1 5684 187 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 2 2934 41 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 3 4440 34 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 4 5230 60 PRO-DOPAMINE REGULATOR (KB220) A FIFTY YEAR SOJOURN TO COMBAT REWARD DEFICIENCY SYNDROME (RDS): EVIDENCE BASED BIBLIOGRAPHY (ANNOTATED). BACKGROUND: WE ARE FACING A SIGNIFICANT CHALLENGE IN COMBATTING THE CURRENT OPIOID AND DRUG EPIDEMIC WORLDWIDE. IN THE USA, ALTHOUGH THERE HAS BEEN NOTABLE PROGRESS, IN 2017 ALONE 72,000 PEOPLE DIED FROM A NARCOTIC OVERDOSE. THE NIAAA & NIDA CONTINUE TO STRUGGLE WITH INNOVATION TO CURB OR ELIMINATE THIS UNWANTED EPIDEMIC. THE CURRENT FDA LIST OF APPROVED MEDICATION ASSISTANCE TREATMENTS (MATS) WORK BY PRIMARILY BLOCKING DOPAMINE FUNCTION AND RELEASE AT THE PRE-NEURON IN THE NUCLEUS ACCUMBENS. WE OPPOSE THIS OPTION IN THE LONG TERM TERTIARY TREATMENT BUT AGREE FOR SHORT TERM HARM REDUCTION POTENTIAL. BIBLIOGRAPHY PRESENTATION: AS AN ALTERNATIVE MOTIF, THE UTILIZATION OF A WELL-RESEARCHED NEURO-NUTRIENT CALLED KB220 HAS BEEN INTENSELY INVESTIGATED IN AT LEAST 38 STUDIES SHOWING EVIDENT EFFECTS RELATED TO EVERYTHING FROM AMA RATE, ATTENUATION OF CRAVING BEHAVIOR, REWARD SYSTEM ACTIVATION INCLUDING BOLD DOPAMINE SIGNALING, RELAPSE PREVENTION, AS WELL AS REDUCTION IN STRESS, ANGER, AND AGGRESSIVE BEHAVIORS. WE ARE CONTINUING RESEARCH ESPECIALLY AS IT RELATES TO GENETIC RISK, INCLUDING THE NOW PATENTED GENETIC ADDICTION RISK SCORE (GARS((R))) AND THE DEVELOPMENT OF "PRECISION ADDICTION MANAGEMENT (PAM)" TO POTENTIALLY COMBAT THE OPIOID/PSYCHOSTIMULANT EPIDEMIC. CONCLUSION: BASED ON ANIMAL RESEARCH AND CLINICAL TRIALS AS PRESENTED HEREIN, THE PRO-DOPAMINE REGULATOR KNOWN AS KB220 SHOWS PROMISE IN THE ADDICTION AND PAIN SPACE. OTHER NEUROBIOLOGICAL AND GENETIC STUDIES ARE REQUIRED TO HELP UNDERSTAND THE MECHANISM OF ACTION OF THIS NEURO-NUTRIENT. HOWEVER, THE EVIDENCE TO DATE POINTS TO INDUCTION OF "DOPAMINE HOMEOSTASIS"ENABLING AN ASYMPTOTIC APPROACH FOR EPIGENETIC INDUCED "NORMALIZATION" OF BRAIN NEUROTRANSMITTER SIGNALING AND ASSOCIATED IMPROVED FUNCTION IN THE FACE OF EITHER GENETIC OR EPIGENETIC IMPAIRMENT OF THE BRAIN REWARD CASCADE (BRC).WITH THAT SAID, WE ARE ENCOURAGED ABOUT THESE RESULTS AS PUBLISHED OVER THE LAST 50 YEARS AND LOOK FORWARD TO CONTINUED ADVANCEMENTS RELATED TO APPROPRIATE NUTRIGENOMIC SOLUTIONS TO THE MILLIONS OF VICTIMS OF ALL ADDICTIONS (FROM DRUGS TO FOOD TO SMOKING TO GAMBLING AND GAMING ESPECIALLY IN OUR NEXT GENERATION) CALLED REWARD SURFEIT SYNDROME (RSS) IN ADOLESCENTS AND REWARD DEFICIENCY SYNDROME (RDS) IN ADULTHOOD. 