Treatment of Neonatal Abstinence Syndrome: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 3 by Conner Chen.

The management of neonatal abstinence syndrome (NAS) is varied and involves a combination of nonpharmacologic and pharmacologic therapy. The treatment goals for NAS include preventing NAS-associated complications and restoring normal newborn activities, such as nutrition intake, weight gain, sleep, and adjustment to the social environment. As with all pharmacological treatments, the potential risks and benefits of treatment must be considered for each patient.

  • neonatal abstinence syndrome (NAS)
  • reward deficiency syndrome (RDS)
  • genetic addiction risk severity (GARS)

1. Nonpharmacological Interventions

Nonpharmacologic care should be initiated at birth for all substance-exposed newborns, and the parent/caregiver should also be actively involved. It should continue throughout the newborn’s hospitalization and after discharge, regardless of the need for pharmacologic treatment. When used appropriately, nonpharmacologic therapies can help newborns with neonatal abstinence syndrome (NAS) avoid or reduce the amount of pharmacologic therapy required. However, they do not serve as a substitute for pharmacotherapy when it is necessary. Nonpharmacologic therapies entail individualized assessments of the newborn and parent/caregiver’s functioning; the environment, to determine specific newborn–parent/caregiver dyad triggers for dysregulation; and adaptative responses to the environment to reduce physiological and neurobehavioral symptoms and promote newborn–parent/caregiver dyadic regulation [1].
General care measures [1][2]:
General care measures in NAS include identifying the signs, symptoms, and triggers of physiological behavioral dysregulation and individualizing the care of the newborn based on these observations as well as promoting organization, competence, and physiological stability in newborns by identifying techniques that improve symptomatology that are specific to each newborn. For example, gentle vertical rocking can help reduce excessive irritability. Moreover, tremors and hypertonicity can be reduced by utilizing swaddling and positioning (i.e., the side-lying C position), which decrease motoric hyperactivity and allow newborns to organize their behaviors and become calm.
Newborn–parent/caregiver relationship [1]:
Nonpharmacologic interventions in this domain include assessing parental functioning and interaction with the newborn to help reduce dysregulation and promote dyadic synchronization [3]; educating the parent/caregiver on how to identify the signs of withdrawal; teaching the parent/caregiver about their newborn’s sensitivities; helping the parent/caregiver develop strategies and respond to the newborn in a manner that reduces the newborn’s dysregulation and expression of NAS; aiding the parent/caregiver in understanding their feelings surrounding their newborn’s functioning so they can respond more appropriately; and managing maternal issues such as mental illness, limited health care access, intimate partner violence, etc., in order to maintain a healthy newborn–parent/caregiver relationship, which is vital for the newborn’s development [4].
Environment [2]:
Nonpharmacologic interventions in this domain include identifying potential sensory and environmental input sources of dysregulation for newborns and altering the environment to minimize their effects and dysregulation. For example, a newborn who becomes hypertonic or irritable with eye contact might need the parent/caregiver to avoid eye contact while feeding, handling, or performing other activities together. In addition, a newborn who becomes easily overstimulated by noise can be cared for in a quiet area. Finally, rooming-in (i.e., the colocation of the newborn and the parent/caregiver after delivery and beyond) has been found to reduce NAS severity [2][5][6] and is recommended in the inpatient setting.
Feeding:
For newborns with NAS, formula feeding should not necessarily be the default. In fact, breastfeeding has been shown to be successful in some individuals with opioid use disorder (OUD) [2][7][8][9]. Recommendations involving an individual’s suitability for breastfeeding should be tailored for individuals with one or more of the following traits: the concurrent usage of other prescription medications; participation in prenatal care and/or substance use disorder (SUD) treatment during or after the second trimester; and relapse during the third trimester with abstinence maintained for 30 days prior to delivery.
Breastfeeding by methadone-maintained individuals seems to be safe and can lessen the severity of NAS and the necessity for pharmacological intervention [10][11][12][13]. The concentrations of methadone have been found to be low in human breast milk (range: 21–462 ng/mL) and do not appear to be associated with the parent’s methadone dose [10]. The low concentrations of methadone found in human breast milk are unlikely to have a significant impact on the newborn’s display of NAS, and other breastfeeding-related variables could be responsible for the decreased severity of NAS in breastfed infants of methadone-maintained individuals. In addition, buprenorphine is excreted in low concentrations into human breast milk and seems to be safe for newborns of buprenorphine-maintained individuals [14][15].

2. Pharmacological Interventions

Pharmacological management is initiated for newborns who display significant signs and symptoms of NAS despite adequate and personalized nonpharmacological care. The goal of pharmacological management is a short-term improvement in NAS symptomatology. Currently, opioid therapy is the preferred first-line treatment for NAS. This is based on limited data that show opioid therapy reduces the need for additional medications and shortens hospital stays [2][4][16][17][18][19]. Morphine and methadone are the preferred opioids, and the selection is based on the clinician/hospital. Morphine is typically the preferred agent of the two, while methadone is considered a reasonable alternative. However, there have been studies that indicate that methadone minimally reduces hospital stay and treatment duration when compared to morphine [20][21]. Buprenorphine is another agent that has been used and appears to be effective in the treatment of NAS [22][23]. However, its use in newborns is limited due to the high ethanol content (30%) and its challenging sublingual administration [2].
A 2020 systematic review by Zankl et al. identified 16 trials including 1110 infants [4]. In one of the trials (N = 80 infants), morphine was compared to supportive care alone, and the results showed that morphine increased the length of treatment and hospitalization but shortened the time needed to regain birthweight. In trials that compared morphine to methadone (two trials, N = 147 infants), it was found that they both had comparable rates of breastfeeding success, length of hospitalization, and treatment failure. In trials that compared morphine to buprenorphine (three trials, N = 113 infants), it was found that they both had comparable rates of treatment failure, but the length of hospitalization was shorter in the buprenorphine group. In a separate network meta-analysis utilizing both indirect and direct comparisons (18 trials, N = 1072 infants), six medications were evaluated, including morphine, methadone, buprenorphine, clonidine, phenobarbital, and DTO. Morphine and methadone were associated with the lowest rates of treatment failure, but the differences were not statistically significant [24]. Additionally, buprenorphine was found to have the shortest length of hospitalization.
In addition, according to a meta-analysis by Cleary et al., there were no statistically significant differences in the incidence of NAS in newborns of women on higher doses of opioids when compared to lower doses in studies that used an objective NAS scoring system and prospective studies [25]. Similarly, Bakstad et al. reported that the maternal methadone or buprenorphine dose was not predictive of the occurrence or need for NAS treatment in newborns [26].
A second medication is sometimes required in newborns who have severe NAS that is not sufficiently controlled with a single agent [4][24][27][28]. The two most commonly used second-line medications are clonidine and phenobarbital. Typically, clonidine is the preferred second-line medication due to concerns regarding phenobarbital’s adverse effects, including oversedation, a high alcohol content, challenges with weaning substance-exposed newborns from phenobarbital, and phenobarbital’s potential long-term impacts on neurodevelopment based on animal studies [2][29][30][31][32]. In addition, the concurrent use of phenobarbital and clonidine appears to reduce the consequences of opioid-induced negative neuronal development in newborns with NAS [27][33].

