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.

Hypothesizing in the Face of the Opioid Crisis Coupling Genetic Addiction Risk Severity (GARS) Testing with Electrotherapeutic Nonopioid Modalities Such as H-Wave Could Attenuate Both Pain and Hedonic Addictive Behaviors.

In the United States, amid the opioid overdose epidemic, nonaddicting/nonpharmacological proven strategies are available to treat pain and manage chronic pain effectively without opioids. Evidence supporting the long-term use of opioids for pain is lacking, as is the will to alter the drug-embracing culture in American chronic pain management. Some pain clinicians seem to prefer classical analgesic agents that promote unwanted tolerance to analgesics and subsequent biological induction of the "addictive brain". Reward genes play a vital part in modulation of nociception and adaptations in the dopaminergic circuitry. They may affect various sensory and affective components of the chronic pain syndromes. The Genetic Addiction Risk Severity (GARS) test coupled with the H-Wave at entry in pain clinics could attenuate pain and help prevent addiction. The GARS test results identify high-risk for both drug and alcohol, and H-Wave can be initiated to treat pain instead of opioids. The utilization of H-Wave to aid in pain reduction and mitigation of hedonic addictive behaviors is recommended, notwithstanding required randomized control studies. This frontline approach would reduce the possibility of long-term neurobiological deficits and fatalities associated with potent opioid analgesics.

The Food and Drug Addiction Epidemic: Targeting Dopamine Homeostasis.

Obesity is damaging the lives of more than 300 million people worldwide and maintaining a healthy weight using popular weight loss tactics remains a very difficult undertaking. Managing the obesity problem seems within reach, as better understanding develops, of the function of our genome in drug/nutrient responses. Strategies indicated by this understanding of nutriepigenomics and neurogenetics in the treatment and prevention of metabolic syndrome and obesity include moderation of mRNA expression by DNA methylation, and inhibition of histone deacetylation. Based on an individual's genetic makeup, deficient metabolic pathways can be targeted epigenetically by, for example, the provision of dietary supplementation that includes phytochemicals, vitamins, and importantly functional amino acids. Also, the chromatin structure of imprinted genes that control nutrients during fetal development can be modified. Pathways affecting dopamine signaling, molecular transport and nervous system development are implicated in these strategies. Obesity is a subtype of Reward Deficiency Syndrome (RDS) and these new strategies in the treatment and prevention of obesity target improved dopamine function. It is not merely a matter of gastrointestinal signaling linked to hypothalamic peptides, but alternatively, finding novel ways to improve ventral tegmental area (VTA) dopaminergic function and homeostasis.

Enhancing Brain Pregnenolone May Protect Cannabis Intoxication but Should Not Be Considered as an Anti-addiction Therapeutic: Hypothesizing Dopaminergic Blockade and Promoting Anti-Reward.

Many US states now embrace the medical and recreational use of Cannabis. Changes in the laws have heightened interest and encouraged research into both cannabinoid products and the potential harms of Cannabis use, addiction, and intoxication. Some research into those harms will be reviewed here and misgivings about the use of Pregnenolone, to treat cannabis addiction and intoxication explained. Pregnenolone considered the inactive precursor of all steroid hormones, has recently been shown to protect the brain from Cannabis intoxication. The major active ingredient of Cannabis sativa (marijuana), Δ9-tetrahydrocannabinol (THC) enhances Pregnenolone synthesis in the brain via stimulation of the type-1 cannabinoid (CB1) receptor. This steroid has been shown to inhibit the activity of the CB1 receptor thereby reducing many of the effects of THC. While this mechanism seems correct, in our opinion, Vallee et al., incorrectly suggest that blocking CB1 receptors could open unforeseen approaches to the treatment of cannabis intoxication and addiction. In this hypothesis, we caution the scientific community that, other CB1 receptor blockers, such as, Rimonabant (SR141718) have been pulled off the market in Europe. In addition, CB1 receptor blockers were rejected by the FDA due to mood changes including suicide ideation. Blocking CB1 receptors would result in reduced neuronal release of Dopamine by disinhibition of GABA signaling. Long-term blockade of cannabinoid receptors could occur with raising Pregnenolone brain levels, may induce a hypodopaminergic state, and lead to aberrant substance and non-substance (behavioral) addictions.