2018 5 609 43 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 6 1490 49 DNA DIRECTED PRO-DOPAMINE REGULATION COUPLING SUBLUXATION REPAIR, H-WAVE((R)) AND OTHER NEUROBIOLOGICALLY BASED MODALITIES TO ADDRESS COMPLEXITIES OF CHRONIC PAIN IN A FEMALE DIAGNOSED WITH REWARD DEFICIENCY SYNDROME (RDS): EMERGENCE OF INDUCTION OF "DOPAMINE HOMEOSTASIS" IN THE FACE OF THE OPIOID CRISIS. ADDICTION IS A COMPLEX MULTIFACTORIAL CONDITION. ESTABLISHED GENETIC FACTORS CAN PROVIDE CLEAR GUIDANCE IN ASSESSING THE RISK OF ADDICTION TO SUBSTANCES AND BEHAVIORS. CHRONIC STRESS CAN ACCUMULATE, FORMING DIFFICULT TO RECOGNIZE ADDICTION PATTERNS FROM BOTH GENETIC AND EPIGENETIC (ENVIRONMENTAL) FACTORS. FURTHERMORE, PSYCHOLOGICAL/PHYSICAL/CHEMICAL STRESSORS ARE TYPICALLY CATEGORIZED LINEARLY, DELAYING IDENTIFICATION AND TREATMENT. THE PATIENT IN THIS CASE REPORT IS A CAUCASIAN FEMALE, AGED 36, WHO PRESENTED WITH CHRONIC PAIN AND PARTIAL DISABILITY FOLLOWING A SURGICALLY REPAIRED TRIMALLEOLAR FRACTURE. THE PATIENT HAD A HISTORY OF UNRESOLVED ATTENTION DEFICIT DISORDER AND AN MRI SCAN OF HER BRAIN REVEALED ATROPHY AND FUNCTIONAL ASYMMETRY. IN 2018, THE PATIENT ENTERED THE BAJAJ CHIROPRACTIC CLINIC, WHERE INITIAL TREATMENT FOCUSED ON RE-ESTABLISHING INTEGRITY OF THE SPINE AND LOWER EXTREMITY BIOMECHANICS AND GRADUATED INTO COGNITIVE BEHAVIOR STABILIZATION ASSISTED BY DNA PRO-DOPAMINE REGULATION GUIDED BY GENETIC ADDICTION RISK SEVERITY TESTING. DURING TREATMENT (2018-2021), PROGRESS ACHIEVED INCLUDED: IMPROVED COGNITIVE CLARITY, FOCUS, SLEEP, ANXIETY, AND EMOTIONAL STABILITY IN ADDITION TO PAIN REDUCTION (75%); ELIMINATION OF POWERFUL ANALGESICS; AND REDUCED INTAKE OF PREVIOUSLY UNADDRESSED ALCOHOLISM. TO HELP REDUCE HEDONIC ADDICTIVE BEHAVIORS AND PAIN, COUPLING OF H-WAVE WITH CORRECTIVE CHIROPRACTIC CARE SEEMS PRUDENT. WE EMPHASIZE THE IMPORTANCE OF GENETIC ASSESSMENT ALONG WITH ATTEMPTS AT INDUCING REQUIRED DOPAMINERGIC HOMEOSTASIS VIA PRECISION KB220PAM. IT IS HYPOTHESIZED THAT FROM PREVENTIVE CARE MODELS, A NEW STANDARD IS EMERGING INCLUDING SELF-AWARENESS AND ACCOUNTABILITY FOR REWARD DEFICIENCY AS A FUNCTION OF HYPODOPAMINERGIA. THIS CASE STUDY DOCUMENTS THE PROGRESSION OF A PATIENT DEALING WITH THE COMPLEXITIES OF AN INJURY, PAIN MANAGEMENT, COGNITIVE IMPAIRMENT, ANXIETY, DEPRESSION, AND THE APPLICATION OF UNIVERSAL HEALTH PRINCIPLES TOWARDS CORRECTION VERSUS PALLIATIVE CARE. 2022 7 1651 51 DOPAMINE AND GLUCOSE, OBESITY, AND REWARD DEFICIENCY SYNDROME. OBESITY AS A RESULT OF OVEREATING AS WELL AS A NUMBER OF WELL DESCRIBED EATING DISORDERS HAS BEEN ACCURATELY CONSIDERED TO BE A WORLD-WIDE EPIDEMIC. RECENTLY A NUMBER OF THEORIES BACKED BY A PLETHORA OF SCIENTIFICALLY SOUND NEUROCHEMICAL AND GENETIC STUDIES PROVIDE STRONG EVIDENCE THAT FOOD ADDICTION IS SIMILAR TO PSYCHOACTIVE DRUG ADDICTION. OUR LABORATORY HAS PUBLISHED ON THE CONCEPT KNOWN AS REWARD