND THEIR ROLE IN OPIOID SEEKING BEHAVIOR. THUS, NOVEL INSIGHTS INTO MOLECULAR, NEUROGENETIC AND NEUROPHARMACOLOGICAL BASES OF OUD ARE NEEDED. WE PROPOSE THAT AN ADDICTIVE ENDOPHENOTYPE MAY NOT BE ENTIRELY SPECIFIC TO THE DRUG OF CHOICE BUT RATHER MAY BE GENERALIZABLE TO ALTERED BRAIN REWARD CIRCUITS IMPACTING NET MESOCORTICOLIMBIC DOPAMINE RELEASE. WE SUGGEST THAT GENETIC OR EPIGENETIC ALTERATIONS ACROSS DOPAMINERGIC REWARD SYSTEMS LEAD TO UNCONTROLLABLE SELF-ADMINISTRATION OF OPIOIDS AND OTHER DRUGS. FOR INSTANCE, DIMINISHED AVAILABILITY VIA KNOCKOUT OF DOPAMINE D3 RECEPTOR (DRD3) INCREASES VULNERABILITY TO OPIOIDS. BUILDING UPON THIS CONCEPT VIA THE USE OF A SOPHISTICATED POLYMORPHIC RISK ANALYSIS IN A HUMAN COHORT OF CHRONIC OPIOID USERS, WE FOUND EVIDENCE FOR A HIGHER FREQUENCY OF POLYMORPHIC DRD3 RISK ALLELE (RS6280) THAN OPIOID RECEPTOR MICRO1 (RS1799971). IN CONCLUSION, WHILE OPIOIDERGIC MECHANISMS ARE INVOLVED IN OUD, DOPAMINE-RELATED RECEPTORS MAY HAVE PRIMARY INFLUENCE ON OPIOID-SEEKING BEHAVIOR IN AFRICAN AMERICANS. THESE FINDINGS SUGGEST OUD-TARGETED NOVEL AND IMPROVED NEUROPHARMACOLOGICAL THERAPIES MAY REQUIRE FOCUS ON DRD3-MEDIATED REGULATION OF DOPAMINERGIC HOMEOSTASIS. 2022 6 2580 28 EPIGENETICS OF MICRO-OPIOID RECEPTORS: INTERSECTION WITH HIV-1 INFECTION OF THE CENTRAL NERVOUS SYSTEM. THE ABUSE OF INTRAVENOUS DRUGS, SUCH AS HEROIN, HAS BECOME A MAJOR PUBLIC HEALTH CONCERN DUE TO THE INCREASED RISK OF HIV-1 INFECTION. OPIOIDS SUCH AS HEROIN WERE ORIGINALLY IDENTIFIED AND SUBSEQUENTLY ABUSED FOR THEIR ANALGESIC EFFECTS. HOWEVER, MANY INVESTIGATIONS HAVE FOUND ADDITIONAL EFFECTS OF OPIOIDS, INCLUDING REGULATION OF THE IMMUNE SYSTEM. AS SUCH, CHRONIC OPIOID ABUSE HAS BEEN SHOWN TO PROMOTE HIV-1 PATHOGENESIS AND FACILITATE HIV-1-ASSOCIATED NEUROCOGNITIVE DYSFUNCTION. CLINICAL OPIOIDS, SUCH AS MORPHINE AND METHADONE, AS WELL AS ILLICIT OPIOIDS, SUCH AS HEROIN, EXERT THEIR EFFECTS PRIMARILY THROUGH INTERACTIONS WITH THE MICRO-OPIOID RECEPTOR (MOR). HOWEVER, THE MECHANISMS BY WHICH OPIOIDS ENHANCE NEUROCOGNITIVE DYSFUNCTION THROUGH MOR-MEDIATED SIGNALING PATHWAYS ARE NOT COMPLETELY UNDERSTOOD. NEW FINDINGS IN THE REGULATION OF MOR EXPRESSION, PARTICULARLY EPIGENETIC AND TRANSCRIPTIONAL REGULATION AS WELL AS ALTERNATIVE SPLICING, SHEDS NEW INSIGHTS INTO POSSIBLE MECHANISMS OF HIV-1 AND OPIATE SYNERGY. IN THIS REVIEW, WE IDENTIFY MECHANISMS REGULATING MOR EXPRESSION AND PROPOSE NOVEL MECHANISMS BY WHICH OPIOIDS AND HIV-1 MAY MODULATE THIS REGULATION. ADDITIONALLY, WE SUGGEST THAT DIFFERENTIAL REGULATION OF NEWLY IDENTIFIED MOR ISOFORMS BY OPIOIDS AND HIV-1 HAS FUNCTIONAL CONSEQUENCE IN ENHANCING HIV-1 NEUROCOGNITIVE DYSFUNCTION. 