NIDA-Drug Addiction Treatment Outcome Study (DATOS) Relapse as a Function of Spirituality/Religiosity.

BACKGROUND: The connection between religion/spirituality and deviance, like substance abuse, was first made by Durkheim who defined socially expected behaviors as norms. He explained that deviance is due in large part to their absence (called anomie), and concluded that spirituality lowers deviance by preserving norms and social bonds. Impairments in brain reward circuitry, as observed in Reward Deficiency Syndrome (RDS), may also result in deviance and as such we wondered if stronger belief in spirituality practice and religious belief could lower relapse from drugs of abuse. METHODS: The NIDA Drug Addiction Treatment Outcome Study data set was used to examine post hoc relapse rates among 2,947 clients who were interviewed at 12 months after intake broken down by five spirituality measures. RESULTS: Our main findings strongly indicate, that those with low spirituality have higher relapse rates and those with high spirituality have higher remission rates with crack use being the sole exception. We found significant differences in terms of cocaine, heroin, alcohol, and marijuana relapse as a function of strength of religious beliefs (x2 = 15.18, p = 0.028; logistic regression = 10.65, p = 0.006); frequency of attending religious services (x2 = 40.78, p < 0.0005; logistic regression = 30.45, p < 0.0005); frequency of reading religious books (x2 = 27.190, p < 0.0005; logistic regression = 17.31, p < 0.0005); frequency of watching religious programs (x2 = 19.02, p = 0.002; logistic regression = ns); and frequency of meditation/prayer (x2 = 11.33, p = 0.045; logistic regression = 9.650, p = 0.002). Across the five measures of spirituality, the spiritual participants reported between 7% and 21% less alcohol, cocaine, heroin, and marijuana use than the non-spiritual subjects. However, the crack users who reported that religion was not important reported significantly less crack use than the spiritual participants. The strongest association between remission and spirituality involves attending religious services weekly, the one marker of the five that involves the highest social interaction/social bonding consistent with Durkheim's social bond theory. CONCLUSIONS: Stronger spiritual/religious beliefs and practices are directly associated with remission from abused drugs except crack. Much like the value of having a sponsor, for clients who abuse drugs, regular spiritual practice, particularly weekly attendance at the religious services of their choice is associated with significantly higher remission. These results demonstrate the clinically significant role of spirituality and the social bonds it creates in drug treatment programs.

Connectivity Study of the Neuromechanism of Acute Acupuncture Needling during fMRI in "Overweight" Subjects.

This functional connectivity study depicts how acupoints ST 36 and SP 9 and their sham acupoints acutely act on blood glucose (GLU), core body temperature (CBT), hunger, and sensations pertaining to needling (De-qi) via the limbic system and dopamine (DA) to affect various brain areas in fasting, adult, and "overweight" Chinese males using functional magnetic resonance imaging. Functional connectivity (FC) analysis utilized the amygdala (AMY) and hypothalamus (HYP) as regions of interest (ROIs) in the discrete cosine transform and seed correlation analysis methods. There was a significant difference in the spatial patterns of the distinct brain regions between groups. Correlation results showed that increased HYP-hippocampus FC after ACU was positively correlated with ACU-induced change in CBT; increased HYP-putamen-insula FC after ACU was positively correlated with ACU-induced change in GLU; and increased HYP-anterior cingulate cortex FC after ACU was positively correlated with ACU-induced change in HUNGER suggesting that increased DA modulation during ACU was probably associated with increased poststimulation limbic system and spinothalamic tract connectivity. Decreased HYP-thalamus FC after ACU was negatively correlated or anticorrelated with ACU-induced change in HUNGER suggesting that increased DA modulation during ACU was possibly associated with decreased poststimulation limbic system and spinothalamic tract connectivity. No correlation was found for min SHAM. This was an important study in addressing acute acupuncture effects and neural pathways involving physiology and appetite regulation in overweight individuals.