DEFICIENCY SYNDROME (RDS) WHICH IS A GENETIC AND EPIGENETIC PHENOMENA LEADING TO IMPAIRMENT OF THE BRAIN REWARD CIRCUITRY RESULTING IN A HYPO-DOPAMINERGIC FUNCTION. RDS INVOLVES THE INTERACTIONS OF POWERFUL NEUROTRANSMITTERS AND RESULTS IN ABNORMAL CRAVING BEHAVIOR. A NUMBER OF IMPORTANT FACTS WHICH COULD HELP TRANSLATE TO POTENTIAL THERAPEUTIC TARGETS ESPOUSED IN THIS FOCUSED REVIEW INCLUDE: (1) CONSUMPTION OF ALCOHOL IN LARGE QUANTITIES OR CARBOHYDRATES BINGING STIMULATES THE BRAIN'S PRODUCTION OF AND UTILIZATION OF DOPAMINE; (2) IN THE MESO-LIMBIC SYSTEM THE ENKEPHALINERGIC NEURONS ARE IN CLOSE PROXIMITY, TO GLUCOSE RECEPTORS; (3) HIGHLY CONCENTRATED GLUCOSE ACTIVATES THE CALCIUM CHANNEL TO STIMULATE DOPAMINE RELEASE FROM P12 CELLS; (4) A SIGNIFICANT CORRELATION BETWEEN BLOOD GLUCOSE AND CEREBROSPINAL FLUID CONCENTRATIONS OF HOMOVANILLIC ACID THE DOPAMINE METABOLITE; (5) 2-DEOXYGLUCOSE (2DG), THE GLUCOSE ANALOG, IN PHARMACOLOGICAL DOSES IS ASSOCIATED WITH ENHANCED DOPAMINE TURNOVER AND CAUSES ACUTE GLUCOPRIVATION. EVIDENCE FROM ANIMAL STUDIES AND FMRI IN HUMANS SUPPORT THE HYPOTHESIS THAT MULTIPLE, BUT SIMILAR BRAIN CIRCUITS ARE DISRUPTED IN OBESITY AND DRUG DEPENDENCE AND FOR THE MOST PART, IMPLICATE THE INVOLVEMENT OF DA-MODULATED REWARD CIRCUITS IN PATHOLOGIC EATING BEHAVIORS. BASED ON A CONSENSUS OF NEUROSCIENCE RESEARCH TREATMENT OF BOTH GLUCOSE AND DRUG LIKE COCAINE, OPIATES SHOULD INCORPORATE DOPAMINE AGONIST THERAPY IN CONTRAST TO CURRENT THEORIES AND PRACTICES THAT UTILIZES DOPAMINE ANTAGONISTIC THERAPY. CONSIDERING THAT UP UNTIL NOW CLINICAL UTILIZATION OF POWERFUL DOPAMINE D2 AGONISTS HAVE FAILED DUE TO CHRONIC DOWN REGULATION OF D2 RECEPTORS NEWER TARGETS BASED ON NOVEL LESS POWERFUL D2 AGONISTS THAT UP-REGULATE D2 RECEPTORS SEEMS PRUDENT. WE ENCOURAGE NEW STRATEGIES TARGETED AT IMPROVING DA FUNCTION IN THE TREATMENT AND PREVENTION OF OBESITY A SUBTYPE OF REWARD DEFICIENCY. 2014 8 5855 43 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 9 747 36 CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA AND COGNITIVE DECLINE IN HUMANS: EMBRACING PUTATIVE INDUCTION OF DOPAMINE HOMEOSTASIS. OVER YEARS, THE REGULAR USE OF CANNABIS HAS SUBSTANTIALLY INCREASED AMONG YOUNG ADULTS, AS INDICATED BY THE RISE IN CANNABIS USE DISORDER (CUD), WITH AN ESTIMATED PREVALENCE OF 8. 3% IN THE UNITED STATES. RESEARCH SHOWS THAT EXPOSURE TO CANNABIS IS ASSOCIATED WITH HYPODOPAMINERGIC ANHEDONIA (DEPRESSION), COGNITIVE DECLINE, POOR MEMORY, INATTENTION, IMPAIRED LEARNING PERFORMANCE, REDUCED DOPAMINE BRAIN RESPONSE-ASSOCIATED EMOTIONALITY, AND INCREASED ADDICTION SEVERITY IN YOUNG ADULTS. THE ADDICTION MEDICINE COMMUNITY IS INCREASING CONCERN BECAUSE OF THE HIGH CONTENT OF DELTA-9-TETRAHYDROCANNABINOL (THC) CURRENTLY