2012 7 1789 22 EFFECT OF CHRONIC HEROIN AND COCAINE ADMINISTRATION ON GLOBAL DNA METHYLATION IN BRAIN AND LIVER. DRUG ABUSE IS ASSOCIATED WITH EPIGENETIC CHANGES, SUCH AS HISTONE MODIFICATIONS AND DNA METHYLATION. THE PURPOSE OF THE PRESENT STUDY WAS TO EXAMINE THE EFFECT OF CHRONIC COCAINE AND HEROIN ADMINISTRATION ON GLOBAL DNA METHYLATION IN BRAIN AND LIVER. MALE, 8 WEEK OLD, C57BL/6J MICE RECEIVED HEROIN IN A CHRONIC 'INTERMITTENT' ESCALATING DOSE PARADIGM, OR COCAINE IN A CHRONIC ESCALATING DOSE 'BINGE' PARADIGM, WHICH MIMIC THE HUMAN PATTERN OF OPIOID OR COCAINE ABUSE RESPECTIVELY. FOLLOWING SACRIFICE, LIVERS AND BRAINS WERE REMOVED AND DNA WAS EXTRACTED FROM THEM. THE EXTRACTED DNA WAS HYDROLYZED AND 2'-DEOXYCYTIDINE AND 5-METHYL-2'-DEOXYCYTIDINE WERE DETERMINED BY HPLC-UV. THE % 5-METHYL-2'-DEOXYCYTIDINE CONTENT OF DNA WAS SIGNIFICANTLY HIGHER IN THE BRAIN COMPARED TO THE LIVER. THERE WERE NO DIFFERENCES BETWEEN THE CONTROL ANIMALS AND THE COCAINE OR HEROIN TREATED ANIMALS IN NEITHER OF THE TISSUES EXAMINED, WHICH IS SURPRISING SINCE COCAINE ADMINISTRATION INDUCED GROSS MORPHOLOGICAL CHANGES IN THE LIVER. MOREOVER, THERE WAS NO DIFFERENCE IN THE % 5-METHYL-2'-DEOXYCYTIDINE CONTENT OF DNA BETWEEN THE COCAINE AND THE HEROIN TREATED ANIMALS. THE GLOBAL DNA METHYLATION STATUS IN THE BRAIN AND LIVER OF MICE CHRONICALLY TREATED WITH COCAINE OR HEROIN REMAINS UNAFFECTED, BUT THIS FINDING CANNOT EXCLUDE THE EXISTENCE OF ANATOMICAL REGION OR GENE-SPECIFIC METHYLATION DIFFERENCES. THIS IS THE FIRST TIME THAT GLOBAL DNA METHYLATION IN THE LIVER AND WHOLE BRAIN HAS BEEN STUDIED FOLLOWING CHRONIC COCAINE OR HEROIN TREATMENT. 2013 8 4631 35 NEUROGENETICS OF ACUTE AND CHRONIC OPIATE/OPIOID ABSTINENCE: TREATING SYMPTOMS AND THE CAUSE. THIS REVIEW BEGINS WITH A COMPREHENSIVE HISTORY OF OPIOID DEPENDENCE AND TREATMENT IN THE UNITED STATES. THE FOCUS IS AN EVIDENCE-BASED TREATMENT MODEL FOR OPIOID/OPIATE DEPENDENT INDIVIDUALS. THE ROLE OF REWARD GENETIC POLYMORPHISMS AND THE EPIGENETIC MODIFICATIONS THAT LEAD TO VULNERABILITY TO USE AND MISUSE OF OPIATES/OPIOID TO TREAT PAIN ARE REVIEWED. THE NEUROCHEMICAL MECHANISMS OF ACUTE OPIATE WITHDRAWAL AND OPIATE/OPIOID REWARD MECHANISMS ARE EXPLORED WITH A GOAL OF IDENTIFYING SPECIFIC TREATMENT TARGETS. ALTERATIONS IN FUNCTIONAL BRAIN CONNECTIVITY BASED ON NEUROBIOLOGICAL MECHANISMS IN HEROIN DEPENDENCE AND ABSTINENCE ARE ALSO REVIEWED. A NEW CLINICAL MODEL AN ALTERNATIVE TO MERELY BLOCKING ACUTE WITHDRAWAL SYMPTOMS AS IDENTIFIED IN THE DSM -5 IS PROPOSED. GENETIC DIAGNOSIS AT THE ONSET OF DETOXIFICATION, TO DETERMINE RISK STRATIFICATION, AND IDENTIFY POLYMORPHIC GENE TARGETS FOR PHARMACEUTICAL AND NUTRACEUTICAL INTERVENTIONS, FOLLOWED BY THE SIMULTANEOUS INITIATION OF MEDICATION ASSISTED THERAPY (MAT), TO ENABLE PSYCHOLOGICAL EXTINCTION, AND STEADY PRO-DOPAMINERGIC THERAPY WITH THE GOAL OF DEVELOPING "DOPAMINE HOMEOSTASIS" IS RECOMMENDED. THE OBJECTIVE OF THESE INTERVENTIONS IS TO PREVENT FUTURE RELAPSE BY TREATING ALL "REWARD DEFICIENCY SYNDROME" (RDS) BEHAVIORS AND EVENTUALLY MAKE AN ADDICTION-FREE LIFE POSSIBLE. 