Predicting subsequent relapse by drug-related cue-induced brain activation in heroin addiction: an event-related functional magnetic resonance imaging study.

Abnormal salience attribution is implicated in heroin addiction. Previously, combining functional magnetic resonance imaging (fMRI) and a drug cue-reactivity task, we demonstrated abnormal patterns of subjective response and brain reactivity in heroin-dependent individuals. However, whether the changes in cue-induced brain response were related to relapse was unknown. In a prospective study, we recruited 49 heroin-dependent patients under methadone maintenance treatment, a gold standard treatment (average daily dose 41.8 ± 16.0 mg), and 20 healthy subjects to perform the heroin cue-reactivity task during fMRI. The patients' subjective craving was evaluated. They participated in a follow-up assessment for 3 months, during which heroin use was assessed and relapse was confirmed by self-reported relapse or urine toxicology. Differences between relapsers and non-relapsers were analyzed with respect to the results from heroin-cue responses. Compared with healthy subjects, relapsers and non-relapsers commonly demonstrated significantly increased brain responses during the processing of heroin cues in the mesolimbic system, prefrontal regions and visuospatial-attention regions. However, compared with non-relapsers, relapsers demonstrated significantly greater cue-induced craving and the brain response mainly in the bilateral nucleus accumbens/subcallosal cortex and cerebellum. Although the cue-induced heroin craving was low in absolute measures, the change in craving positively correlated with the activation of the nucleus accumbens/subcallosal cortex among the patients. These findings suggest that in treatment-seeking heroin-dependent individuals, greater cue-induced craving and greater specific regional activations might be related to reward/craving and memory retrieval processes. These responses may predict relapse and represent important targets for the development of new treatment for heroin addiction.

Effects of baclofen and naltrexone, alone and in combination, on the consumption of palatable food in male rats.

Excess consumption of palatable food has been shown to affect reward-related brain regions, and pharmaceutical treatments for drug addiction may also be effective in treating overeating of such foods. The GABA-B agonist baclofen and opioid antagonist naltrexone have both been used to treat addiction, and have been shown to suppress intake of certain foods. The combination of these drugs has shown to be more effective in reducing alcohol consumption than either drug alone. The present study assessed the effects of naltrexone and baclofen, alone and in combination, on intake of foods comprised of various macronutrients. Male Sprague-Dawley rats were given 12-hr daily access to chow and a fat emulsion, sugar-fat emulsion, or a sugar solution for 21 days. Rats were then administered (intraperitoneal) baclofen-naltrexone combinations (0.1 mg/kg naltrexone and 1.0 mg/kg baclofen, 1.0 mg/kg naltrexone and 1.8 mg/kg baclofen), and naltrexone (0.1, 1.0 mg/kg) and baclofen (1.0, 1.8 mg/kg) alone. The high dose of the baclofen-naltrexone combination reduced palatable food intake in both the fat and sugar-fat groups compared with vehicle, without affecting chow consumption in these groups. Naltrexone showed little significant effects on intake of either palatable food or chow. Baclofen also reduced palatable food intake in the fat and fat-sugar groups, but differences were only noted between the low and high dose. The combination of baclofen and naltrexone may be a useful tool in selectively targeting the consumption of high-fat and sugar- and fat-rich foods.

Low dopamine function in attention deficit/hyperactivity disorder: should genotyping signify early diagnosis in children?