3. Neurodevelopmental Issues with Opioid Treatment

Czynski et al. [34] reported that the prevalence of NAS has increased by 333% over the last two decades, which translates to approximately one infant born every 15 min in the United States [35]. This unfortunate statistic reveals that 50–80% of newborn infants exposed to opioids in utero develop NAS. Along these lines, Boardman et al. [36] suggested that a literature summary of 40 years necessitated a reassessment of ways to treat NAS without opioids, even during withdrawal periods. These investigators identified knowledge gaps and urged the scientific community to re-evaluate childhood clinical outcomes such as infant brain development and visual and long-term neurocognitive function. Van den Hoogen et al. [37], assessing the behavioral and cFos responses, known to be a marker for neuronal activation in neonatal animals withdrawing from opioids, found increased cFos expression in spinally projecting neurons within the periaqueductal grey (PAG), locus coeruleus, and rostral ventromedial medulla (RVM). They also observed that the narcotic antagonist naloxone precipitated profound withdrawal symptoms across all developmental levels and stages within several key brainstem regions. Another example of neurodevelopmental issues linked to opioids was investigated by others [34], involving mothers maintained on methadone or buprenorphine but randomized to morphine vs. methadone. Czynski et al. [34] reported that adding phenobarbital to the treatment routine resulted in several medical problems, suggesting that sedative hypnotics may not be an appropriate modality in these NAS cases. Finally, Witt et al. [38] evaluated long-term childhood and infant mortality involving 1900 individuals diagnosed with NAS and 12,283 controls. The results indicated that NAS-diagnosed children were readmitted to the hospital within five years of life more frequently when compared to non-NAS controls. Most perplexing was the finding that in NAS patients there was an unadjusted significant increased mortality risk ratio of 1.94 (95% CI 0.99–3.80). Witt and associates [38] concluded that childhood readmission due to NAS “argues” for innovative (possibly nonpharmacological) early interventions to prevent morbidity and possibly mortality.

4. A Case in Favor of Non-Opioid Treatment in NAS

Opioid pharmacokinetics are influenced in neonates by a higher body water content that can alter drug distribution and metabolic processes that are not mature and can lead to low plasma protein and liver enzyme activity. For example, these factors could affect cleared metabolites, resulting in a prolonged half-life of opioids. This is further complicated by reduced renal excretion, which might be due to immature tubular secretion, glomerular filtration, and reabsorption [39]. In addition, animal experiments have shown that an immature blood–brain barrier in neonates may result in an augmented sensitivity to opioids [40].
An argument against the utilization of opioids to treat NAS has been espoused by some investigators globally [41][42][43][44], and a word search for “acupuncture and NAS” revealed 102 PubMed listings (26 January 2022). Following an extensive review of the literature, including the Cochrane Databases, Jackson et al. [41] reported that acupuncture is a safe and effective nonpharmacological alternative to potent opioids for the treatment of NAS.
If further confirmed in more extensive studies, using nutraceutical complex prodopaminergic regulator (KB220Z) for opiate/opioid detoxification may provide a novel way to eliminate the need for addictive opioids during withdrawal and detoxification. This paradigm shift, which requires extensive research, may translate to a reduction in universally employing powerful and addictive opioids to treat OUD and NAS [45].

5. Snapshot of Dopaminergic Mechanisms in Addiction

As Poisson et al. [46] pointed out, most of the brain’s dopamine neurons are in two midbrain regions: the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc). Others revealed that DA neurons in the VTA mainly project to the ventral striatum, specifically the nucleus accumbens (NAc) core and shell. The NAc shell comprises the mesostriatal pathway and links to certain frontal regions in the prefrontal cortex, pallidum, and amygdala [47][48]. The work of Nestler’s group [49] and others [50][51] has shown that DA neurons in the VTA intermingle with GABAergic (gamma-aminobutyric acid (GABA)) and nd glutamatergic neurons. In contrast, the SNc DA neurons project to the dorsomedial (DMS) and dorsolateral (DLS) striatum almost exclusively and comprise a well-known nigrostriatal system [52][53][54]. Importantly, in the striatum, Gerfen [55] showed that DA neurons contact GABAergic medium spiny neurons (MSNs) that contain excitatory type 1 (D1-MSNs) or inhibitory type 2 (D2-MSNs) DA receptors. Kupchik et al. [56] have further confirmed this work. The primary role of DA’s modulatory effect on striatal activity due to these outputs involves the control of specific behaviors (such as motivation and reward learning). It is indeed well known that most highly addictive psychoactive drugs (such as cocaine, alcohol, and morphine) cause the release of DA in the NAc and other striatal regions. According to Collins and Saunders [57], based on terminal mechanisms, DA release may play an essential role in many infractions related to aberrant drug use and cravings and even drug reinstatement or relapse, the cornerstone of unwanted SUD [58][59][60][61][62]. A review of the literature revealed that DA neurons across the VTA and SNc circuitry impact a wide array of behavioral functions, showing significant overlap or co-occurrence across many reward-related behaviors [63][64][65][66]. Mesostriatal DA neurons contribute to the execution of goal-directed behaviors and learning. However, nigrostriatal DA, specifically in the DLS, impacts movement control and even the execution of rigid habitual actions that translate to addiction heterogeneity [67][68][69][70][71][72]. It is important to recognize that DA has a powerful effect on many behaviors that, when impaired, induce in the reward circuitry maladapted dysfunctional behaviors and addiction, including poor decision making, a prominent underpinning of compulsive behaviors [73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104].

6. Evidence-Based Prodopaminergic Regulation (KB220)

Genetic polymorphisms of the catechol-o-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genes appear to affect the length of stay and the need for pharmacotherapy in newborns with prenatal opioid exposure [105]. These findings are consistent with data from adult studies that demonstrated that variations in these genes are associated with adult opioid dependence variability [106]. Epigenetic modifications to the OPRM1 gene have also been linked to the severity of NAS [107]. Thus, it appears prudent to incorporate genetic testing in order to reveal reward circuitry gene polymorphisms, especially those associated with dopaminergic pathways and opioid receptors, as a means of improving NAS treatment outcomes [108].
In the most recent reiteration, additional nutrients have been added to the formula, such as β-nicotinamide adenine dinucleotide (β-NAD) to function as a catalyst for dopamine synthesis [109] and N-acetyl-cysteine [110] to help promote glutaminergic drive in the VTA to release DA in the NAc.
The neurological effects of precision amino-acid enkephalinase inhibition therapy (KB220)  in naïve rodents, uncovered in studies conducted by Marcelo Febo [111], showed blood oxygen level dependent (BOLD) activation using KB220 in regions of interest related to the brain reward circuitry. Specifically, there was a significant increase in the functional connectivity of the NAc with the medial and lateral anterior thalamic nucleus and the surrounding somatosensory cortex. Another important finding revealed that KB220Z augmented the connectivity between corticothalamic areas and this region of the reward system.
Additionally, with KB220Z vs. placebo, when the anterior thalamic nucleus was the selected seed RIO, there was minimal evidence of connectivity observed outside this area. Febo et al. [111] found a significant enhancement in connectivity with surrounding sensory cortical areas and the regions mentioned above, including the NAc (both left and right). A more substantial effect on the resting state functional connectivity (rsFC) in the dorsal hippocampus was of real interest. Furthermore, connectivity was increased between the left and right dorsal hippocampi, the upper limb somatosensory regions, the NAc and limbic cortical areas, and the anterior cingulate.
A follow-up study utilizing KB220Z was also administered to abstinent Chinese heroin abusers to help map the brain reward circuitry interaction potential in humans. Along these lines, it is noteworthy that Willuhn et al. [112] reported that cocaine use and even non-substance-related addictive behavior surge as dopaminergic function is decreased. Understanding that reduced or deficient levels of brain DA enhance heroin-seeking behavior. Treatment strategies, including a DA agonist therapy that conserves dopamine function, could prevent relapse to opioids.
The effect of KB220Z on the reward circuitry of ten heroin addicts undergoing protracted abstinence for an average of 16.9 months was investigated [113]. Specifically, in a randomized, placebo-controlled crossover study of KB220Z, five subjects completed the triple-blinded experiment. Additionally, nine patients were genotyped utilizing the genetic addiction risk severity (GARS) test.
KB220Z induced an enhanced BOLD activation in caudate–accumbens–dopaminergic pathways compared to placebo following a one-hour acute administration. Moreover, KB220Z also attenuated the resting state activity in the putamen of abstinent heroin-dependent subjects. In the second phase of this preliminary investigation of all ten abstinent heroin-dependent patients, three brain regions of interest were significantly activated from the resting state by KB220Z compared to placebo.
Interestingly, augmented functional connectivity was observed in a putative network that included the cerebellum, medial frontal gyrus, dorsal anterior cingulate, NAc, occipital cortical area, and posterior cingulate. These results and other qEEG studies [114][115] support the notion of a putative anticraving/anti-relapse role for KB220Z in opioid dependence by direct or indirect dopaminergic interaction.
Preclinical experiments and human trials associated with KB220 variants have been published and reviewed [116]. Early formulations of KB220 increased brain enkephalin levels in rodents [112], reduced alcohol-seeking behavior in C57/BL mice [113], and converted ethanol-preferring C57/BL mice via pharmacogenetics to the same level of nonpreference as alcohol-averse DBA mice [112]. Thus, based on these and other animal and human studies [114][115][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147], using KB220Z might be an ideal treatment for NAS, particularly to counteract underlying brain hypodopaminergia.