2017 9 91 26 A PILOT STUDY EXAMINING THE RELATIONSHIP BETWEEN CHRONIC HEROIN USE AND TELOMERE LENGTH AMONG INDIVIDUALS OF AFRICAN ANCESTRY. BACKGROUND: PRIOR RESEARCH HAS SUGGESTED A POSSIBLE LINK BETWEEN HEROIN USE AND SHORTENED TELOMERE LENGTH (TL), A MARKER OF CELLULAR AGING AND GENOMIC STABILITY. WE SOUGHT TO REPLICATE THESE FINDINGS BY EXAMINING THE RELATIONSHIP BETWEEN TL AND HEROIN USE AMONG INDIVIDUALS OF AFRICAN ANCESTRY. METHODS: THIS CROSS-SECTIONAL STUDY EXAMINED TL AMONG 57 PARTICIPANTS [17.5 % FEMALE; MEAN AGE 48.0 (+/-6.80) YEARS] OF AFRICAN ANCESTRY WITH OPIOID USE DISORDER (OUD) AND A MEAN HEROIN USE DURATION OF 18.2 (+/-10.7) YEARS. QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) WAS USED TO CALCULATE TL AS THE RATIO BETWEEN TELOMERE REPEAT COPY NUMBER (T) AND A SINGLE-COPY GENE, COPY NUMBER (S). THE PRIMARY DEPENDENT VARIABLE WAS TL (T/S RATIO) MEASURED IN KILOBASE PAIRS. COVARIATES INCLUDED HEROIN USE YEARS AND PERSONALITY TRAITS. USING A HYBRID APPROACH, MULTIPLE LINEAR REGRESSION AND BAYESIAN LINEAR REGRESSION EXAMINED THE ASSOCIATION OF CHRONOLOGICAL AGE, HEROIN USE YEARS AND PERSONALITY TRAITS WITH TL. RESULTS: THE MULTIPLE LINEAR REGRESSION MODEL FIT THE DATA WELL, R(2) = 0.265, F(7,49) = 2.53, P < .026. CHRONOLOGICAL AGE (BETA = -0.36, P = .017), NEUROTICISM (BETA = 0.46, P = .044), AND CONSCIENTIOUSNESS (BETA = 0.52, P = .040) WERE SIGNIFICANT PREDICTORS OF TL. BAYESIAN LINEAR REGRESSION PROVIDED MODERATE SUPPORT FOR THE ALTERNATE HYPOTHESIS THAT CHRONOLOGICAL AGE AND TL ARE ASSOCIATED, BF(10) = 5.77, R(2) = 0.120. THE POSTERIOR SUMMARY OF THE COEFFICIENT WAS M = 0.719 (SD = 0.278, 95 % CREDIBLE INTERVAL [-1.28, -0.163]). CONCLUSIONS: CONTRARY TO PRIOR STUDIES, THESE FINDINGS SUGGEST THAT HEROIN USE DURATION MAY NOT BE SIGNIFICANTLY ASSOCIATED WITH TL AMONG INDIVIDUALS OF AFRICAN ANCESTRY, HIGHLIGHTING THE NEED FOR MORE RIGOROUS RESEARCH TO ELUCIDATE THE COMPLEXITY OF THIS RELATIONSHIP. 2023 10 609 26 BEYOND MOR: CAN INDUCTION OF DOPAMINE HOMEOSTASIS ALONG WITH ELECTROTHERAPY ATTENUATE THE OPIOID CRISIS? ONE IMPORTANT AREA FOR CONSIDERATION ESPECIALLY IN TERMS OF COMBATING THE ONGOING NEVER ENDING OPIOID CRISIS, RELATES TO NOVEL NEWER ASSESSMENTS FOR ALL ADDICTIVE BEHAVIORS BOTH SUBSTANCE AND NON-SUBSTANCE BEHAVIORS (RDS). IT IS VERY IMPORTANT TO IDENTIFY EARLY IN ONE'S LIFE THE POSSIBILITY OF, BECAUSE OF KNOWN DNA ANTECEDENTS, THE PRESENCE OF PRE-ADDICTION. THE DEVELOPMENT OF THE GENETIC ADDICTION RISK SEVERITY (GARS) TEST, BLUM'S GROUP BELIEVES THAT THIS TYPE OF TESTING SHOULD BE THE "STANDARD OF CARE" FOLLOWING ADDITIONAL STUDIES. UNDERSTANDABLY THAT WHILE POLYMORPHISMS IN THE MU-OPIOID RECEPTOR (MOR) IS OF REAL CONCERN IN TERMS OF SETTING PEOPLE UP FOR PREDISPOSITION TO OPIOID DEPENDENCE, THE GENETIC AND EPIGENETIC STATUS OF DOPAMINERGIC FUNCTION MUST BE CONSIDERED AS WELL. WHILE THIS SOUNDS BOLD (WHICH IT IS) THE RESULTS SHOULD BE PROTECTED BY THE G.I. N. A. LAW ENACTED IN THE USA IN 2011. ONE AVENUE OF FURTHER INVESTIGATION, INSTEAD OF PROVIDING POWERFUL OPIOIDS FOR OPIOID DEPENDENCE, IS TO SEEK OUT NON-ADDICTIVE ALTERNATIVES. ACCORDINGLY, OTHER NON-ADDICTIVE MODALITIES INCLUDING GENETIC GUIDED KB220 (AMINO-ACID-ENKEPHALINASE-N-ACETYLCYSTEINE-NAD), NON-INVASIVE RTMS FOR PSYCHIATRY AND PAIN, EPIGENETIC REMODELING, GENE EDITS, NON-INVASIVE H-WAVE FOR PAIN MANAGEMENT AND ENHANCED FUNCTIONALITY, BRAIN SPOTTING, COGNITIVE BEHAVIORAL THERAPY AWARENESSS INTEGRATION THERAPY, NUCALM, TRAUMA