Attention deficit/hyperactivity disorder (ADHD) is present in 8% to 12% of children, and 4% of adults worldwide. Children with ADHD can have learning impairments, poor selfesteem, social dysfunction, and an increased risk of substance abuse, including cigarette smoking. Overall, the rate of treatment with medication for patients with ADHD has been increasing since 2008, with ≥ 2 million children now being treated with stimulants. The rise of adolescent prescription ADHD medication abuse has occurred along with a concomitant increase of stimulant medication availability. Of adults presenting with a substance use disorder (SUD), 20% to 30% have concurrent ADHD, and 20% to 40% of adults with ADHD have a history of SUD. Following a brief review of the etiology of ADHD, its diagnosis and treatment, we focus on the benefits of early and appropriate testing for a predisposition to ADHD. We suggest that by genotyping patients for a number of known, associated dopaminergic polymorphisms, especially at an early age, misdiagnoses and/or over-diagnosis can be reduced. Ethical and legal issues of early genotyping are considered. As many as 30% of individuals with ADHD are estimated to either have secondary side-effects or are not responsive to stimulant medication. We also consider the benefits of non-stimulant medication and alternative treatment modalities, which include diet, herbal medications, iron supplementation, and neurofeedback. With the goals of improving treatment of patients with ADHD and SUD prevention, we encourage further work in both genetic diagnosis and novel treatment approaches.

Crossroads of pain and addiction.

BACKGROUND: Despite the fact that chronic pain and addiction often coexist, few pain training programs offer significant experiential and didactic training in drug abuse and addiction. Similarly, addiction medicine programs often offer little training in pain management. What follows is a review of the intersection between these two specialties from the perspective of clinicians that practice both. OBJECTIVE: The objective of this study was to review the historical backdrop, terminology, vulnerability, and neurobiology of addiction; explore the effects of drug, delivery system, timing, and environment on drug self-administration; and review strategies used in managing patients with coexisting addiction and chronic pain. SETTING: The University of Florida has training programs in both pain management and addiction medicine. The collaboration of these two subspecialties has led to the development of a successful pain management clinic that manages difficult patients based on the strategies that are discussed. CONCLUSIONS: It is possible to successfully manage patients with coexisting chronic pain and addictive disorders. Addiction medicine and pain management training programs should offer didactic and experiential training in both subspecialties.

Do dopaminergic gene polymorphisms affect mesolimbic reward activation of music listening response? Therapeutic impact on Reward Deficiency Syndrome (RDS).

Using fMRI, Menon and Levitin [9] clearly found for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus, and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Importantly, responses in the NAc and VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Listing to pleasant music induced a strong response and significant activation of the VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. Blum et al. [10] provided the first evidence that the dopamine D2 receptor gene (DRD2) Taq 1 A1 allele significantly associated with severe alcoholism whereby the author's suggested that they found the first "reward gene" located in the mesolimbic system. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. However, little is known about why some people have a more or less powerful mesolimbic experience when they are listening to music. It is well-known that music may induce an endorphinergic response that is blocked by naloxone, a known opioid antagonist (Goldstein [19]). Opioid transmission in the NAc is associated with dopamine release in the VTA. Moreover, dopamine release in the VTA is linked to polymorphisms of the DRD2 gene and even attention-deficit hyperactivity disorder (ADHD), whereby carriers of the DRD2 A1 allele show a reduced NAc release of dopamine (DA). Thus it is conjectured that similar mechanisms in terms of adequate dopamine release and subsequent activation of reward circuitry by listening to music might also be affected by an individual's D2 density in the VTA mediated interaction of the NAc. It is therefore hypothesized that carriers of DRD2 A1 allele may respond significantly differently to carriers of the DRD2 A2 genotype. In this regard, carriers of the D2 A1 allele have a blunted response to glucose and monetary rewards. In contrast powerful D2 agonists like bromocryptine show a heightened activation of the reward circuitry only in DRD2 A1 allele carriers. If music causes a powerful activation in spite of the DRD2 A1 allele due to a strong DA neuronal release which subsequently impinges on existing D2 receptors, then it is reasonable to assume that music is a strong indirect D2 agonist (by virtue of DA neuronal release in the NAc) and may have important therapeutic applicability in Reward Deficiency Syndrome (RDS) related behaviors including Substance Use Disorder (SUD). Ross et al. [18] found that music therapy appears to be a novel motivational tool in a severely impaired inpatient sample of patients with co-occurring mental illness and addiction.