7. Common Neurochemical Mechanisms Related to Alcohol and Opiate/Opioid-Induced Withdrawal Symptomatology

Wallace et al. [148] reported that as many as 47% of pregnant women misuse/abuse alcohol, and at least 6% misuse or abuse illegal drugs such as opioids. The European Monitoring Centre for Drugs and Drug Addiction has noted that approximately 500 thousand opioid-dependent Europeans are, unfortunately, on opioid maintenance substitution therapy (OMST) [149]. It is indeed a fact that about 30,000 opioid-dependent women have become pregnant [150]. The treatment of women involved with a combination of alcohol and opioid dependence is very complex and is a challenge that must be faced to attenuate the onslaught of unwanted NAS [151][152].
Since the early 1970s, Blum’s group has investigated the common neurochemical and genetic underpinnings of all addictive behaviors. One area of investigation by this group was a common mechanism among opiates, alcohol, and neurotransmitter involvement in withdrawal symptomology—the commonality concept related to condensation products derived from the identification of in vivo isoquinoline formation. There is enough evidence to suggest that these condensation amines “link” to opiates. The message here is that when one imbibes alcohol, opiate-like isoquinolines are formed [153]. These isoquinolines induce a robust enhancement of ethanol-induced withdrawal symptoms (EIW) [154]. For example, a series of experiments revealed that the inhibition of catecholamine synthesis results in the potentiation of EIW [155]; haloperidol, a D2 dopamine receptor (DRD2), potentiates EIW [156]; serotonergic blockers potentiate EIW [157]; dopamine suppresses EIW [158]; morphine suppresses EIW [159][160]; naloxone inhibits alcohol dependence [161]; and clonidine enhances EIW [162][163][164].
Of interest is the finding that by employing quantitative electroencephalography (qEEG) as an imaging tool, Miller et al. [131] showed the impact of one formulation of KB220 as a putative activator of the mesolimbic system. These investigators [131] found that intravenous administration reduces or “normalizes” aberrant electrophysiological parameters of the brain reward circuitry region. Specifically, KB220 significantly normalized widespread theta and alpha activity in alcoholics and heroin abusers, showing several neurotransmitter-linked polymorphic genes measured by the GARS test. The authors [131] suggested that the chronic activation of dopaminergic receptors, such as DRD2, will increase upregulation, induce an augmented “dopamine sensitivity,” and ultimately “enhance the sense of happiness,” specifically, for example, in carriers of the DRD2 A1 allele.