THERAPY, AWARENESS TOOLS, GENOGRAMS, EXERCISE, SPORTS, FITNESS PROGRAMS (ONE HOUR PER DAY), LIGHT THERAPY AND EVEN LAUGHING THERAPY AS WELL AS ANY OTHER KNOWN MODALITIES THAT CAN INDUCE REWARD SYMMETRY. WHILE THE SHORT TERM USE OF OPIOIDS FOR OPIOID DEPENDENCE TO REDUCE HARM IS CERTAINLY ACCEPTABLE, CLINICIANS SHOULD CONSIDER A BETTER LONG-TERM PLAN. 2023 11 4937 31 PATERNAL MORPHINE EXPOSURE IN RATS REDUCES SOCIAL PLAY IN ADOLESCENT MALE PROGENY WITHOUT AFFECTING DRUG-TAKING BEHAVIOR IN JUVENILE MALES OR FEMALE OFFSPRING. THE ONGOING OPIOID ADDICTION CRISIS NECESSITATES THE IDENTIFICATION OF NOVEL RISK FACTORS TO IMPROVE PREVENTION AND TREATMENT OF OPIOID USE DISORDER. PARENTAL OPIOID EXPOSURE HAS RECENTLY EMERGED AS A POTENTIAL REGULATOR OF OFFSPRING VULNERABILITY TO OPIOID MISUSE, IN ADDITION TO HERITABLE GENETIC LIABILITY. AN UNDERSTUDIED ASPECT OF THIS "MISSING HERITABILITY" IS THE DEVELOPMENTAL PRESENTATION OF THESE CROSS-GENERATIONAL PHENOTYPES. THIS IS AN ESPECIALLY RELEVANT QUESTION IN THE CONTEXT OF INHERITED ADDICTION-RELATED PHENOTYPES, GIVEN THE PROMINENT ROLE OF DEVELOPMENTAL PROCESSES IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS. PATERNAL MORPHINE SELF-ADMINISTRATION WAS PREVIOUSLY SHOWN TO ALTER THE SENSITIVITY TO THE REINFORCING AND ANTINOCICEPTIVE PROPERTIES OF OPIOIDS IN THE NEXT GENERATION. HERE, PHENOTYPING WAS EXPANDED TO INCLUDE THE ADOLESCENT PERIOD, WITH A FOCUS ON ENDOPHENOTYPES RELATED TO OPIOID USE DISORDERS AND PAIN. PATERNAL MORPHINE EXPOSURE DID NOT ALTER HEROIN OR COCAINE SELF-ADMINISTRATION IN MALE AND FEMALE JUVENILE PROGENY. FURTHER, BASELINE SENSORY REFLEXES RELATED TO PAIN WERE UNALTERED IN MORPHINE-SIRED ADOLESCENT RATS OF EITHER SEX. HOWEVER, MORPHINE-SIRED ADOLESCENT MALES EXHIBITED A REDUCTION IN SOCIAL PLAY BEHAVIOR. OUR FINDINGS SUGGEST THAT, IN MORPHINE-SIRED MALE OFFSPRING, PATERNAL OPIOID EXPOSURE DOES NOT AFFECT OPIOID INTAKE DURING ADOLESCENCE, SUGGESTING THAT THIS PHENOTYPE DOES NOT EMERGE UNTIL LATER IN LIFE. ALTERED SOCIAL BEHAVIORS IN MALE MORPHINE-SIRED ADOLESCENTS INDICATE THAT THE CHANGES IN DRUG-TAKING BEHAVIOR IN ADULTS SIRED BY MORPHINE-EXPOSED SIRES MAY BE DUE TO MORE COMPLEX FACTORS NOT YET FULLY ASSESSED. 2023 12 5855 26 SUBSTANCE USE DISORDER A BIO-DIRECTIONAL SUBSET OF REWARD DEFICIENCY SYNDROME. THIS COMMENTARY IS TO INFORM CLINICIANS CHALLENGED WITH AN INCREASE IN PEOPLE SEEKING TREATMENT FOR SUBSTANCE USE DISORDER (SUD), THAT THE NINETY PERCENT REVOLVING DOOR, IS, IN PART, DUE TO POST-WITHDRAWAL, UNTREATED NEUROTOXICITY. THIS IMPAIRMENT ATTENUATES NEUROTRANSMITTER SIGNALING AND COMPROMISES RESTING STATE FUNCTIONAL CONNECTIVITY, LEADING TO UNWANTED SEQUELAE INCLUDING DEPRESSION, SLEEP DISTURBANCES, SENSATION SEEKING, LACK OF SATISFACTION AND IMPULSIVITY. NEUROIMAGING STUDIES INDICATE THAT NEUROBIOLOGICAL RECOVERY CAN TAKE YEARS. LIKE A "DOUBLE EDGE SWORD" SUD HAS A BIOLOGICAL BI -DIRECTIONAL (BIO-DIRECTIONAL) EFFECT ON THE BRAIN REWARD CIRCUITRY. THE ACUTE INTAKE OF PSYCHOACTIVE DRUGS RESULTS IN HEIGHTENED DOPAMINERGIC ACTIVITY, WHILE, THE OPPOSITE, HYPODOPAMINERGIA