FOUND IN ORAL AND VAPING CANNABIS PRODUCTS, THE COGNITIVE EFFECTS OF CANNABIS MAY BECOME MORE PRONOUNCED IN YOUNG ADULTS WHO USE THESE CANNABIS PRODUCTS. PRELIMINARY RESEARCH SUGGESTS THAT IT IS POSSIBLE TO INDUCE 'DOPAMINE HOMEOSTASIS,' THAT IS, RESTORE DOPAMINE FUNCTION WITH DOPAMINE UPREGULATION WITH THE PROPOSED COMPOUND AND NORMALIZE BEHAVIOR IN CHRONIC CANNABIS USERS WITH CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA (DEPRESSION) AND COGNITIVE DECLINE. THIS PSYCHOLOGICAL, NEUROBIOLOGICAL, ANATOMICAL, GENETIC, AND EPIGENETIC RESEARCH ALSO COULD PROVIDE EVIDENCE TO USE FOR THE DEVELOPMENT OF AN APPROPRIATE POLICY REGARDING THE DECRIMINALIZATION OF CANNABIS FOR RECREATIONAL USE. 2021 10 4469 49 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 11 4631 46 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 12 1677 40 DRUG ADDICTION: HYPERKATIFEIA/NEGATIVE REINFORCEMENT AS A FRAMEWORK FOR MEDICATIONS DEVELOPMENT. COMPULSIVE DRUG SEEKING THAT IS ASSOCIATED WITH ADDICTION IS HYPOTHESIZED TO FOLLOW A HEURISTIC FRAMEWORK THAT INVOLVES THREE STAGES (BINGE/INTOXICATION, WITHDRAWAL/NEGATIVE AFFECT, AND PREOCCUPATION/ANTICIPATION) AND THREE DOMAINS OF DYSFUNCTION (INCENTIVE SALIENCE/PATHOLOGIC HABITS, NEGATIVE EMOTIONAL STATES, AND EXECUTIVE FUNCTION, RESPECTIVELY) VIA CHANGES IN THE BASAL GANGLIA, EXTENDED AMYGDALA/HABENULA, AND FRONTAL CORTEX, RESPECTIVELY. THIS REVIEW FOCUSES ON NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS THAT CONTRIBUTE TO HYPERKATIFEIA, DEFINED AS A GREATER INTENSITY OF NEGATIVE EMOTIONAL/MOTIVATIONAL SIGNS AND SYMPTOMS DURING WITHDRAWAL FROM DRUGS OF ABUSE IN THE WITHDRAWAL/NEGATIVE AFFECT STAGE OF THE ADDICTION CYCLE. HYPERKATIFEIA PROVIDES AN ADDITIONAL SOURCE OF MOTIVATION FOR COMPULSIVE DRUG SEEKING VIA NEGATIVE REINFORCEMENT. NEGATIVE REINFORCEMENT REFLECTS AN INCREASE IN THE PROBABILITY OF A RESPONSE TO REMOVE AN AVERSIVE STIMULUS OR DRUG SEEKING TO REMOVE HYPERKATIFEIA THAT IS AUGMENTED BY GENETIC/EPIGENETIC VULNERABILITY, ENVIRONMENTAL TRAUMA, AND PSYCHIATRIC COMORBIDITY. NEUROBIOLOGICAL TARGETS FOR HYPERKATIFEIA IN ADDICTION INVOLVE NEUROCIRCUITRY OF THE EXTENDED AMYGDALA AND ITS CONNECTIONS VIA WITHIN-SYSTEM NEUROADAPTATIONS IN DOPAMINE, ENKEPHALIN/ENDORPHIN OPIOID PEPTIDE, AND GAMMA-AMINOBUTYRIC ACID/GLUTAMATE SYSTEMS AND BETWEEN-SYSTEM NEUROADAPTATIONS IN PROSTRESS CORTICOTROPIN-RELEASING FACTOR, NOREPINEPHRINE, GLUCOCORTICOID, DYNORPHIN, HYPOCRETIN, AND NEUROIMMUNE SYSTEMS AND ANTISTRESS NEUROPEPTIDE Y, NOCICEPTIN, ENDOCANNABINOID, AND OXYTOCIN SYSTEMS. SUCH NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS ARE HYPOTHESIZED TO MEDIATE A NEGATIVE HEDONIC SET POINT THAT GRADUALLY GAINS ALLOSTATIC LOAD AND SHIFTS FROM A HOMEOSTATIC HEDONIC STATE TO AN