References

  1. Velez, M.; Jansson, L.M. The Opioid Dependent Mother and Newborn Dyad: Nonpharmacologic Care. J. Addict. Med. 2008, 2, 113–120.
  2. Patrick, S.W.; Barfield, W.D.; Poindexter, B.B.; Committee on Fetus and Newborn, Committee on Substance Use and Prevention. Neonatal Opioid Withdrawal Syndrome. Pediatrics 2020, 146, e2020029074.
  3. Howard, M.B.; Schiff, D.M.; Penwill, N.; Si, W.; Rai, A.; Wolfgang, T.; Moses, J.M.; Wachman, E.M. Impact of Parental Presence at Infants’ Bedside on Neonatal Abstinence Syndrome. Hosp. Pediatr. 2017, 7, 63–69.
  4. Zankl, A.; Martin, J.; Davey, J.G.; Osborn, D.A. Opioid treatment for opioid withdrawal in newborn infants. Cochrane Database Syst. Rev. 2021, 2021, CD002059.
  5. Macmillan, K.D.L.; Rendon, C.P.; Verma, K.; Riblet, N.; Washer, D.B.; Holmes, A.V. Association of Rooming-in with Outcomes for Neonatal Abstinence Syndrome. JAMA Pediatr. 2018, 172, 345–351.
  6. Abrahams, R.R.; Kelly, S.A.; Payne, S.; Thiessen, P.N.; Mackintosh, J.; Janssen, P.A. Rooming-in compared with standard care for newborns of mothers using methadone or heroin. Can. Fam. Physician 2007, 53, 1722–1730.
  7. Academy of Breastfeeding Medicine Protocol Committee; Jansson, L.M. ABM Clinical Protocol #21: Guidelines for Breastfeeding and the Drug-Dependent Woman. Breastfeed. Med. 2009, 4, 225–228.
  8. Sachs, H.C.; Frattarelli, D.A.C.; Galinkin, J.L.; Green, T.P.; Johnson, T.; Neville, K.; Paul, I.M.; Anker, J.V.D.; Committee on Drugs. The Transfer of Drugs and Therapeutics Into Human Breast Milk: An Update on Selected Topics. Pediatrics 2013, 132, e796–e809.
  9. Favara, M.T.; Carola, D.; Jensen, E.; Cook, A.; Genen, L.; Dysart, K.; Greenspan, J.S.; Aghai, Z.H. Maternal breast milk feeding and length of treatment in infants with neonatal abstinence syndrome. J. Perinatol. 2019, 39, 876–882.
  10. Jansson, L.M.; Choo, R.; Velez, M.L.; Harrow, C.; Schroeder, J.R.; Shakleya, D.M.; Huestis, M.A. Methadone Maintenance and Breastfeeding in the Neonatal Period. Pediatrics 2008, 121, 106–114.
  11. Abdel-Latif, M.E.; Pinner, J.; Clews, S.; Cooke, F.; Lui, K.; Oei, J. Effects of Breast Milk on the Severity and Outcome of Neonatal Abstinence Syndrome Among Infants of Drug-Dependent Mothers. Pediatrics 2006, 117, e1163–e1169.
  12. Isemann, B.; Meinzen-Derr, J.; Akinbi, H. Maternal and neonatal factors impacting response to methadone therapy in infants treated for neonatal abstinence syndrome. J. Perinatol. 2011, 31, 25–29.
  13. Welle-Strand, G.K.; Skurtveit, S.; Jansson, L.M.; Bakstad, B.; Bjarkø, L.; Ravndal, E. Breastfeeding reduces the need for withdrawal treatment in opioid-exposed infants. Acta Paediatr. 2013, 102, 1060–1066.
  14. Ilett, K.F.; Hackett, L.P.; Gower, S.; Doherty, D.A.; Hamilton, D.; Bartu, A.E. Estimated Dose Exposure of the Neonate to Buprenorphine and Its Metabolite Norbuprenorphine via Breastmilk During Maternal Buprenorphine Substitution Treatment. Breastfeed. Med. 2012, 7, 269–274.
  15. Jansson, L.M.; Spencer, N.; McConnell, K.; Velez, M.; Tuten, M.; Harrow, C.A.; Jones, H.E.; Swortwood, M.J.; Barnes, A.J.; Scheidweiler, K.B.; et al. Maternal Buprenorphine Maintenance and Lactation. J. Hum. Lact. 2016, 32, 675–681.
  16. Kaltenbach, K.; O’Grady, K.E.; Heil, S.H.; Salisbury, A.L.; Coyle, M.G.; Fischer, G.; Martin, P.R.; Stine, S.; Jones, H.E. Prenatal exposure to methadone or buprenorphine: Early childhood developmental outcomes. Drug Alcohol Depend. 2018, 185, 40–49.
  17. Hall, E.S.; Wexelblatt, S.L.; Crowley, M.; Grow, J.L.; Jasin, L.R.; Klebanoff, M.A.; McClead, R.E.; Meinzen-Derr, J.; Mohan, V.K.; Stein, H.; et al. A Multicenter Cohort Study of Treatments and Hospital Outcomes in Neonatal Abstinence Syndrome. Pediatrics 2014, 134, e527–e534.
  18. Zimmermann, U.; On behalf of the Swiss neonatal abstinence syndrome study group; Rudin, C.; Duò, A.; Held, L.; Bucher, H.U. Treatment of opioid withdrawal in neonates with morphine, phenobarbital, or chlorpromazine: A randomized double-blind trial. Eur. J. Pediatr. 2019, 179, 141–149.
  19. Osborn, D.A.; Jeffery, H.E.; Cole, M.J. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database Syst. Rev. 2010, CD002059.
  20. Davis, J.M.; Shenberger, J.; Terrin, N.; Breeze, J.L.; Hudak, M.; Wachman, E.M.; Marro, P.; Oliveira, E.L.; Harvey-Wilkes, K.; Czynski, A.; et al. Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial. JAMA Pediatr. 2018, 172, 741–748.
  21. Tolia, V.N.; Murthy, K.; Bennett, M.M.; Greenberg, R.G.; Benjamin, D.K.; Smith, P.B.; Clark, R.H. Morphine vs Methadone Treatment for Infants with Neonatal Abstinence Syndrome. J. Pediatr. 2018, 203, 185–189.
  22. Kraft, W.K. Buprenorphine in Neonatal Abstinence Syndrome. Clin. Pharmacol. Ther. 2017, 103, 112–119.
  23. Kraft, W.K.; Adeniyi-Jones, S.C.; Chervoneva, I.; Greenspan, J.S.; Abatemarco, D.; Kaltenbach, K.; Ehrlich, M.E. Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome. N. Engl. J. Med. 2017, 376, 2341–2348.
  24. Disher, T.; Gullickson, C.; Singh, B.; Cameron, C.; Boulos, L.; Beaubien, L.; Campbell-Yeo, M. Pharmacological Treatments for Neonatal Abstinence Syndrome. JAMA Pediatr. 2019, 173, 234.
  25. Cleary, B.J.; Donnelly, J.; Strawbridge, J.; Gallagher, P.J.; Fahey, T.; Clarke, M.; Murphy, D.J. Methadone dose and neonatal abstinence syndrome-systematic review and meta-analysis. Addiction 2010, 105, 2071–2084.
  26. Bakstad, B.; Sarfi, M.; Welle-Strand, G.K.; Ravndal, E. Opioid Maintenance Treatment during Pregnancy: Occurrence and Severity of Neonatal Abstinence Syndrome: A national prospective study. Eur. Addict. Res. 2009, 15, 128–134.
  27. Streetz, V.N.; Gildon, B.L.; Thompson, D.F. Role of Clonidine in Neonatal Abstinence Syndrome. Ann. Pharmacother. 2016, 50, 301–310.
  28. Merhar, S.L.; Ounpraseuth, S.; Devlin, L.A.; Poindexter, B.B.; Young, L.W.; Berkey, S.D.; Crowley, M.; Czynski, A.J.; Kiefer, A.S.; Whalen, B.L.; et al. Phenobarbital and Clonidine as Secondary Medications for Neonatal Opioid Withdrawal Syndrome. Pediatrics 2021, 147, e2020017830.
  29. Bio, L.L.; Siu, A.; Poon, C.Y. Update on the pharmacologic management of neonatal abstinence syndrome. J. Perinatol. 2011, 31, 692–701.
  30. Forcelli, P.; Janssen, M.J.; Stamps, L.A.; Sweeney, C.; Vicini, S.; Gale, K. Therapeutic strategies to avoid long-term adverse outcomes of neonatal antiepileptic drug exposure. Epilepsia 2010, 51, 18–23.
  31. Forcelli, P.A.; Kim, J.; Kondratyev, A.; Gale, K. Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain. Epilepsia 2011, 52, e207–e211.
  32. Forcelli, P.A.; Kozlowski, R.; Snyder, C.; Kondratyev, A.; Gale, K. Effects of Neonatal Antiepileptic Drug Exposure on Cognitive, Emotional, and Motor Function in Adult Rats. J. Pharmacol. Exp. Ther. 2012, 340, 558–566.
  33. Piccotti, L.; Voigtman, B.; Vongsa, R.; Nellhaus, E.M.; Rodriguez, K.J.; Davies, T.H.; Quirk, S. Neonatal Opioid Withdrawal Syndrome: A Developmental Care Approach. Neonatal Netw. 2019, 38, 160–169.