OCCURS FOLLOWING CHRONIC ABUSE. INDIVIDUALS WITH SUD CAN HAVE A GENETIC PREDISPOSITION, COMPOUNDED BY STRESS AND NEUROTOXICALLY INDUCED, EPIGENETIC INSULTS THAT IMPACT RECOVERY FROM PROTRACTED ABSTINENCE. FOLLOW-UP POST -SHORT-TERM RECOVERY USUALLY INCLUDES SUPPORTIVE THERAPIES AND PROGRAMS LIKE 12 -STEPS AND OTHER FELLOWSHIPS. HOWEVER, RELAPSE WILL USUALLY OCCUR IF POST -SHORT-TERM RECOVERY HYPODOPAMINERGIA IS NOT TREATED WITH ATTEMPTS AT EPIGENETIC MANIPULATION OF COMPROMISED BRAIN NEUROCHEMISTRY USING SOME MANNER OF PRO-DOPAMINE REGULATION. 2017 13 4440 25 MOLECULAR GENETIC TESTING IN PAIN AND ADDICTION: FACTS, FICTION AND CLINICAL UTILITY. THE BRAIN REWARD CASCADE (BRC) IS AN INTERACTION OF NEUROTRANSMITTERS AND THEIR RESPECTIVE GENES TO CONTROL THE AMOUNT OF DOPAMINE RELEASED WITHIN THE BRAIN. ANY VARIATIONS WITHIN THIS PATHWAY, WHETHER GENETIC OR ENVIRONMENTAL (EPIGENETIC), MAY RESULT IN ADDICTIVE BEHAVIORS AS WELL AS ALTERED PAIN TOLERANCE. WHILE THERE ARE MANY STUDIES CLAIMING A GENETIC ASSOCIATION WITH ADDICTION AND OTHER BEHAVIORAL INFRACTIONS, DEFINED AS REWARD DEFICIENCY SYNDROME (RDS), NOT ALL ARE SCIENTIFICALLY ACCURATE AND IN SOME CASE JUST WRONG. ALBEIT OUR BIAS, WE DISCUSS HEREIN THE FACTS AND FICTIONS BEHIND MOLECULAR GENETIC TESTING IN RDS (INCLUDING PAIN AND ADDICTION) AND THE SIGNIFICANCE BEHIND THE DEVELOPMENT OF THE GENETIC ADDICTION RISK SCORE (GARSPREDX), THE FIRST TEST TO ACCURATELY PREDICT ONE'S GENETIC RISK FOR RDS. 2015 14 4418 30 MOLECULAR AND EPIGENETIC ASPECTS OF OPIOID RECEPTORS IN DRUG ADDICTION AND PAIN MANAGEMENT IN SPORT. OPIOIDS ARE SUBSTANCES DERIVED FROM OPIUM (NATURAL OPIOIDS). IN ITS RAW STATE, OPIUM IS A GUMMY LATEX EXTRACTED FROM PAPAVER SOMNIFERUM. THE USE OF OPIOIDS AND THEIR NEGATIVE HEALTH CONSEQUENCES AMONG PEOPLE WHO USE DRUGS HAVE BEEN STUDIED. TODAY, OPIOIDS ARE STILL THE MOST COMMONLY USED AND EFFECTIVE ANALGESIC TREATMENTS FOR SEVERE PAIN, BUT THEIR USE AND ABUSE CAUSES DETRIMENTAL SIDE EFFECTS FOR HEALTH, INCLUDING ADDICTION, THUS IMPACTING THE USER'S QUALITY OF LIFE AND CAUSING OVERDOSE. THE MESOCORTICOLIMBIC DOPAMINERGIC CIRCUITRY REPRESENTS THE BRAIN CIRCUIT MEDIATING BOTH NATURAL REWARDS AND THE REWARDING ASPECTS OF NEARLY ALL DRUGS OF ABUSE, INCLUDING OPIOIDS. HENCE, UNDERSTANDING HOW OPIOIDS AFFECT THE FUNCTION OF DOPAMINERGIC CIRCUITRY MAY BE USEFUL FOR BETTER KNOWLEDGE OF THE PROCESS AND TO DEVELOP EFFECTIVE THERAPEUTIC STRATEGIES IN ADDICTION. THE AIM OF THIS REVIEW WAS TO SUMMARIZE THE MAIN FEATURES OF OPIOIDS AND OPIOID RECEPTORS AND FOCUS ON THE MOLECULAR AND UPCOMING EPIGENETIC MECHANISMS LEADING TO OPIOID ADDICTION. SINCE SYNTHETIC OPIOIDS CAN BE EFFECTIVE FOR PAIN MANAGEMENT, THEIR ABILITY TO INDUCE ADDICTION IN ATHLETES, WITH THE RISK OF INCURRING DOPING, IS ALSO DISCUSSED. 