ALLOSTATIC HEDONIC STATE. BASED ON PRECLINICAL STUDIES AND TRANSLATIONAL STUDIES TO DATE, MEDICATIONS AND BEHAVIORAL THERAPIES THAT RESET BRAIN STRESS, ANTISTRESS, AND EMOTIONAL PAIN SYSTEMS AND RETURN THEM TO HOMEOSTASIS WOULD BE PROMISING NEW TARGETS FOR MEDICATION DEVELOPMENT. SIGNIFICANCE STATEMENT: THE FOCUS OF THIS REVIEW IS ON NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS THAT CONTRIBUTE TO HYPERKATIFEIA, DEFINED AS A GREATER INTENSITY OF NEGATIVE EMOTIONAL/MOTIVATIONAL SIGNS AND SYMPTOMS DURING WITHDRAWAL FROM DRUGS OF ABUSE IN THE WITHDRAWAL/NEGATIVE AFFECT STAGE OF THE DRUG ADDICTION CYCLE AND A DRIVING FORCE FOR NEGATIVE REINFORCEMENT IN ADDICTION. MEDICATIONS AND BEHAVIORAL THERAPIES THAT REVERSE HYPERKATIFEIA BY RESETTING BRAIN STRESS, ANTISTRESS, AND EMOTIONAL PAIN SYSTEMS AND RETURNING THEM TO HOMEOSTASIS WOULD BE PROMISING NEW TARGETS FOR MEDICATION DEVELOPMENT. 2021 13 4624 42 NEUROBIOLOGY OF KB220Z-GLUTAMINERGIC-DOPAMINERGIC OPTIMIZATION COMPLEX [GDOC] AS A LIQUID NANO: CLINICAL ACTIVATION OF BRAIN IN A HIGHLY FUNCTIONAL CLINICIAN IMPROVING FOCUS, MOTIVATION AND OVERALL SENSORY INPUT FOLLOWING CHRONIC INTAKE. BACKGROUND: WITH NEUROGENETIC AND EPIGENETIC TOOLS UTILIZED IN RESEARCH AND NEUROIMAGING, WE ARE UNRAVELING THE MYSTERIES OF BRAIN FUNCTION, ESPECIALLY AS IT RELATES TO REWARD DEFICIENCY (RDS). WE ENCOURAGE THE DEVELOPMENT OF PHARMACEUTICALS OR NUTRACEUTICALS THAT PROMOTE A REDUCTION IN DOPAMINE RESISTANCE AND BALANCE BRAIN NEUROCHEMISTRY, LEADING TO DOPAMINE HOMEOSTASIS. WE DISCLOSE SELF-ASSESSMENT OF A HIGHLY FUNCTIONAL PROFESSIONAL UNDER WORK-RELATED STRESS FOLLOWING KB220Z USE, A LIQUID (AQUA) NANO GLUTAMINERGIC-DOPAMINERGIC OPTIMIZATION COMPLEX (GDOC). CASE PRESENTATION: SUBJECT TOOK GDOC FOR ONE MONTH. SUBJECT SELF-ADMINISTERED GDOC USING ONE-HALF-OUNCE TWICE A DAY. DURING FIRST THREE DAYS, UNIQUE BRAIN ACTIVATION OCCURRED; RESEMBLING WHITE NOISE AFTER 30 MINUTES AND SENSATION WAS STRONG FOR 45 MINUTES AND THEN DISSIPATED. HE DESCRIBED EFFECT AS IF HIS EYESIGHT IMPROVED SLIGHTLY AND POINTED OUT THAT HIS SENSE OF SMELL AND SLEEP GREATLY IMPROVED. SUBJECT EXPERIENCED A CALMING EFFECT SIMILAR TO MEDITATION THAT COULD BE LINKED TO DOPAMINE RELEASE. HE ALSO REPORTED CONTROL OF GOING OVER THE EDGE AFTER A HARD DAY'S WORK, WHICH WAS COUPLED WITH A SLIGHT INCREASE IN ENERGY, INCREASED MOTIVATION TO WORK, INCREASED FOCUS AND MULTI-TASKING, WITH CLEARER PURPOSE OF TASK AT HAND. SUBJECT FELT LESS INHIBITED IN A SOCIAL SETTING AND SUGGESTED SYNDROME THAT GDOC INCREASED HIS BEHAVIOR ACTIVATING SYSTEM (REWARD), WHILE HAVING A DECREASE IN THE BEHAVIOR INHIBITION SYSTEM (CAUTION). CONCLUSION: THESE RESULTS AND OTHER RELATED STUDIES REVEAL AN IMPROVED MOOD, WORK-RELATED FOCUS, AND