  34. Czynski, A.J.; Davis, J.M.; Dansereau, L.M.; Engelhardt, B.; Marro, P.; Bogen, D.L.; Hudak, M.L.; Shenberger, J.; Wachman, E.M.; Oliveira, E.L.; et al. Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome. J. Pediatr. 2020, 219, 146–151.e1.
  35. Haight, S.C.; Ko, J.Y.; Tong, V.T.; Bohm, M.K.; Callaghan, W.M. Opioid use disorder documented at delivery hospitalization—United States, 1999–2014. Morb. Mortal. Wkly. Rep. 2018, 67, 845–849.
  36. Boardman, J.P.; Mactier, H.; Devlin, L.A. Opioids and the developing brain: Time to rethink perinatal care for infants of opioid-dependent mothers. Arch. Dis. Child. Fetal Neonatal Ed. 2021, 107, 98–104.
  37. Hoogen, N.J.V.D.; Kwok, C.H.T.; Trang, T. Identifying the Neurodevelopmental Differences of Opioid Withdrawal. Cell Mol. Neurobiol. 2021, 41, 1145–1155.
  38. Witt, C.E.; Rudd, K.; Bhatraju, P.; Rivara, F.P.; Hawes, S.E.; Weiss, N.S. Neonatal abstinence syndrome and early childhood morbidity and mortality in Washington state: A retrospective cohort study. J. Perinatol. 2017, 37, 1124–1129.
  39. Lu, H.; Rosenbaum, S. Developmental Pharmacokinetics in Pediatric Populations. J. Pediatr. Pharmacol. Ther. 2014, 19, 262–276.
  40. Kerui, G.; Jasmin, L. Dual effects of brain sparing opioid in newborn rats: Analgesia and hyperalgesia. Neurobiol. Pain 2018, 3, 1–7.
  41. Jackson, H.J.; Lopez, C.; Miller, S.; Engelhardt, B. A Scoping Review of Acupuncture as a Potential Intervention for Neonatal Abstinence Syndrome. Med. Acupunct. 2019, 31, 69–84.
  42. Filippelli, A.C.; White, L.F.; Spellman, L.W.; Broderick, M.; Highfield, E.S.; Sommers, E.; Gardiner, P. Non-insertive Acupuncture and Neonatal Abstinence Syndrome: A Case Series from an Inner-city Safety Net Hospital. Glob. Adv. Health Med. 2012, 1, 48–52.
  43. Mangat, A.; Schmölzer, G.; Kraft, W. Pharmacological and non-pharmacological treatments for the Neonatal Abstinence Syndrome (NAS). Semin. Fetal Neonatal Med. 2019, 24, 133–141.
  44. Brocato, B.; Lewis, D.; Eyal, F.; Baker, S.; Armistead, C.; Kaye, A.D.; Cornett, E.M.; Whitehurst, R.M. The Impact of a Prenatal Education Program for Opioid-Dependent Mothers on Breastfeeding Rates of Infants at Risk for Neonatal Abstinence Syndrome. Adv. Ther. 2022, 39, 3104–3111.
  45. Blum, K.; Trachtenberg, M.C.; Ramsay, J.C. Improvement of Inpatient Treatment of the Alcoholic as a Function of Neurotransmitter Restoration: A Pilot Study. Int. J. Addict. 1988, 23, 991–998.
  46. Poisson, C.L.; Engel, L.; Saunders, B.T. Dopamine Circuit Mechanisms of Addiction-Like Behaviors. Front. Neural Circuits 2021, 15, 752420.
  47. Swanson, L. The projections of the ventral tegmental area and adjacent regions: A combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res. Bull. 1982, 9, 321–353.
  48. Ikemoto, S. Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accum-bens-olfactory tubercle complex. Brain Res. Rev. 2007, 56, 27–78.
  49. Olson, V.G.; Nestler, E.J. Topographical organization of GABAergic neurons within the ventral tegmental area of the rat. Synapse 2007, 61, 87–95.
  50. Nair-Roberts, R.; Chatelain-Badie, S.; Benson, E.; White-Cooper, H.; Bolam, J.; Ungless, M. Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat. Neuroscience 2008, 152, 1024–1031.
  51. Bouarab, C.; Thompson, B.; Polter, A.M. VTA GABA Neurons at the Interface of Stress and Reward. Front. Neural Circuits 2019, 13, 78.
  52. Beckstead, R.M.; Domesick, V.B.; Nauta, W.J. Efferent connections of the substantia nigra and ventral tegmental area in the rat. Brain Res. 1979, 175, 191–217.
  53. Fields, H.L.; Hjelmstad, G.O.; Margolis, E.B.; Nicola, S.M. Ventral Tegmental Area Neurons in Learned Appetitive Behavior and Positive Reinforcement. Annu. Rev. Neurosci. 2007, 30, 289–316.
  54. Britt, J.P.; Benaliouad, F.; McDevitt, R.A.; Stuber, G.D.; Wise, R.A.; Bonci, A. Synaptic and Behavioral Profile of Multiple Glutamatergic Inputs to the Nucleus Accumbens. Neuron 2012, 76, 790–803.
  55. Gerfen, C.R. D1 Dopamine Receptor Supersensitivity in the Dopamine-Depleted Striatum Animal Model of Parkinson’s Disease. Neuroscientist 2003, 9, 455–462.
  56. Kupchik, Y.M.; Brown, R.; Heinsbroek, J.; Lobo, M.K.; Schwartz, D.J.; Kalivas, P.W. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections. Nat. Neurosci. 2015, 18, 1230–1232.
  57. Collins, A.L.; Saunders, B.T. Heterogeneity in striatal dopamine circuits: Form and function in dynamic reward seeking. J. Neurosci. Res. 2020, 98, 1046–1069.
  58. Koob, G.F.; Bloom, F.E. Cellular and Molecular Mechanisms of Drug Dependence. Science 1988, 242, 715–723.
  59. Ahmed, S.H.; Koob, G.F. Transition from Moderate to Excessive Drug Intake: Change in Hedonic Set Point. Science 1998, 282, 298–300.
  60. Lobo, M.K.; Covington, H.E.; Chaudhury, D.; Friedman, A.K.; Sun, H.; Damez-Werno, D.; Dietz, D.M.; Zaman, S.; Koo, J.W.; Kennedy, P.J.; et al. Cell Type–Specific Loss of BDNF Signaling Mimics Optogenetic Control of Cocaine Reward. Science 2010, 330, 385–390.
  61. Thompson, D.; Martini, L.; Whistler, J.L. Altered Ratio of D1 and D2 Dopamine Receptors in Mouse Striatum Is Associated with Behavioral Sensitization to Cocaine. PLoS ONE 2010, 5, e11038.
  62. Oliver, R.J.; Purohit, D.C.; Kharidia, K.M.; Mandyam, C.D. Transient Chemogenetic Inhibition of D1-MSNs in the Dorsal Striatum Enhances Methamphetamine Self-Administration. Brain Sci. 2019, 9, 330.
  63. Björklund, A.; Dunnett, S. Dopamine neuron systems in the brain: An update. Trends Neurosci. 2007, 30, 194–202.
  64. Lammel, S.; Lim, B.K.; Malenka, R.C. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 2014, 76, 351–359.
  65. Morales, M.; Margolis, E.B. Ventral tegmental area: Cellular heterogeneity, connectivity and behaviour. Nat. Rev. Neurosci. 2017, 18, 73–85.
  66. Cox, J.; Witten, I.B. Striatal circuits for reward learning and decision-making. Nat. Rev. Neurosci. 2019, 20, 482–494.
  67. Haber, S.N.; Fudge, J.L.; McFarland, N.R. Striatonigrostriatal Pathways in Primates Form an Ascending Spiral from the Shell to the Dorsolateral Striatum. J. Neurosci. 2000, 20, 2369–2382.
  68. Hassani, O.K.; Cromwell, H.; Schultz, W. Influence of Expectation of Different Rewards on Behavior-Related Neuronal Activity in the Striatum. J. Neurophysiol. 2001, 85, 2477–2489.
  69. Everitt, B.J. Neural and psychological mechanisms underlying compulsive drug seeking habits and drug memories—Indications for novel treatments of addiction. Eur. J. Neurosci. 2014, 40, 2163–2182.
  70. Everitt, B.J.; Robbins, T. Neural systems of reinforcement for drug addiction: From actions to habits to compulsion. Nat. Neurosci. 2005, 8, 1481–1489.
  71. Wise, R.A. Forebrain substrates of reward and motivation. J. Comp. Neurol. 2005, 493, 115–121.
  72. Wise, R.A. Roles for nigrostriatal—Not just mesocorticolimbic—Dopamine in reward and addiction. Trends Neurosci. 2009, 32, 517–524.
  73. Berridge, K.C. The debate over dopamine’s role in reward: The case for incentive salience. Psychopharmacology 2007, 191, 391–431.