2023 15 3774 29 INTERACTION OF GONADAL HORMONES, DOPAMINERGIC SYSTEM, AND EPIGENETIC REGULATION IN THE GENERATION OF SEX DIFFERENCES IN SUBSTANCE USE DISORDERS: A SYSTEMATIC REVIEW. SUBSTANCE USE DISORDER (SUD) IS A CHRONIC CONDITION CHARACTERIZED BY PATHOLOGICAL DRUG-TAKING AND SEEKING BEHAVIORS. REMARKABLY DIFFERENT BETWEEN MALES AND FEMALES, SUGGESTING THAT DRUG ADDICTION IS A SEXUALLY DIFFERENTIATED DISORDER. THE NEUROBIOLOGICAL BASES OF SEX DIFFERENCES IN SUD INCLUDE SEX-SPECIFIC REWARD SYSTEM ACTIVATION, INFLUENCED BY INTERACTIONS BETWEEN GONADAL HORMONE LEVEL CHANGES, DOPAMINERGIC REWARD CIRCUITS, AND EPIGENETIC MODIFICATIONS OF KEY REWARD SYSTEM GENES. THIS SYSTEMATIC REVIEW, ADHERING TO PICOS AND PRISMA-P 2015 GUIDELINES, HIGHLIGHTS THE SEX-DEPENDENT ROLES OF ESTROGENS, PROGESTERONE, AND TESTOSTERONE IN SUD. IN PARTICULAR, ESTRADIOL ELEVATES AND PROGESTERONE REDUCES DOPAMINERGIC ACTIVITY IN SUD FEMALES, WHILST TESTOSTERONE AND PROGESTERONE AUGMENT SUD BEHAVIOR IN MALES. FINALLY, SUD IS ASSOCIATED WITH A SEX-SPECIFIC INCREASE IN THE RATE OF OPIOID AND MONOAMINERGIC GENE METHYLATION. THE STUDY REVEALS THE NEED FOR DETAILED RESEARCH ON GONADAL HORMONE LEVELS, DOPAMINERGIC OR REWARD SYSTEM ACTIVITY, AND EPIGENETIC LANDSCAPES IN BOTH SEXES FOR EFFICIENT SUD THERAPY DEVELOPMENT. 2023 16 2934 29 GENETIC ADDICTION RISK SCORE (GARS) , A PREDICTOR OF VULNERABILITY TO OPIOID DEPENDENCE. THE INTERACTION OF NEUROTRANSMITTERS AND GENES THAT CONTROL THE RELEASE OF DOPAMINE IS THE BRAIN REWARD CASCADE (BRC). VARIATIONS WITHIN THE BRC, WHETHER GENETIC OR EPIGENETIC, MAY PREDISPOSE INDIVIDUALS TO ADDICTIVE BEHAVIORS AND ALTERED PAIN TOLERANCE. THIS DISCUSSION AUTHORED BY A GROUP OF CONCERNED SCIENTISTS AND CLINICIANS EXAMINES THE GENETIC ADDICTION RISK SCORE (GARS), THE FIRST TEST TO ACCURATELY PREDICT VULNERABILITY TO PAIN, ADDICTION, AND OTHER COMPULSIVE BEHAVIORS, DEFINED AS REWARD DEFICIENCY SYNDROME (RDS). INNOVATIVE STRATEGIES TO COMBAT EPIDEMIC OPIOID, IATROGENIC PRESCRIPTION DRUG ABUSE AND DEATH, BASED ON THE ROLE OF DOPAMINERGIC TONE IN PAIN PATHWAYS, ARE PROPOSED. SENSITIVITY TO PAIN MAY RESIDE IN THE MESOLIMBIC PROJECTION SYSTEM, WHERE GENETIC POLYMORPHISMS ASSOCIATE WITH A PREDISPOSITION TO PAIN VULNERABILITY OR TOLERANCE. THEY PROVIDE UNIQUE THERAPEUTIC TARGETS THAT COULD ASSIST IN THE TREATMENT OF PAIN, AND IDENTIFY RISK FOR SUBSEQUENT ADDICTION. PHARMACOGENOMIC TESTING OF CANDIDATE GENES LIKE CB1, MU RECEPTORS, AND PENK MIGHT RESULT IN PHARMACOGENOMIC, PERSONALIZED SOLUTIONS, AND IMPROVED CLINICAL OUTCOMES. GENETICALLY IDENTIFYING RISK FOR ALL RDS BEHAVIORS, ESPECIALLY IN COMPROMISED POPULATIONS, MAY BE A FRONTLINE TOOL TO ASSIST MUNICIPALITIES TO PROVIDE BETTER RESOURCE ALLOCATION. 2018 17 4469 32 MOLECULAR NEUROLOGICAL CORRELATES OF ENDORPHINERGIC/DOPAMINERGIC MECHANISMS IN REWARD CIRCUITRY LINKED TO ENDORPHINERGIC DEFICIENCY SYNDROME (EDS). THE CONSENSUS OF THE CURRENT LITERATURE STRONGLY SUPPORTS THE CONCEPT THAT BRAIN NEUROTRANSMITTERS, AND SECOND MESSENGERS INVOLVED IN THE NET RELEASE OF DOPAMINE IN THE MESOLIMBIC REGION, ESPECIALLY THE NUCLEUS ACCUMBENS (NAC), IS DIRECTLY LINKED TO MOTIVATION, ANTI-STRESS, INCENTIVE SALIENCE (WANTING), AND WELL-BEING. THE ROLE OF DOPAMINE IN TERMS OF ALCOHOL WITHDRAWAL SYMPTOMOLOGY, COCAINE CRAVING BEHAVIOR, DOPAMINE -CONDENSATION PRODUCTS (TIQS), AND MORE RECENTLY, THE