SLEEP. THESE EFFECTS AS A SUBJECTIVE FEELING OF BRAIN ACTIVATION MAYBE DUE TO DIRECT OR INDIRECT DOPAMINERGIC INTERACTION. WHILE THIS CASE IS ENCOURAGING, WE MUST AWAIT MORE RESEARCH IN A LARGER RANDOMIZED PLACEBO-CONTROLLED STUDY TO MAP THE ROLE OF GDOC, ESPECIALLY IN A NANO-SIZED PRODUCT, TO DETERMINE THE POSSIBLE EFFECTS ON CIRCUIT INHIBITORY CONTROL AND MEMORY BANKS AND THE INDUCTION OF DOPAMINE HOMEOSTASIS INDEPENDENT OF EITHER HYPO- OR HYPER-DOPAMINERGIC TRAITS/STATES. 2016 14 1091 33 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 15 4848 34 OPIOID-INDUCED STRUCTURAL AND FUNCTIONAL PLASTICITY OF MEDIUM-SPINY NEURONS IN THE NUCLEUS ACCUMBENS. OPIOID USE DISORDER (OUD) IS A CHRONIC RELAPSING CLINICAL CONDITION WITH TREMENDOUS MORBIDITY AND MORTALITY THAT FREQUENTLY PERSISTS, DESPITE TREATMENT, DUE TO AN INDIVIDUAL'S UNDERLYING PSYCHOLOGICAL, NEUROBIOLOGICAL, AND GENETIC VULNERABILITIES. EVIDENCE SUGGESTS THAT THESE VULNERABILITIES MAY HAVE NEUROCHEMICAL, CELLULAR, AND MOLECULAR BASES. KEY NEUROPLASTIC EVENTS WITHIN THE MESOCORTICOLIMBIC SYSTEM THAT EMERGE THROUGH CHRONIC EXPOSURE TO OPIOIDS MAY HAVE A DETERMINATIVE INFLUENCE ON BEHAVIORAL SYMPTOMS ASSOCIATED WITH OUD. IN PARTICULAR, STRUCTURAL AND FUNCTIONAL ALTERATIONS IN THE DENDRITIC SPINES OF MEDIUM SPINY NEURONS (MSNS) WITHIN THE NUCLEUS ACCUMBENS (NAC) AND ITS DOPAMINERGIC PROJECTIONS FROM THE VENTRAL TEGMENTAL AREA (VTA) ARE BELIEVED TO FACILITATE THESE BEHAVIORAL SEQUELAE. ADDITIONALLY, GLUTAMATERGIC NEURONS FROM THE PREFRONTAL CORTEX, THE BASOLATERAL AMYGDALA, THE HIPPOCAMPUS, AND THE THALAMUS PROJECT TO THESE SAME MSNS, PROVIDING AN ENRICHED TARGET FOR SYNAPTIC PLASTICITY. HERE, WE REVIEW LITERATURE RELATED TO NEUROADAPTATIONS IN NAC MSNS FROM DOPAMINERGIC AND GLUTAMATERGIC PATHWAYS IN OUD. WE ALSO DESCRIBE NEW FINDINGS RELATED TO TRANSCRIPTIONAL, EPIGENETIC, AND MOLECULAR MECHANISMS IN MSN PLASTICITY IN THE DIFFERENT STAGES OF OUD. 2021 16 6266 25 THE NEUROBIOLOGY OF SUICIDE. THE STRESS-DIATHESIS MODEL POSITS THAT SUICIDE IS THE RESULT OF AN INTERACTION BETWEEN STATE-DEPENDENT (ENVIRONMENTAL) STRESSORS AND A TRAIT-LIKE DIATHESIS OR SUSCEPTIBILITY TO SUICIDAL BEHAVIOUR, INDEPENDENT OF PSYCHIATRIC DISORDERS. FINDINGS FROM POST-MORTEM STUDIES OF THE BRAIN AND FROM GENOMIC AND IN-VIVO NEUROIMAGING STUDIES INDICATE A BIOLOGICAL BASIS FOR THIS DIATHESIS, INDICATING THE IMPORTANCE OF NEUROBIOLOGICAL SCREENING AND INTERVENTIONS, IN ADDITION TO COGNITIVE AND MOOD INTERVENTIONS, IN THE PREVENTION OF SUICIDE. EARLY-LIFE ADVERSITY AND EPIGENETIC MECHANISMS MIGHT EXPLAIN SOME OF THE LINK BETWEEN SUICIDE RISK AND BRAIN CIRCUITRY AND NEUROCHEMISTRY ABNORMALITIES. RESULTS FROM A RANGE OF STUDIES USING DIVERSE DESIGNS AND POST-MORTEM AND IN-VIVO TECHNIQUES