  74. Flagel, S.B.; Clark, J.J.; Robinson, T.E.; Mayo, L.; Czuj, A.; Willuhn, I.; Akers, C.A.; Clinton, S.M.; Phillips, P.E.M.; Akil, H. A selective role for dopamine in stimulus–reward learning. Nature 2011, 469, 53–57.
  75. Tiffany, S.T. A cognitive model of drug urges and drug-use behavior: Role of automatic and nonautomatic processes. Psychol. Rev. 1990, 97, 147–168.
  76. Willuhn, I.; Burgeno, L.M.; Everitt, B.J.; Phillips, P.E.M. Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use. Proc. Natl. Acad. Sci. USA 2012, 109, 20703–20708.
  77. Willuhn, I.; Burgeno, L.; Groblewski, P.A.; Phillips, P.E.M. Excessive cocaine use results from decreased phasic dopamine signaling in the striatum. Nat. Neurosci. 2014, 17, 704–709.
  78. Ostlund, S.B. The push and pull of dopamine in cue-reward learning. Anim. Learn. Behav. 2019, 47, 273–274.
  79. Ostlund, S.B.; LeBlanc, K.H.; Kosheleff, A.R.; Wassum, K.M.; Maidment, N.T. Phasic Mesolimbic Dopamine Signaling Encodes the Facilitation of Incentive Motivation Produced by Repeated Cocaine Exposure. Neuropsychopharmacology 2014, 39, 2441–2449.
  80. Hogarth, L. Addiction is driven by excessive goal-directed drug choice under negative affect: Translational critique of habit and compulsion theory. Neuropsychopharmacology 2020, 45, 720–735.
  81. Volkow, N.; Fowler, J.; Wang, G.; Baler, R.; Telang, F. Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology 2009, 56, 3–8.
  82. Volkow, N.D.; Wang, G.-J.; Telang, F.; Fowler, J.S.; Logan, J.; Childress, A.-R.; Jayne, M.; Ma, Y.; Wong, C. Cocaine Cues and Dopamine in Dorsal Striatum: Mechanism of Craving in Cocaine Addiction. J. Neurosci. 2006, 26, 6583–6588.
  83. Volkow, N.D.; Wise, R.A.; Baler, R. The dopamine motive system: Implications for drug and food addiction. Nat. Rev. Neurosci. 2017, 18, 741–752.
  84. Wang, Y.-C.; Ho, U.-C.; Ko, M.-C.; Liao, C.-C.; Lee, L.-J. Differential neuronal changes in medial prefrontal cortex, basolateral amygdala and nucleus accumbens after postweaning social isolation. Anat. Embryol. 2012, 217, 337–351.
  85. Vandaele, Y.; Ahmed, S.H. Habit, choice, and addiction. Neuropsychopharmacology 2021, 46, 689–698.
  86. Aarts, E.; van Holstein, M.; Cools, R. Striatal Dopamine and the Interface between Motivation and Cognition. Front. Psychol. 2011, 2, 163.
  87. Bardo, M.T.; Neisewander, J.; Kelly, T.H. Individual Differences and Social Influences on the Neurobehavioral Pharmacology of Abused Drugs. Pharmacol. Rev. 2013, 65, 255–290.
  88. Bello, E.P.; Mateo, Y.; Gelman, D.M.; Noaín, D.; Shin, J.H.; Low, M.J.; Alvarez, V.; Lovinger, D.M.; Rubinstein, M. Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat. Neurosci. 2011, 14, 1033–1038.
  89. Blum, K.; Braverman, E.R.; Holder, J.M.; Lubar, J.F.; Monastra, V.J.; Miller, D.; Lubar, J.O.; Chen, T.J.; Comings, D.E. The Reward Deficiency Syndrome: A Biogenetic Model for the Diagnosis and Treatment of Impulsive, Addictive and Compulsive Behaviors. J. Psychoact. Drugs 2000, 32, 1–112.
  90. Blum, K.; Thanos, P.K.; Oscar-Berman, M.; Febo, M.; Baron, D.; Badgaiyan, R.D.; Gardner, E.; Demetrovics, Z.; Fahlke, C.; Haberstick, B.C.; et al. Dopamine in the Brain: Hypothesizing Surfeit or Deficit Links to Reward and Addiction. J. Reward Defic. Syndr. 2015, 1, 95–104.
  91. Buckholtz, J.W.; Treadway, M.T.; Cowan, R.L.; Woodward, N.D.; Li, R.; Ansari, M.S.; Baldwin, R.M.; Schwartzman, A.N.; Shelby, E.S.; Smith, C.E.; et al. Dopaminergic Network Differences in Human Impulsivity. Science 2010, 329, 532.
  92. Burton, A.C.; Nakamura, K.; Roesch, M.R. From ventral-medial to dorsal-lateral striatum: Neural correlates of reward-guided decision-making. Neurobiol. Learn. Mem. 2015, 117, 51–59.
  93. Di Chiara, G.; Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl. Acad. Sci. USA 1988, 85, 5274–5278.
  94. Griffiths, R.R.; Brady, J.V.; Bradford, L.D. Predicting the Abuse Liability of Drugs with Animal Drug Self-Administration Procedures: Psychomotor Stimulants and Hallucinogens. Adv. Behav. Pharmacol. 1979, 2, 163–208.
  95. Ito, R.; Dalley, J.; Howes, S.R.; Robbins, T.; Everitt, B. Dissociation in Conditioned Dopamine Release in the Nucleus Accumbens Core and Shell in Response to Cocaine Cues and during Cocaine-Seeking Behavior in Rats. J. Neurosci. 2000, 20, 7489–7495.
  96. Ito, R.; Dalley, J.; Robbins, T.; Everitt, B. Dopamine Release in the Dorsal Striatum during Cocaine-Seeking Behavior under the Control of a Drug-Associated Cue. J. Neurosci. 2002, 22, 6247–6253.
  97. Leyton, M. Altered dopamine transmission as a familial risk trait for addictions. Curr. Opin. Behav. Sci. 2017, 13, 130–138.
  98. Leyton, M.; Vezina, P. Dopamine ups and downs in vulnerability to addictions: A neurodevelopmental model. Trends Pharmacol. Sci. 2014, 35, 268–276.
  99. Murray, J.E.; Belin, D.; Everitt, B. Double Dissociation of the Dorsomedial and Dorsolateral Striatal Control Over the Acquisition and Performance of Cocaine Seeking. Neuropsychopharmacology 2012, 37, 2456–2466.
  100. Nutt, D.J.; Lingford-Hughes, A.; Erritzoe, D.; Stokes, P. The dopamine theory of addiction: 40 years of highs and lows. Nat. Rev. Neurosci. 2015, 16, 305–312.
  101. Ray, L.A.; Courtney, K.E.; Hutchison, K.E.; MacKillop, J.; Galvan, A.; Ghahremani, D.G. Initial evidence that OPRM1 genotype moderates ventral and dorsal striatum functional connectivity during alcohol cues. Alcohol. Clin. Exp. Res. 2014, 38, 78–89.
  102. Ritz, M.C.; Lamb, R.J.; Goldberg, S.R.; Kuhar, M.J. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 1987, 237, 1219–1223.
  103. Venniro, M.; Caprioli, D.; Shaham, Y. Animal models of drug relapse and craving: From drug priming-induced rein-statement to incubation of craving after voluntary abstinence. Prog. Brain Res. 2016, 224, 25–52.
  104. Ztaou, S.; Lhost, J.; Watabe, I.; Torromino, G.; Amalric, M. Striatal cholinergic interneurons regulate cognitive and affective dysfunction in partially dopamine-depleted mice. Eur. J. Neurosci. 2018, 48, 2988–3004.
  105. Wachman, E.M.; Hayes, M.J.; Brown, M.S.; Paul, J.; Harvey-Wilkes, K.; Terrin, N.; Huggins, G.S.; Aranda, J.V.; Davis, J.M. Association of OPRM1 and COMT Single-Nucleotide Polymorphisms with Hospital Length of Stay and Treatment of Neonatal Abstinence Syndrome. JAMA 2013, 309, 1821–1827.
  106. Mague, S.D.; Blendy, J.A. OPRM1 SNP (A118G): Involvement in disease development, treatment response, and animal models. Drug Alcohol Depend. 2010, 108, 172–182.
  107. Wachman, E.M.; Hayes, M.J.; Lester, B.M.; Terrin, N.; Brown, M.S.; Nielsen, D.; Davis, J.M. Epigenetic Variation in the Mu-Opioid Receptor Gene in Infants with Neonatal Abstinence Syndrome. J. Pediatr. 2014, 165, 472–478.
  108. Blum, K.; Berman, M.O.; Jacobs, W.; McLaughlin, T.; Gold, M.S. Buprenorphine Response as a Function of Neurogenetic Polymorphic Antecedents: Can Dopamine Genes Affect Clinical Outcomes in Reward Deficiency Syndrome (RDS)? J. Addict. Res. Ther. 2014, 5, 1000185.