Caffeine content of decaffeinated coffee.

Caffeine is the most widely consumed drug in the world with coffee representing a major source of intake. Despite widespread availability, various medical conditions necessitate caffeine-restricted diets. Patients on certain prescription medications are advised to discontinue caffeine intake. Such admonition has implications for certain psychiatric patients because of pharmacokinetic interactions between caffeine and certain anti-anxiety drugs. In an effort to abstain from caffeine, patients may substitute decaffeinated for caffeinated coffee. However, decaffeinated beverages are known to contain caffeine in varying amounts. The present study determined the caffeine content in a variety of decaffeinated coffee drinks. In phase 1 of the study, 10 decaffeinated samples were collected from different coffee establishments. In phase 2 of the study, Starbucks espresso decaffeinated (N=6) and Starbucks brewed decaffeinated coffee (N=6) samples were collected from the same outlet to evaluate variability of caffeine content of the same drink. The 10 decaffeinated coffee samples from different outlets contained caffeine in the range of 0-13.9 mg/16-oz serving. The caffeine content for the Starbucks espresso and the Starbucks brewed samples collected from the same outlet were 3.0-15.8 mg/shot and 12.0-13.4 mg/16-oz serving, respectively. Patients vulnerable to caffeine effects should be advised that caffeine may be present in coffees purported to be decaffeinated. Further research is warranted on the potential deleterious effects of consumption of "decaffeinated" coffee that contains caffeine on caffeine-restricted patients. Additionally, further exploration is merited for the possible physical dependence potential of low doses of caffeine such as those concentrations found in decaffeinated coffee.

Can drug design inhibit abuse?

A recent federal report indicates that prescription drug abuse is now the second leading category of illicit drug use, following marijuana use. Control strategies typically focus on reducing the diversion of prescription drugs from legitimate sources. The proliferation of unregulated Internet sources, however, has rendered control strategies less effective. This study examines a new approach that focuses on reducing abusability through the use of abuse-resistant drug designs. Drugs with and without such designs are compared and abuse levels assessed using multiple sources. In every instance, drugs employing abuse-resistant designs were found to have significantly lower levels of abuse than comparator drugs without such designs.

Effects of sustained gamma-hydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons.

BACKGROUND: Gamma-hydroxybutyrate is currently used to promote nighttime sleep in the treatment of narcolepsy; however, it is also a drug of abuse ("Liquid Ecstasy") associated with a withdrawal syndrome with anxiety features. Of interest, the activity of locus coeruleus neurons is a reflective index of these above mentioned behavioral states. METHODS: Using in vivo extracellular unitary recordings, sustained administration of gamma-hydroxybutyrate (40 mg/kg/day via minipump implanted subcutaneously) on the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons was assessed in rats. RESULTS: A 2-day and 10-day gamma-hydroxybutyrate administration decreased the spontaneous firing activity of locus coeruleus neurons by 52% and 54%, respectively, when compared with controls. A similar degree of attenuation on evoked burst firing of norepinephrine neurons also occurred in these rats (2-day gamma-hydroxybutyrate: 47% and 10-day gamma-hydroxybutyrate: 58%), when compared with controls. In contrast, rats treated with gamma-hydroxybutyrate for 10 days followed by removal of the minipump for 36 hours resulted in a 33% augmentation in spontaneous locus coeruleus activity as compared with controls. Furthermore, a robust 79% increase in burst firing in response to paw-pinch was exhibited in theses rats. CONCLUSIONS: Chronic gamma-hydroxybutyrate treatment inhibits the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons, whereas these indices are enhanced during drug withdrawal. The alteration in norepinephrine activity during chronic gamma-hydroxybutyrate administration may contribute to the ability of this agent to induce sleep and regulate narcoleptic episodes. Enhanced norepinephrine activity during withdrawal may be related to symptoms of anxiety on rapid termination of this drug in abusers.