SHOW IMPAIRMENTS OF THE SEROTONIN NEUROTRANSMITTER SYSTEM AND THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS STRESS-RESPONSE SYSTEM IN THE DIATHESIS FOR SUICIDAL BEHAVIOUR. THESE IMPAIRMENTS MANIFEST AS IMPAIRED COGNITIVE CONTROL OF MOOD, PESSIMISM, REACTIVE AGGRESSIVE TRAITS, IMPAIRED PROBLEM SOLVING, OVER-REACTIVITY TO NEGATIVE SOCIAL SIGNS, EXCESSIVE EMOTIONAL PAIN, AND SUICIDAL IDEATION, LEADING TO SUICIDAL BEHAVIOUR. BIOMARKERS RELATED TO THE DIATHESIS MIGHT HELP TO INFORM RISK-ASSESSMENT PROCEDURES AND TREATMENT CHOICE IN THE PREVENTION OF SUICIDE. 2014 17 265 49 ADVERSE EFFECTS OF RECREATIONAL AND MEDICAL CANNABIS. PURPOSE OF REVIEW: THIS COMPREHENSIVE REVIEW DISCUSSES THE ADVERSE EFFECTS KNOWN TODAY ABOUT MARIJUANA, FOR EITHER MEDICAL OR RECREATIONAL USE. IT REVIEWS THE ROLE OF CANNABIS IN THE TREATMENT OF CHRONIC PAIN, COGNITIVE AND NEUROLOGICAL ADVERSE EFFECTS, SPECIAL CASES AND ADDICTION. RECENT FINDINGS: CANNABINOIDS WORK THROUGH THE ENDOCANNABINOIDS SYSTEM AND INHIBIT THE RELEASE OF GABA AND GLUTAMATE IN THE BRAIN, IMPACT NEUROMODULATION, AS WELL AS DOPAMINE, ACETYLCHOLINE AND NOREPINEPHRINE RELEASE. THEY AFFECT REWARD, LEARNING AND PAIN. THE USE OF CANNABIS IS INCREASING NATIONALLY AND WORLD-WIDE FOR BOTH RECREATIONAL AND MEDICINAL PURPOSES, HOWEVER, THERE IS RELATIVELY ONLY LOW QUALITY EVIDENCE TO THE EFFICACY AND ADVERSE EFFECTS OF THIS. CANNABIS AND ITS DERIVATIVES MAY BE USED FOR TREATMENT OF CHRONIC PAIN. THEY ARE VIA CB1 RECEPTORS THAT ARE THOUGHT TO MODULATE NOCICEPTIVE SIGNALS IN THE BRAIN. CB2 RECEPTORS IN THE DRG LIKELY AFFECT PAIN INTEGRATION IN THE AFFERENT PATHWAYS, AND PERIPHERALLY CB2 ALSO AFFECTS NORADRENERGIC PATHWAYS INFLUENCING PAIN. A LARGE PROPORTION OF USERS MAY SEE MORE THAN 50% OF CHRONIC PAIN ALLEVIATION COMPARED WITH PLACEBO. CANNABIS AFFECTS COGNITION, MOST NOTABLY EXECUTIVE FUNCTION, MEMORY AND ATTENTION, AND MAY DETERIORATE THE BOUNDARY BETWEEN EMOTIONAL AND EXECUTIVE PROCESSING. CANNABIS IMPAIRS MEMORY IN THE SHORT RUN, WHICH BECOME MORE SIGNIFICANT WITH CHRONIC USE, AND MAY ALSO BE ACCOMPANIED BY POORER EFFORT, SLOWER PROCESSING AND IMPACTED ATTENTION. IT IS GENERALLY BELIEVED THAT LONG-TERM USE AND EARLIER AGE ARE RISK FACTOR FOR NEUROCOGNITIVE DEFICITS; NEUROIMAGING STUDIES HAVE SHOWN REDUCED HIPPOCAMPAL VOLUME AND DENSITY. EXECUTIVE FUNCTIONS AND MEMORY ARE WORSE IN ADOLESCENT USERS VERSUS ADULTS. CANNABIS ADDICTION IS DIFFERENT AND LIKELY LESS COMMON THAN OTHER ADDICTIVE SUBSTANCES, BUT UP TO 10% OF USERS MEET CRITERIA FOR LIFETIME CANNABIS DEPENDENCE. ADDICTION PATTERNS MAY BE LINKED TO GENETIC AND EPIGENETIC DIFFERENCES. IT IS STILL UNCLEAR WHETHER ABSTINENCE REVERSES PATTERNS OF ADDICTION, AND MORE RESEARCH IS REQUIRED INTO THIS TOPIC. SUMMARY: CANNABIS