  109. Tucker, K.R.; Cavolo, S.L.; Levitan, E.S. Elevated mitochondria-coupled NAD(P)H in endoplasmic reticulum of dopamine neurons. Mol. Biol. Cell 2016, 27, 3214–3220.
  110. Hodebourg, R.; Murray, J.E.; Fouyssac, M.; Puaud, M.; Everitt, B.J.; Belin, D. Heroin seeking becomes dependent on dorsal striatal dopaminergic mechanisms and can be decreased by N-acetylcysteine. Eur. J. Neurosci. 2019, 50, 2036–2044.
  111. Febo, M.; Blum, K.; Badgaiyan, R.D.; Perez, P.D.; Colon-Perez, L.M.; Thanos, P.K.; Ferris, C.F.; Kulkarni, P.; Giordano, J.; Baron, D.; et al. Enhanced functional connectivity and volume between cognitive and reward centers of naïve rodent brain produced by pro-dopaminergic agent KB220Z. PLoS ONE 2017, 12, e0174774.
  112. Blum, K.; Briggs, A.H.; Trachtenberg, M.C.; Delallo, L.; Wallace, J.E. Enkephalinase inhibition: Regulation of ethanol intake in genetically predisposed mice. Alcohol 1987, 4, 449–456.
  113. Blum, K.; Elston, S.F.; DeLallo, L.; Briggs, A.H.; Wallace, J.E. Ethanol acceptance as a function of genotype amounts of brain enkephalin. Proc. Natl. Acad. Sci. USA 1983, 80, 6510–6512.
  114. Brown, R.J.; Blum, K.; Trachtenberg, M.C. Neurodynamics of Relapse Prevention: A Neuronutrient Approach to Outpatient DUI Offenders. J. Psychoact. Drugs 1990, 22, 173–187.
  115. Blum, K.; Trachtenberg, M.C.; Elliott, C.E.; Dingler, M.L.; Sexton, R.L.; Samuels, A.I.; Cataldie, L. Enkephalinase inhibition and precursor amino acid loading improves inpatient treatment of alcohol and polydrug abusers: Double-blind placebo-controlled study of the nutri-tional adjunct SAAVE. Alcohol 1988, 5, 481–493.
  116. Blum, K.; Modestino, E.J.; Gondre-Lewis, M.C.; Baron, D.; Thanos, P.K.; Downs, B.W.; Siwicki, D.; Lott, L.; Braverman, E.R.; Moran, M.; et al. Dopamine Regulator (KB220) A Fifty Year Sojourn to Combat Reward Deficiency Syndrome (RDS): Evidence Based Bibliography (Annotated). CPQ Neurol. Psychol. 2018, 1, 2.
  117. Blum, K.; Allison, D.; Trachtenberg, M.C.; Williams, R.W. Reduction of both drug hunger and withdrawal against advice rate of cocaine abusers in a 30-day inpatient treatment program by the neuronutrient Tropamine. Curr. Ther. Res. 1988, 43, 1204–1214.
  118. Blum, K.; Trachtenberg, M.C.; Cook, D.W. Neuronutrient effects on weight loss in carbohydrate bingers; an open clinical trial. Curr. Ther. Res. 1990, 48, 217–233.
  119. Cold, J.A. NeuRecover-SATM in the Treatment of Cocaine Withdrawal and Craving: A Pilot Study Clin. Drug Investig. 1996, 12, 1.
  120. DeFrance, J.F.; Hymel, C.; Trachtenberg, M.C.; Ginsberg, L.D.; Schweitzer, F.C.; Estes, S.; Chen, T.J.; Braverman, E.R.; Cull, J.G.; Blum, K. Enhancement of attention pro-cessing by Kantroll in healthy humans: A pilot study. Clin. Electroencephalogr. 1997, 28, 68–75.
  121. Chen, T.J.H.; Blum, K.; Payte, J.T.; Schoolfield, J.; Hopper, D.; Stanford, M.; Braverman, E.R. Narcotic antagonists in drug dependence: Pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy. Med. Hypotheses 2004, 63, 538–548.
  122. Blum, K.; Chen, T.J.; Meshkin, B.; Downs, B.W.; Gordon, C.A.; Blum, S.; Mengucci, J.F.; Braverman, E.R.; Arcuri, V.; Varshavskiy, M.; et al. Reward deficiency syndrome in obesity: A pre-liminary cross-sectional trial with a Genotrim variant. Adv. Ther. 2006, 23, 1040–1051.
  123. Chen, T.J.H.; Blum, K.; Waite, R.L.; Meshkin, B.; Schoolfield, J.; Downs, B.W.; Braverman, E.E.; Arcuri, V.; Varshavskiy, M.; Blum, S.H.; et al. Gene\Narcotic Attenuation Program attenuates substance use disorder, a clinical subtype of reward deficiency syndrome. Adv. Ther. 2007, 24, 402–414.
  124. Blum, K.; Chen, T.J.H.; Downs, B.W.; Meshkin, B.; Blum, S.H.; Martinez Pons, M. Synaptamine (SG8839), TM an Ami-no-Acid Enkephalinase Inhibition Nutraceutical Improves Recovery of Alcoholics, A Subtype of Reward Deficiency Syndrome (RDS). Trends Appl. Sci. Res. 2007, 2, 132–138.
  125. Chen, T.J.; Blum, K.; Kaats, G.; Braverman, E.R.; Eisenberg, A.; Sherman, M.; Davis, K.; Comings, D.E.; Wood, R.; Pullin, D.; et al. Chromium Picolinate (Crp) A putative An-ti-Obesity Nutrient Induces Changes in Body Composition as Function Of The Taq1 Dopamine D2 Receptor Gene. Gene Ther. Mol. Biol. 2007, 11, 161–170.
  126. Blum, K.; Chen, T.J.; Williams, L.; Chen, A.L.; Downs, W.B.; Waite, R.L.; Huntington, T.; Sims, S.; Prihoda, R.; Reinking, J.; et al. A short term pilot open label study to evaluate efficacy and safety of LG839, a customized DNA directed nutraceutical in obesity: Exploring Nutrigenomics. Gene Ther. Mol. Biol. 2008, 12, 371–382.
  127. Blum, K.; Chen, A.L.C.; Chen, T.J.H.; Rhoades, P.; Prihoda, T.J.; Downs, B.W.; Waite, R.L.; Williams, L.; Braverman, E.R.; Braverman, D.; et al. LG839: Anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome. Adv. Ther. 2008, 25, 894–913.
  128. Blum, K.; Chen, T.J.; Chen, A.L.; Rhoades, P.; Prihoda, T.J.; Downs, B.W.; Bagchi, D.; Bagchi, M.; Blum, S.H.; Williams, L.; et al. Dopamine D2 Receptor Taq A1 allele predicts treatment compliance of LG839 in a subset analysis of pilot study in the Netherlands. Gene Ther. Mol. Biol. 2008, 12, 129–140.
  129. Blum, K.; Chen, A.L.; Chen, T.J.; Bowirrat, A.; Waite, R.L.; Kerner, M.; Blum, S.H.; Downs, B.W.; Savarimuthu, S.; Rhoades, P.; et al. Putative targeting of Dopamine D2 receptor function in Reward Deficiency Syndrome (RDS) by Synaptamine Complex™ Variant (KB220): Clinical trial showing anti anxiety effects. Gene Ther. Mol. Biol. 2009, 13, 214–230.
  130. Braverman, E.R.; Braverman, D.; Acrui, V.; Kerner, M.; Downs, B.W.; Blum, K. Targeting noradrenergic and dopaminergic mechanistic sites, hormonal deficiency repletion therapy and exercise: A case report. Am. J. Bariatr. Med. 2010, 25, 18–28.
  131. Miller, D.K.; Bowirrat, A.; Manka, M.; Miller, M.; Stokes, S.; Manka, D.; Allen, C.; Gant, C.; Downs, B.W.; Smolen, A.; et al. Acute intravenous synaptamine complex variant KB220™ “normalizes” neurological dysregulation in patients during protracted abstinence from alcohol and opiates as ob-served using quantitative electroencephalographic and genetic analysis for reward polymorphisms: Part 1, pilot study with 2 case reports. Postgrad Med. 2010, 122, 188–213.
  132. Blum, K.; Chen, T.J.H.; Morse, S.; Giordano, J.; Chen, A.L.C.; Thompson, J.; Allen, C.; Smolen, A.; Lubar, J.; Stice, E.; et al. Overcoming qEEG Abnormalities and Reward Gene Deficits during Protracted Abstinence in Male Psychostimulant and Polydrug Abusers Utilizing Putative Dopamine D2Agonist Therapy: Part 2. Postgrad. Med. 2010, 122, 214–226.
  133. Chen, D.; Liu, Y.; He, W.; Wang, H.; Wang, Z. Neurotransmitter-precursor-supplement intervention for detoxified heroin addicts. J. Huazhong Univ. Sci. Technol. 2012, 32, 422–427.
  134. Miller, M.; Chen, A.L.; Stokes, S.D.; Silverman, S.; Bowirrat, A.; Manka, M.; Manka, D.; Miller, D.K.; Perrine, K.; Chen, T.J.; et al. Early Intervention of Intravenous KB220IV- Neuroadaptagen Amino-Acid Therapy (NAAT)™ Improves Behavioral Outcomes in a Residential Addiction Treatment Program: A Pilot Study. J. Psychoact. Drugs 2012, 44, 398–409.
