Kristina Dushaj

Withdrawal from Buprenorphine/Naloxone and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note.

BACKGROUND While numerous studies support the efficacy of methadone and buprenorphine for the stabilization and maintenance of opioid dependence, clinically significant opioid withdrawal symptoms occur upon tapering and cessation of dosage. METHODS We present a case study of a 35 year old Caucasian female (Krissie) who was prescribed increasing dosages of prescription opioids after carpel tunnel surgery secondary to chronic pain from reflex sympathetic dystrophy and fibromyalgia. Over the next 5 years, daily dosage requirements increased to over 80 mg of Methadone and 300 ug/hr Fentanyl transdermal patches, along with combinations of 12-14 1600 mcg Actig lollipop and oral 100 mg Morphine and 30 mg oxycodone 1-2 tabs q4-6hr PRN for breakthrough pain. Total monthly prescription costs including supplemental benzodiazepines, hypnotics and stimulants exceeded

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

50,000. The patient was subsequently transferred to Suboxone® in 2008, and the dosage was gradually tapered until her admission for inpatient detoxification with KB220Z a natural dopaminergic agonist. We carefully documented her withdrawal symptoms when she precipitously stopped taking buprenorphine/naloxone and during follow-up while taking KB220Z daily. We also genotyped the patient using a reward gene panel including (9 genes 18 alleles): DRD 2,3,4; MOA-A; COMT; DAT1; 5HTTLLR; OPRM1; and GABRA3. FINDINGS At 432 days post Suboxone® withdrawal the patient is being maintained on KB220Z, has been urine tested and is opioid free. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait. This preliminary case data suggest that the daily use of KB220Z could provide a cost effective alternative substitution adjunctive modality for Suboxone®. We encourage double-blind randomized -placebo controlled studies to test the proposition that KB220Z may act as a putative natural opioid substitution maintenance adjunct.

Hypothesizing repetitive paraphilia behavior of a medication refractive Tourette's syndrome patient having rapid clinical attenuation with KB220Z-nutrigenomic amino-acid therapy (NAAT)

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.

Evoked potentials and neuropsychological tests validate Positron Emission Topography (PET) brain metabolism in cognitively impaired patients.

Background and aims Many patients presenting multiple behaviors including drug and food abuse as well as other pathological repetitive unwanted activities such as gambling, self-mutilation and paraphilias may not be appropriately diagnosed. Here we present a case of a male presenting many of these seemingly diverse behaviors and finally diagnosed with reward deficiency syndrome (RDS) by his attending physician. Methods The use of the dopamine agonist, ropinirole after two weeks showed improvement in terms of sexual behavior but tolerance set in and was discontinued especially when an infraction occurred with the patients insurance. In this article, we carefully explore the potential of ropinirole to downregulate dopamine receptors causing adenylate cyclase receptor supersensitivity and tolerance a feature of neurotransmitter cross-talk. Based on previous scientific evidence showing KB220Znutrigenomic amino-acid therapy (NAAT) to rapidly (post one-hour) activate dopaminergic pathways in both the pre-frontal cortex cingulate gyrus (relapse loci) and ventral tegmental area-caudate-accumbens-putamen (craving and emotion loci) the patient was prescribed NAAT. Results and discussion Within one week of utilization the repetitive paraphilia was eliminated. There were also a number of other positive effects such as enhanced focus that persisted even after the patient stopped using KB220Z suggesting neuroplasticity (e.g. altruistic thoughts). However, these observed profound benefits require more in-depth study, especially in a large cohort against a placebo. While this report focused on a rapid response rather than long-term benefits previously associated with NAAT, it is somewhat encouraging and longer term required follow-up and larger placebo controlled studies are warranted before any definitive conclusions could be gleaned from this case report.