GENETIC ASPECTS OF DRUG-SEEKING AND PRO-DOPAMINE REGULATION, PROVIDE COMPELLING EVIDENCE OF THE RELEVANT MOLECULAR NEUROLOGICAL CORRELATES OF DOPAMINERGIC /ENDORPHINERGIC MECHANISMS IN REWARD CIRCUITRY DUE TO GENETIC POLYMORPHISMS AND EPIGENETIC INSULTS. IN THE FACE OF AN AMERICANS OPIOID EPIDEMIC, THE CLINICAL CONSENSUS IS TO TREAT OPIOID USE DISORDER (OUD) WITH LIFE-LONG OPIOID SUBSTITUTION THERAPY. HOWEVER, THE AUTHORS SUGGEST A PARADIGM SHIFT INVOLVING NOVEL MODALITIES LIKE TARGETING THE ENDORPHINERGIC SYSTEM LINKED TO DOPAMINE RELEASE AT THE NAC, IN TERMS OF THE INDUCTION OF REQUIRED "DOPAMINE HOMEOSTASIS." UTILIZING THE KNOWN GENETIC - ENVIRONMENTAL INTERACTION THEOREM P = G +E, THE AUTHORS PROVIDE A CLEAR RATIONALE FOR THE ADOPTION OF GENETIC RISK TESTING COUPLED WITH ENDORPHINERGIC/DOPAMINE REGULATION TO ADDRESS DYSFUNCTION ACROSS THE BRAIN REWARD CIRCUITRY. THE GOAL OF ALTERING RESTING-STATE, FUNCTIONAL CONNECTIVITY MAY REQUIRE A GENTLE "NEUROTRANSMITTER FIX" VIS ENKEPHALINASE INHIBITION TO OVERCOME OR COMBAT - SELF-INDUCTION OF ACUTE DOPAMINE RELEASE VIA PSYCHOACTIVE SUBSTANCE MISUSE RESULTING IN CHRONIC DOPAMINE DOWN-REGULATION. AS SUBSETS OF REWARD DEFICIENCY, WE ARE POISED TO PROVIDE NOVEL, GENETICALLY GUIDED THERAPY FOR ENDORPHINERGIC, OPIOIDERGIC, AND DOPAMINERGIC DEFICIENCIES AND RELATED SYNDROMES, UTILIZING "PRECISION ADDICTION MANAGEMENT. 2020 18 2489 25 EPIGENETICALLY MODIFIED NUCLEOTIDES IN CHRONIC HEROIN AND COCAINE TREATED MICE. EPIGENETIC CHANGES INCLUDE THE ADDITION OF A METHYL GROUP TO THE 5' CARBON OF THE CYTOSINE RING, KNOWN AS DNA METHYLATION, WHICH RESULTS IN THE GENERATION OF THE FIFTH DNA BASE, NAMELY 5-METHYLCYTOSINE. DURING ACTIVE OR PASSIVE DEMETHYLATION, AN INTERMEDIATE MODIFIED BASE IS FORMED, 5-HYDROXYMETHYLCYTOSINE. WE HAVE CURRENTLY QUANTIFIED 5-METHYLCYTOSINE AND 5-HYDROXYMETHYLCYTOSINE IN THE LIVER AND BRAIN OF MICE TREATED WITH COCAINE OR HEROIN, USING LIQUID CHROMATOGRAPHY/TANDEM MASS SPECTROMETRY (LC-MS/MS). OUR RESULTS SHOW THAT GLOBAL 5-METHYLCYTOSINE LEVELS ARE NOT AFFECTED BY HEROIN OR COCAINE ADMINISTRATION, NEITHER IN THE LIVER NOR IN THE BRAIN. HOWEVER, 5-HYDROXYMETHYLCYTOSINE LEVELS ARE REDUCED IN THE LIVER FOLLOWING COCAINE ADMINISTRATION, WHILE THEY ARE NOT AFFECTED BY COCAINE IN THE BRAIN OR BY HEROIN ADMINISTRATION IN THE LIVER AND THE BRAIN. ELUCIDATION OF THE EPIGENETIC PHENOMENA THAT TAKES PLACE WITH RESPECT TO DRUG ABUSE AND ADDICTION, VIA QUANTITATIVE ANALYSIS OF DIFFERENT MODIFIED BASES, MAY ENABLE A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS AND MAY LEAD TO MORE PERSONALIZED AND EFFECTIVE TREATMENT OPTIONS. 2014 19 5035 31 PHARMACOEPIGENOMICS OF OPIATES AND METHADONE MAINTENANCE TREATMENT: CURRENT DATA AND PERSPECTIVES. CURRENT TREATMENTS OF OPIOID ADDICTION INCLUDE PRIMARILY MAINTENANCE MEDICATIONS SUCH AS METHADONE. CHRONIC EXPOSURE TO OPIATE AND/OR LONG-LASTING MAINTENANCE TREATMENT INDUCE MODULATIONS OF GENE EXPRESSION IN BRAIN AND PERIPHERAL TISSUES. THERE IS INCREASING EVIDENCE THAT EPIGENETIC MODIFICATIONS UNDERLIE THESE MODULATIONS. THIS REVIEW SUMMARIZES