  135. Blum, K.; Oscar-Berman, M.; Femino, J.; Waite, R.L.; Benya, L.; Giordano, J.; Borsten, J.; Downs, W.B.; Braverman, E.R.; Loehmann, R.; et al. Withdrawal from Buprenorphine/Naloxone and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note. J. Addict. Res. Ther. 2013, 4, 2–11.
  136. McLaughlin, T.; Blum, K.; Berman, M.O.; Febo, M.; Agan, G.; Fratantonio, J.L.; Simpatico, T.; Gold, M.S. Putative dopamine agonist (KB220Z) attenuates lucid nightmares in PTSD patients: Role of enhanced brain reward functional connectivity and homeostasis redeeming joy. J. Behav. Addict. 2015, 4, 106–115.
  137. McLaughlin, T.; Blum, K.; Oscar-Berman, M.; Febo, M.; Demetrovics, Z.; Agan, G.; Fratantonio, J.; Gold, M.S. Using the Neuroadaptagen KB200z™ to Ameliorate Terrifying, Lucid Nightmares in RDS Patients: The Role of Enhanced, Brain-Reward, Functional Connectivity and Dopaminergic Homeostasis. J. Reward Defic. Syndr. 2015, 1, 24–35.
  138. McLaughlin, T.; Febo, M.; Badgaiyan, R.D.; Barh, D.; Dushaj, K.; Braverman, E.R.; Li, M.; Madigan, M.A.; Blum, K. KB220Z a Pro-Dopamine Regulator Associated with the Protracted, Alleviation of Terrifying Lucid Dreams. Can We Infer Neuroplasticity-induced Changes in the Reward Circuit? J. Reward Defic. Syndr. Addict. Sci. 2017, 2, 3–13.
  139. McLaughlin, T.; Han, D.; Nicholson, J.; Steinberg, B.; Blum, K.; Febo, M.; Braverman, E.; Li, M.; Fried, L.; Badgaiyan, R. Improvement of long-term memory access with a pro-dopamine regulator in an elderly male: Are we targeting dopamine tone? J. Syst. Integr. Neurosci. 2017, 3, 1–7.
  140. Steinberg, B.; Blum, K.; McLaughlin, T.; Lubar, J.; Febo, M.; Braverman, E.R.; Badgaiyan, R.D. Low-Resolution Electromagnetic Tomog-raphy (LORETA) of changed Brain Function Provoked by Pro Dopamine Regulator (KB220z) in one Adult ADHD case. Open J. Clin. Med. Case Rep. 2016, 2, 11.
  141. Duquette, L.L.; Mattiace, F.; Blum, K.; Waite, R.L.; Boland, T.; McLaughlin, T.; Dushaj, K.; Febo, M.; Badgaiyan, R.D. Neurobiology of KB220Z-Glutaminergic-Dopaminergic Optimization Complex as a Liquid Nano: Clinical Activation of Brain in a Highly Functional Clinician Improving Focus, Motivation and Overall Sensory Input Following Chronic Intake. Clin. Med. Rev. Case Rep. 2016, 3, 1410104.
  142. Mclaughlin, T.; Oscar-Berman, M.; Simpatico, T.; Giordano, J.; Jones, S.; Barh, D.; Downs, W.B.; Waite, R.L.; Madigan, M.; Dushaj, K.; et al. Hypothesizing repetitive paraphilia behavior of a medication refractive Tourette’s syndrome patient having rapid clinical attenuation withKB220Z-nutrigenomic amino-acid therapy (NAAT). J. Behav. Addict. 2013, 2, 117–124.
  143. Solanki, N.; Abijo, T.; Galvao, C.; Darius, P.; Blum, K.; Gondré-Lewis, M.C. Administration of a putative pro-dopamine regulator, a neuronutrient, mitigates alcohol intake in alcohol-preferring rats. Behav Brain Res. 2020, 385, 112563.
  144. Blum, K.; Cull, J.G.; Chen, T.J.; Garcia-Swan, S.; Holder, J.M.; Wood, R.; Braverman, E.R.; Bucci, L.R.; Trachtenberg, M.G. Clinical evidence For Effectiveness of Phencal in maintaining weight loss in an open-label, controlled, 2-year study. Curr. Ther. Res. 1997, 55, 745–763.
  145. Blum, K.; Modestino, E.J.; Lott, L.; Siwicki, D.; Baron, D.; Howeedy, A.; Badgaiyan, R.D. Introducing “Precision Addiction Management (PAM®)” as an Adjunctive Genetic Guided Therapy for Abusable Drugs in America. Open Access J. Behav. Sci. Psychol. 2018, 1, 1–4.
  146. Steinberg, B.; Carey, E.; Modestino, J.E.; Mclaughlin, T.; Lubar, J.; Thanos, P.K.; Baron, D.; Blum, K. Pro-Dopamine Regulation with KB220Z Improves Working Memory in an Adult with ADHD-A Case Report and Replication. Open J. Clin. Med. Case Rep. 2019, 5, 1–28.
  147. Schoenthaler, S.J.; Blum, K.; Braverman, E.R.; Giordano, J.; Thompson, B.; Berman, M.O.; Badgaiyan, R.D.; Madigan, M.A.; Dushaj, K.; Li, M.; et al. NIDA-Drug Addiction Treatment Outcome Study (DATOS) Relapse as a Function of Spirituality/Religiosity. J. Reward Defic. Syndr. 2015, 1, 36–45.
  148. Wallace, C.; Burns, L.; Gilmour, S.; Hutchinson, D. Substance use, psychological distress and violence among pregnant and breastfeeding Australian women. Aust. N. Z. J. Public Health 2007, 31, 51–56.
  149. Lobmaier, P.; Gossop, M.; Waal, H.; Bramness, J. The pharmacological treatment of opioid addiction—A clinical perspective. Eur. J. Clin. Pharmacol. 2010, 66, 537–545.
  150. Gyarmathy, V.A.; Giraudon, I.; Hedrich, D.; Montanari, L.; Guarita, B.; Wiessing, L. Drug use and pregnancy—Challenges for public health. Eurosurveillance 2009, 14, 19142.
  151. Florey, C.D. EUROMAC. A European concerted action: Maternal alcohol consumption and its relation to the outcome of pregnancy and child development at 18 months. Methods. Int. J. Epidemiol. 1992, 21 (Suppl. 1), S38–S39.
  152. Mactier, H. The management of heroin misuse in pregnancy: Time for a rethink? Arch. Dis. Child Fetal Neonatal Ed. 2011, 96, F457–F460.
  153. Blum, K.; Hamilton, M.G.; Hirst, M.; Wallace, J.E. Putative Role of Isoquinoline Alkaloids in Alcoholism: A Link to Opiates. Alcohol. Clin. Exp. Res. 1978, 2, 113–120.
  154. Blum, K.; Eubanks, J.D.; Wallace, J.E.; Schwertner, H.; Morgan, W.W. Possible role of tetrahydroisoquinoline alkaloids in post alcohol intoxication states. Ann. N. Y. Acad. Sci. 1976, 273, 234–246.
  155. Blum, K.; Wallace, J. Effects of catecholamine synthesis inhibition on ethanol-induced withdrawal symptoms in mice. J. Cereb. Blood Flow Metab. 1974, 51, 109–111.
  156. Blum, K.; Eubanks, J.D.; Wallace, J.E.; Hamilton, H. Enhancement of Alcohol Withdrawal Convulsions in Mice by Haloperidol. Clin. Toxicol. 1976, 9, 427–434.
  157. Blum, K.; Wallace, J.E.; Schwertner, H.A.; Eubanks, J.D. Enhancement of ethanol-induced withdrawal convulsions by blockade of 5-hydroxytryptamine receptors. J. Pharm. Pharmacol. 1976, 28, 832–835.
  158. Blum, K.; Eubanks, J.D.; Wallace, J.E.; Schwertner, H.A. Suppression of ethanol withdrawal by dopamine. Experientia 1976, 32, 493–495.
  159. Blum, K.; Wallace, J.E.; Schwerter, H.A.; Eubanks, J.D. Morphine suppression of ethanol withdrawal in mice. Experientia 1976, 32, 79–82.
  160. Blum, K.; Baron, D.; McLaughlin, T.; Gold, M.S. Molecular neurological correlates of endorphinergic/dopaminergic mechanisms in reward circuitry linked to endorphinergic deficiency syndrome (EDS). J. Neurol. Sci. 2020, 411, 116733.
  161. Blum, K.; Futterman, S.; Wallace, J.E.; Schwertner, H.A. Naloxone-induced inhibition of ethanol dependence in mice. Nature 1977, 265, 49–51.
  162. Blum, K.; Briggs, A.H.; DeLallo, L. Clonidine enhancement of ethanol withdrawal in mice. Subst. Alcohol Actions Misuse 1983, 4, 59–63.
  163. Roehrich, H.; Gold, M.S. Clonidine. Adv. Alcohol Subst. Abus. 1988, 7, 1–16.
  164. Gold, M.S.; Blum, K. Clonidine: The Locus Coeruleus & Noradrenergic Hyperactivity Theory for Opioid and other Drug Withdrawal from 1977 to Present. In Clonidine; Oxford Press: Oxford, UK, 2021.
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