Dopamine in the Brain: Hypothesizing Surfeit or Deficit Links to Reward and Addiction

Fluorodeoxyglucose (FDG) Positron Emission Topography (PET) brain hypometabolism (HM) correlates with diminished cognitive capacity and risk of developing dementia. However, because clinical utility of PET is limited by cost, we sought to determine whether a less costly electrophysiological measure, the P300 evoked potential, in combination with neuropsychological test performance, would validate PET HM in neuropsychiatric patients. We found that patients with amnestic and non-amnestic cognitive impairment and HM (n = 43) evidenced significantly reduced P300 amplitudes, delayed latencies, and neuropsychological deficits, compared to patients with normal brain metabolism (NM; n = 187). Data from patients with missing cognitive test scores (n = 57) were removed from the final sample, and logistic regression modeling was performed on the modified sample (n = 173, p = .000004). The logistic regression modeling, based on P300 and neuropsychological measures, was used to validate membership in the HM vs. NM groups. It showed classification validation in 13/25 HM subjects (52.0%) and in 125/148 NM subjects (84.5%), correlating with total classification accuracy of 79.8%. In this paper, abnormal P300 evoked potentials coupled with cognitive test impairment validates brain metabolism and mild/moderate cognitive impairment (MCI). To this end, we cautiously propose incorporating electrophysiological and neuropsychological assessments as cost-effective brain metabolism and MCI indicators in primary care. Final interpretation of these results must await required additional studies confirming these interesting results.

Declinol, a Complex Containing Kudzu, Bitter Herbs (Gentian, Tangerine Peel) and Bupleurum, Significantly Reduced Alcohol Use Disorders Identification Test (AUDIT) Scores in Moderate to Heavy Drinkers: A Pilot Study

Recently there has been debate concerning the role of brain dopamine in reward and addiction. David Nutt and associates eloquently proposed that dopamine (DA) may be central to psycho stimulant dependence and some what important for alcohol, but not important for opiates, nicotine or even cannabis. Others have also argued that surfeit theories can explain for example cocaine seeking behavior as well as non-substance-related addictive behaviors. It seems prudent to distinguish between what constitutes “surfeit” compared to” deficit” in terms of short-term (acute) and long-term (chronic) brain reward circuitry responsivity. In an attempt to resolve controversy regarding the contributions of mesolimbic DA systems to reward, we review the three main competing explanatory categories: “liking”, “learning”, and “wanting”. They are (a) the hedonic impact -liking reward, (b) the ability to predict rewarding effects-learning and (c) the incentive salience of reward-related stimuli -wanting. In terms of acute effects, most of the evidence seems to favor the “surfeit theory”. Due to preferential dopamine release at mesolimbic-VTA-caudate-accumbens loci most drugs of abuse and Reward Deficiency Syndrome (RDS) behaviors have been linked to heightened feelings of well-being and hyperdopaminergic states.The “dopamine hypotheses” originally thought to be simple, is now believed to be quite complex and involves encoding the set point of hedonic tone, encoding attention, reward expectancy, and incentive motivation. Importantly, Willuhn et al. shows that in a self-administration paradigm, (chronic) excessive use of cocaine is caused by decreased phasic dopamine signaling in the striatum. In terms of chronic addictions, others have shown a blunted responsivity at brain reward sites with food, nicotine, and even gambling behavior. Finally, we are cognizant of the differences in dopaminergic function as addiction progresses and argue that relapse may be tied to dopamine deficiency. Vulnerability to addiction and relapse may be the result of the cumulative effects of dopaminergic and other neurotransmitter genetic variants and elevated stress levels. We therefore propose that dopamine homeostasis may be a preferred goal to combat relapse.

Should the United States Government Repeal Restrictions on Buprenorphine/Naloxone Treatment?

It is well established that inherited human aldehyde dehydrogenase 2 (ALDH-2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH-2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH-2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However not all of the anti-alcohol properties of diadzin are due to inhibition of ALDH-2. This is in agreement with our earlier work showing significant interaction effects of both pyrozole (ALDH-2 inhibitor) and methyl-pyrozole (non-inhibitor) and ethanols depressant effects. Moreover, it has been suggested that selective ALDH 2 inhibitors reduce craving for alcohol by increasing dopamine in the nucleus accumbens (NAc). In addition there is significant evidence related to the role of the genetics of bitter receptors (TAS2R) and its stimulation as an aversive mechanism against alcohol intake. The inclusion of bitters such as Gentian & Tangerine Peel in Declinol provides stimulation of gut TAS2R receptors which is potentially synergistic with the effects of Kudzu. Finally the addition of Radix Bupleuri in the Declinol formula may have some protective benefits not only in terms of ethanol induced liver toxicity but neurochemical actions involving endorphins, dopamine and epinephrine. With this information as a rationale, we report herein that this combination significantly reduced Alcohol Use Disorders Identification Test (AUDIT) scores administered to ten heavy drinkers (M=8, F=2; 43.2 ± 14.6 years) attending a recovery program. Specifically, from the pre-post comparison of the AUD scores, it was found that the score of every participant decreased after the intervention which ranged from 1 to 31. The decrease in the scores was found to be statistically significant with the p-value of 0.00298 (two-sided paired test; p-value = 0.00149 for one-sided test). Albeit this being a small pilot, we are encouraged about these significant results, and caution any interpretation until larger controlled studies are executed.