USE HAS BECOME MORE ABUNDANT FOR BOTH MEDICAL AND RECREATIONAL USE. IT CARRIES LIKELY BENEFITS IN THE FORM OF ANALGESIA, ANTI-EMESIS AND IMPROVED APPETITE IN CHRONIC PATIENTS. THE EVIDENCE REVIEWING ADVERSE EFFECTS OF THIS USE ARE STILL LIMITED, HOWEVER, EXITING DATA POINTS TO A CLEAR LINK WITH NEUROCOGNITIVE DETERIORATION, BACKED BY LOSS OF BRAIN VOLUME AND DENSITY. ADDICTION IS LIKELY COMPLEX AND VARIABLE, AND NO GOOD DATA EXISTS TO SUPPORT TREATMENT AT THIS POINT. IT IS BECOMING CLEAR THAT USE IN EARLIER AGES CARRIES A HIGHER RISK FOR LONG-TERM DEFICITS. AS WITH ANY OTHER DRUG, THESE RISKS SHOULD BE CONSIDERED ALONGSIDE BENEFITS PRIOR TO A DECISION ON CANNABIS USE. 2021 18 3774 28 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 19 6617 34 UNDERPINNING THE NEUROBIOLOGICAL INTRICACIES ASSOCIATED WITH OPIOID TOLERANCE. THE OPIOID CRISIS IS A MAJOR THREAT OF THE 21ST CENTURY, WITH A REMARKABLE JUXTAPOSITION OF USE AND ABUSE. OPIOIDS ARE THE MOST POTENT AND EFFICACIOUS CLASS OF ANALGESICS, BUT DESPITE THEIR PROVEN THERAPEUTIC EFFICACY, THEY HAVE RECENTLY BEEN DEGRADED TO THIRD-LINE THERAPY FOR THE MANAGEMENT OF CHRONIC PAIN IN CLINICS. THE REASON BEHIND THIS IS THE DEVELOPMENT OF POTENTIAL SIDE EFFECTS AND TOLERANCE AFTER REPEATED DOSING. OPIOID TOLERANCE IS THE MAJOR LIMITING FACTOR LEADING TO THE WITHDRAWAL OF TREATMENT, SEVERE SIDE EFFECTS DUE TO DOSE ESCALATION, AND SOMETIMES EVEN DEATH OF THE PATIENTS. EVERY DAY MORE THAN 90 PEOPLE DIE DUE TO OPIOIDS OVERDOSE IN AMERICA, AND A SIMILAR TREND HAS BEEN SEEN ACROSS THE GLOBE. OVER THE PAST TWO DECADES, RESEARCHERS HAVE BEEN TRYING TO DISSECT THE NEUROBIOLOGICAL MECHANISM OF OPIOID TOLERANCE. RESEARCH ON OPIOID TOLERANCE SHIFTED TOWARD CENTRAL NERVOUS SYSTEM-BASED ADAPTATIONS BECAUSE TOLERANCE IS MUCH MORE THAN JUST A CELLULAR PHENOMENON. THUS, NEUROBIOLOGICAL ADAPTATIONS ASSOCIATED WITH OPIOID TOLERANCE ARE IMPORTANT TO UNDERSTAND IN ORDER TO FIND NEWER PAIN THERAPEUTICS. THESE ADAPTATIONS ARE ASSOCIATED WITH ALTERATIONS IN ASCENDING AND DESCENDING PAIN PATHWAYS, REWARD CIRCUITRY MODULATIONS, RECEPTOR DESENSITIZATION AND DOWN-REGULATION, RECEPTOR INTERNALIZATION, HETERODIMERIZATION, AND ALTERED EPIGENETIC REGULATION. THE PRESENT REVIEW IS FOCUSED ON NOVEL CIRCUITRIES ASSOCIATED WITH OPIOID TOLERANCE IN DIFFERENT AREAS OF THE BRAIN, SUCH AS PERIAQUEDUCTAL GRAY, ROSTRAL VENTROMEDIAL MEDULLA, DORSAL RAPHE NUCLEUS, VENTRAL TEGMENTAL AREA, AND NUCLEUS ACCUMBENS. UNDERSTANDING THE NEUROBIOLOGICAL MODULATIONS ASSOCIATED WITH CHRONIC OPIOID EXPOSURE AND TOLERANCE WILL PAVE THE WAY FOR THE DEVELOPMENT OF NOVEL PHARMACOLOGICAL TOOLS FOR SAFER AND BETTER MANAGEMENT OF CHRONIC PAIN IN PATIENTS. 2020 20 4846 21 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