PUBLISHED RESULTS ON OPIOID-INDUCED EPIGENETIC CHANGES IN ANIMAL MODELS AND IN PATIENTS. THE EPIGENETIC MODIFICATIONS OBSERVED WITH OTHER DRUGS OF ABUSE OFTEN USED BY OPIATE ABUSERS ARE ALSO OUTLINED. SPECIFIC METHADONE MAINTENANCE TREATMENT INDUCED EPIGENETIC MODIFICATIONS AT DIFFERENT TREATMENT STAGES MAY BE COMBINED WITH THE ONES RESULTING FROM PATIENTS' SUBSTANCE USE HISTORY. THEREFORE, RESEARCH COMPARING GROUPS OF ADDICTS WITH SIMILAR HISTORY AND SUBSTANCES USE DISORDERS BUT CONTRASTING FOR WELL-CHARACTERIZED TREATMENT PHENOTYPES SHOULD BE ENCOURAGED. 2017 20 3094 45 GENOMIC AND PERSONALIZED MEDICINE APPROACHES FOR SUBSTANCE USE DISORDERS (SUDS) LOOKING AT GENOME-WIDE ASSOCIATION STUDIES. DRUG ADDICTION, OR SUBSTANCE USE DISORDER (SUD), IS A CHRONIC, RELAPSING DISORDER IN WHICH COMPULSIVE DRUG-SEEKING AND DRUG-TAKING BEHAVIOUR PERSIST DESPITE SERIOUS NEGATIVE CONSEQUENCES. DRUG ABUSE REPRESENTS A PROBLEM THAT DESERVES GREAT ATTENTION FROM A SOCIAL POINT OF VIEW, AND FOCUSES ON THE IMPORTANCE OF GENETIC STUDIES TO HELP IN UNDERSTANDING THE GENETIC BASIS OF ADDICTION AND ITS MEDICAL TREATMENT. DESPITE THE COMPLEXITY OF DRUG ADDICTION DISORDERS, AND THE HIGH NUMBER OF ENVIRONMENTAL VARIABLES PLAYING A ROLE IN THE ONSET, RECURRENCE, AND DURATION OF THE SYMPTOMS, SEVERAL STUDIES HAVE HIGHLIGHTED THE NON-NEGLIGIBLE ROLE OF GENETICS, AS DEMONSTRATED BY HERITABILITY AND GENOME-WIDE ASSOCIATION STUDIES. A CORRELATION BETWEEN THE RELATIVE RISK OF ADDICTION TO SPECIFIC SUBSTANCES AND HERITABILITY HAS BEEN RECENTLY OBSERVED, SUGGESTING THAT NEUROBIOLOGICAL MECHANISMS MAY BE, AT LEAST IN PART, INHERITED. ALL THESE OBSERVATIONS POINT TOWARDS A SCENARIO WHERE THE CORE NEUROBIOLOGICAL FACTORS OF ADDICTION, INVOLVING THE REWARD SYSTEM, IMPULSIVITY, COMPULSIVITY, STRESS, AND ANXIETY RESPONSE, ARE TRANSMITTED, AND THEREFORE, GENES AND MUTATIONS UNDERLYING THEIR VARIATION MIGHT BE DETECTED. IN THE LAST FEW YEARS, THE DEVELOPMENT OF NEW AND MORE EFFICIENT SEQUENCING TECHNOLOGIES HAS PAVED THE WAY FOR LARGE-SCALE STUDIES IN SEARCHING FOR GENETIC AND EPIGENETIC FACTORS AFFECTING DRUG ADDICTION DISORDERS AND THEIR TREATMENTS. THESE STUDIES HAVE BEEN CRUCIAL TO PINPOINT SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN GENES THAT AFFECT THE REACTION TO MEDICAL TREATMENTS. THIS IS CRITICALLY IMPORTANT TO IDENTIFY PHARMACOGENOMIC APPROACHES FOR SUBSTANCE USE DISORDER, SUCH AS OPRM1 SNPS AND METHADONE REQUIRED DOSES FOR MAINTENANCE TREATMENT (MMT). NEVERTHELESS, DESPITE THE PROMISING RESULTS OBTAINED BY GENOME-WIDE ASSOCIATION AND PHARMACOGENOMIC STUDIES, SPECIFIC STUDIES RELATED TO POPULATION GENETICS DIVERSITY ARE LACKING, UNDERMINING THE OVERALL APPLICABILITY OF THE PRELIMINARY FINDINGS, AND THUS POTENTIALLY AFFECTING THE PORTABILITY AND THE ACCURACY OF THE GENETIC STUDIES. IN THIS REVIEW, FOCUSING ON CANNABIS, COCAINE AND HEROIN USE, WE REPORT THE STATE-OF-THE-ART GENOMICS AND PHARMACOGENOMICS OF SUDS, AND THE POSSIBLE FUTURE PERSPECTIVES RELATED TO MEDICAL TREATMENT RESPONSE IN PEOPLE THAT ASK FOR ASSISTANCE IN SOLVING DRUG-RELATED PROBLEMS. 2021