Genome wide sequencing compared to candidate gene association studies for predisposition to substance abuse a subset of Reward Deficiency Syndrome (RDS): are we throwing the baby out with the bathwater?

ABSTRACT Attention must be focused on needed changes to the current United States law that restricts physicians who prescribe buprenorphine for the detoxification or treatment of Opioid Use Disorder, to accepting no more than 100 patients. The current system does not provide comprehensive treatment as defined by the American Society of Addiction Medicine (ASAM) criteria. In addition, it suffers from both fragmentation and stigma and will require a significant change to comply with ASAMs call for integrated delivery of comprehensive addiction treatment. This commentary calls for the development and implementation of “best practice,” by recommending caution in lifting the 100 patient limit until substantial achievement of this goal occurs. The authors call for an increase to 200 in the patient limit to be restricted to those physicians who are Board Certified in Addiction Medicine by the American Board of Addiction Medicine (ABAM) or in Addiction Psychiatry by the American Board of Psychiatry and Neurology (ABPN), or other responsible medical organizations. Any additional restriction lifting should follow a systemic evolution that rewards and documents competency. Such a system would involve the integration of treatment, treatment systems, and recovery with prescription medication. In addition, it should monitor emotional blunting, treatment progress and initiation of genetic addiction risk testing.

Hypothesizing Music Intervention Enhances Brain Functional Connectivity Involving Dopaminergic Recruitment: Common Neuro-correlates to Abusable Drugs

In 1990 Blum, Noble and associates utilized a candidate approach to associate the first genetic polymorphic association with severe alcoholism that was published in JAMA. This experiment was based on a “blue print” of the reward circuitry proposed as the “brain Reward Cascade”. Impairment of this system leads to aberrant substance seeking behavior. Over the last five years newer and more sophisticated techniques have been developed, including whole genome sequencing, as well as exome sequencing. While there are different schools of thought regarding appropriate approaches to dissecting a very complex disorder known as Reward Deficiency Syndrome (RDS) as an umbrella term for all addictions, future approaches may combine both genome sequencing with gene candidates. Importantly, GWAS/WES generally provides the most value for highly penetrant, rare alleles and as such may not currently be as informative as the candidate gene approach. However, since there is convergence of GWAS and neurotransmitter clusters including specific genes (e.g. DRD1, DRD2, DAt1, etc.) albeit small contributions for each gene, thousands of studies have elucidated risk alleles to RDS behaviors. Thus, we are proposing herein that we should not hasten to “throw out the baby with the bathwater”, because genetic addiction risk stratification depends upon the current candidate gene analysis.

Evoked Potentials and Memory/Cognition Tests Validate Brain Atrophy as Measured by 3T MRI (NeuroQuant) in Cognitively Impaired Patients

The goal of this review is to explore the clinical significance of music listening on neuroplasticity and dopaminergic activation by understanding the role of music therapy in addictive behavior treatment. fMRI data has shown that music listening intensely modifies mesolimbic structural changes responsible for reward processing (e.g., nucleus accumbens [NAc]) and may control the emotional stimuli’s effect on autonomic and physiological responses (e.g., hypothalamus). Music listening has been proven to induce the endorphinergic response blocked by naloxone, a common opioid antagonist. NAc opioid transmission is linked to the ventral tegmental area (VTA) dopamine release. There are remarkable commonalities between listening to music and the effect of drugs on mesolimbic dopaminergic activation. It has been found that musical training before the age of 7 results in changes in white-matter connectivity, protecting carriers with low dopaminergic function (DRD2A1 allele, etc.) from poor decision-making, reward dependence, and impulsivity. In this article, we briefly review a few studies on the neurochemical effects of music and propose that these findings are relevant to the positive clinical findings observed in the literature. We hypothesize that music intervention enhances brain white matter plasticity through dopaminergic recruitment and that more research is needed to explore the efficacy of these therapies.